Home About us Current issue Ahead of Print Back issues Submission Instructions Advertise Contact Login   

Search Article 
Advanced search 
Saudi Journal of Kidney Diseases and Transplantation
Users online: 119 Home Bookmark this page Print this page Email this page Small font sizeDefault font size Increase font size 

ARTICLES Table of Contents   
Year : 2003  |  Volume : 14  |  Issue : 3  |  Page : 259-275
Advances in Genetic Detection of Kidney Disease

Division of Renal Diseases and Hypertension, Department of Internal Medicine, The University of Texas Medical School at Houston, Houston, TX 77030, USA

Click here for correspondence address and email


The Human Genome Project has provided a vast amount of molecular genetic information for the analysis of normal and diseased genes. This new information provides new opportunities for precise diagnosis, assessment of predisposition and risk factors, and novel therapeutic strategies. At the same time, this constantly expanding knowledge base represents one of the most difficult challenges in molecular medicine. For monogenic diseases, nearly 2000 human disease genes have thus far been identified. Most of these conditions are characterized by large mutational variation and even greater phenotypic variation. In nephrology, several genetic diseases have been elucidated that provide new insight into the structure, function and developmental biology of the glomerulus, tubules and urogenital tracts, as well as renal cell tumors. Great improvements in the diagnostic resolution of genetic disease have been achieved, such that single base pair mutations can be readily detected. Because of accurate diagnosis and risk assessment, genetic testing may be valuable in improving disease management and preventive care when genotype-specific therapies are available. Moreover, such testing may identify de novo mutations and potentially aid in understanding the disease process. This review summarizes recent advances in the renal genetic database and methods for genetic testing of renal diseases.

Keywords: Genetics, Genotype, Mutation, Linkage analysis, Glomerulus, Nephrology

How to cite this article:
Dosekun AK, Foringer JR, Kone BC. Advances in Genetic Detection of Kidney Disease. Saudi J Kidney Dis Transpl 2003;14:259-75

How to cite this URL:
Dosekun AK, Foringer JR, Kone BC. Advances in Genetic Detection of Kidney Disease. Saudi J Kidney Dis Transpl [serial online] 2003 [cited 2022 Nov 27];14:259-75. Available from: https://www.sjkdt.org/text.asp?2003/14/3/259/32997

   Introduction Top

Discovery of the gene structure, sequence, and/or location are essential components to the development of new genetic tests for diagnosis, disease prediction, or screening. The two main approaches to disease gene location [linkage mapping (linkage analysis followed by positional cloning) and candidate gene mapping have been highly successful in the monogenic diseases, but no comparable progress has been made in the elucidation of the common complex diseases or "traits." The candidate gene approach involves the selection of candidate genes with a suspected relationship to disease. The suspicion may be derived from a theory of the pathogenesis of the disease, knowledge of biochemical or physiologic pathways that are associated with the disease, or from pharmacologic actions known to impact the disease. In addition, rare monogenic forms of the disease and animal models may supply candidate genes for study. In contrast, genome-wide scanning for disease associations assumes no prior knowledge or theory of relationships. This methodology has become increasingly refined and utilized.
"Genetic" tests refer to the clinical analysis of nucleic acids, chromosomes, proteins, or informative metabolites to detect genotypes, karyotypes, or phenotypes related to heritable diseases. "Molecular genetic" tests commonly refer to direct or indirect analysis of DNA to detect the presence of the disease mutation. Genetic tests can be used for three principal purposes: (a) diagnosis (either presymptomatic or symptomatic), (b) assessment of genetic risk, so-called "predictive testing," and (c) identification of carriers. Predictive testing is useful in instances in which the disease mutation eventually leads to the disease (presymptomatic testing), and in cases in which development of the disease is likely but not certain when the gene mutation is present (predispositional testing). Carrier test­ing is used to identify individuals who harbor a gene mutation for an autosomal recessive or X-linked recessive disease. The use of genetic tests for carrier detection is controversial when genotype-specific interventions are unavailable, since the individual's genetic susceptibility to a disease could result in considerable anxiety and, potentially, discri­mination in employment or insurance. For genetic testing to yield meaningful results, a formal genetics consultation may be appro­priate, family members may also need to be tested, and more than one test methodology may be required. Prenatal and preimplantation testing and newborn screening are also available for certain diseases. A compre­hensive and updated list of available genetic tests, testing laboratories, and genetics clinics can be found at the Gene Tests-Gene Clinics Web site (http://www.geneclinics.org/).

Genetic tests may be broadly classified into three groups: (a) clinical tests, in which results are reported to the provider or patient as an aid to diagnosis, prevention, or treatment; (b) research tests, in which the results, generally not provided to the patient or provider, better inform the understanding of a disease or serve to refine a clinical test; and (c) investigational tests, which may prove to be valuable but have not yet been valida­ted or accepted by the medical community. Molecular genetic testing can be further categorized as direct analysis of DNA by mutation analysis, mutation scanning, or sequence analysis, or indirect analysis of DNA by linkage analysis, in which DNA sequence polymorphisms located near or within a gene of interest are tracked within familial inheritance of a disease-causing mutation. Direct DNA analysis offers the advantage that only a single sample needs to be examined and, once a mutation is detected, testing of other at-risk family members is uncomplicated. However, direct mutation analysis is possible only when the gene or genomic region associated with a disorder is known, and the mutation detection rate may be low in complex genes or genes in which new mutations more frequently occur. Diag­nostic potential may be further compromised if families are too small to establish with certainty the genetic candidate region out of several possible ones, or if genetic hetero­geneity - a single disease caused by more than one defective gene - exists. In contrast, linkage analysis requires only knowledge of gene location and informative loci. However, linkage studies entail accurate clinical diag­nosis of the disease in the affected family members, knowledge of the genetic associa­tions in the family, the willing participation of family members to be tested, and typically a relatively large number of affected family members in order to establish the culpable disease gene within each family. The clinical validity of any genetic test is a function of both its sensitivity and the penetrance (the proportion of people with the mutation who will actually manifest the disease) of the mutations detected by the test. When a genetic test is highly sensitive, it can be applied to carrier detection without the need for genetic information of an affected family member. A list of current and emerging mole­cular genetic tests for selected heritable renal diseases is presented in [Table - 1].

   Mutation Detection and Screening Technologies Top

In molecular diagnosis, scanning methods search for unknown mutations in candidate or known disease genes, whereas screening technologies seek to detect known mutations. In many molecular diagnostic assays, muta­tions cluster in specific, easily analyzed gene regions. A number of methods have been advanced and are in popular use to scan for unknown mutations. [1],[2],[3],[4] Complete gene sequencing remains the gold standard for mutation detection, and has become increa­singly practical for analysis of smaller genes (up to ~10 kB) given newer high-throughput sequencers. Several other techniques exploit detection of biophysical differences in normal and mutated DNA. Denaturing gradient gel electrophoresis detects sequence differences by analyzing the migration distance of dsDNA when subjected to increasingly dena­turing conditions, a reflection of the partial melting behavior of dsDNA. This method typically yields detection rates of up to 95% under optimized conditions. [5] Single-strand conformation analysis exploits non-denaturing electrophoresis to detect sequence-dependent structural differences in DNA, and may detect 80-90% of known sequence variants. [6] Hetero­duplex analysis employs gel electrophoresis to detect single-base mismatches between normal and mutated sequences. When coupled with denaturing high-performance liquid chromatography (DHPLC), a system that distinguishes heteroduplex from homoduplex DNA in DNA fragments (typically PCR products of up to ~500 bp) by HLPC, this technology yields mutation detection rates of 95-99%. [7]] Chemical or enzymatic cleavage of mismatch DNA is also based on hetero­duplex analysis, but identifies the precise position of the mutated sequence by chemical or enzymatic cleavage of the mismatched position. [8],[9] Protein-truncation methodology uses coupled transcription-translation of the mutated exonic sequence to detect stop mutations. [10] The test has been used to detect inactivating mutations of one gene copy in the diagnosis of certain hereditary cancers. Other techniques are being developed for mutation detection, including DNA chip analysis [11] and analysis of ssDNA by MALDI­TOF mass spectrometry. [12]

Several methods have been developed for rapid, high-throughput screening of point mutations (reviewed in reference13). Allele­specific oligonucleotide blot hybridization detects the ability of labeled DNA samples to hybridize to blotted control or mutated sequences. [14] The oligonucleotide-ligation assay is a related method with improved signal detection power in which a labeled reporter oligonucleotide is covalently attached to an immobilized reference oligonucleotide with the sample DNA as template. [1] The reference and reporter oligonucleotide are contiguous and complementary to the muta­tion-containing region such that the sequence mismatch represents the last nucleotide of different immobilized oligonucleotide. Ligation fails to occur in the case of a mis­match. A variation of this method, padlock probe, exploits differentiation of ligated DNA circles comprised of fully base-paired and mismatched sample sequences. Solid-state minisequencing in a 96-well multiplex system has also been developed to detect mutations.

   Genetic Polycystic Kidney Diseases Top

Autosomal Dominant Polycystic Kidney Disease (ADPKD) occurs in 1:1000 Cauca­sians and is characterized by progressive renal cyst formation resulting in chronic kidney disease and progressive kidney failure. In 85% of ADPKD cases, mutations in the PKD1 gene (chromosomal locus 16p13.3­p13.12) are causal. Most of the remaining cases result from mutations in PKD2, mapped to chromosome 4q21-23. [15] Cases not linked to these genes suggest the existence of addi­tional PKD loci. Mutations in the PKD1 and PKD2 genes are distributed throughout the genes with no hot spots or clusters of mutations. The gene products - polycystin­1 and polycystin-2, have been fully cloned. [15] Polycystin-1 is a large multi-domain trans­membrane protein that appears to act as a structural station for multiple unrelated ligand interactions in diverse functions as cell­cell, cell-matrix interactions and signaling, cell adhesion, cell development, signal trans­duction, DNA repair and RNA processing, regulation of and direct participation in calcium and other ion transport. Polycystin-2 may function as a Ca 2+ channel. [16]

Genetic analysis is a useful diagnostic tool in ADPKD, especially when imaging results are equivocal, and/or when a definite diagnosis is required in a younger individual, such as a potential living-related kidney donor. Linkage analysis or direct mutation screening is available clinically. The large size of PKD1 as well as a large, replicated non-functional region on the PKD1 gene renders standard molecular diagnostic techniques challenging and commercially impractical. In research laboratories, mutation detection rates of 50­75% have been reported for PKD1 and roughly 75% for PKD2. Recently, clinical testing of the PKD1 and PKD2 genes using long-range PCR to filter out nonfunctional regions, coupled with DHPLC heteroduplex analysis, and direct sequencing of the impli­cated fragments has become available, but the detection rate for disease-causing muta­tions is not yet established across several laboratories. [17],[18],[19] One commercial laboratory reports mutation detection rates of 95%. Regardless of the method used, the large number of different mutations and poly­morphisms described for the PKD1 gene necessitate cautious interpretation of results to distinguish true pathogenic changes from neutral polymorphisms. [17],[19]

Autosomal Recessive Polycystic Kidney
Disease (ARPKD) is much less frequent than ADPKD (approximately 1:2000 live births) but is a frequent cause of childhood nephro­pathy. Death occurs in infancy in 35% of cases with significant renal enlargement. The disease gene has recently been identified as the polycystic kidney and hepatic disease 1 (PKHD1) gene, mapped to human chromo­some 6p21. [20],[21] The PKHD1 gene product, fibrocystin, may act as a receptor with critical roles in collecting-duct and biliary develop­ment. [22] The diagnosis of ARPKD is based on clinical grounds, but molecular genetic testing by linkage analysis is available, primarily for prenatal diagnosis, to families with at least one affected child and identified informative markers tightly linked (or iatroge­nic) to the 6p21 locus. In informative ARPKD families, the diagnosis can be made with greater than 95% accuracy. PKHD1 mutation analysis allows an unequivocal diagnosis and accurate genetic counseling even in families displaying diagnostic challenges. [20],[21],[23]

Medullary Cystic Kidney Disease (MCKD and Familial Juvenile Hyperuricemic Nephropathy. Autosomal-dominant MCKD (ADMCKD) is a rare, chronic sclerosing tubulointerstitial nephropathy characterized by hypertension, chronic kidney disease, defective urinary concentrating ability, cysts in the medullary and corticomedullary regions of the kidney, and thickened tubular base­ment membranes. [24] Most patients reach ESRD in adulthood. In the Pafos area of Cyprus, ADMCKD, previously considered rare, is now recognized as the most common cause of ESRD (40%). [25] Two ADMCKD genes, MCKD1 and MCKD2 have been mapped to chromosomes 1q21 [26] and 16q12 [27] respectively; other loci likely exist. Recent studies indicate that MCKD2 and Familial Juvenile Hyperuricemic Nephropathy arise from mutation of the UMOD gene encoding uromodulin and are allelic disorders. [28] ADMCKD may be difficult to diagnose by clinical features alone, especially during the early stage when renal cysts may not be present. Dominant inheritance and DNA linkage analysis are therefore helpful in the diagnosis of this disease.

   Genetic Proteinuric Disorders Top

Finnish-type congenital nephrotic syndrome (CNF), another cause of chronic kidney disease in children, is histopathologically indistinguishable from MCKD, but it has an autosomal recessive pattern of inheritance. Three forms of the disease - juvenile NPHS (NPHS1), infantile NPHS (NPHS2) and adolescent NPHS (NPHS3) are distinguished with different genetic pathogeneses. [29],[30] fourth genetic variant, NPHS4, was recently identified. [31] The NPHS1 gene maps to chro­mosome 2q12-q13 and encodes nephrin, the core protein of the interpodocyte slit diaphragm that may function in cell surface recognition, immune response and cell signa­ling within the podocyte. [32] Two principal NPHS1 disease mutations have been linked to CNF and are found in >90% of Finnish patients. Outside of Finland, a variety of additional NPHS1 mutations have been found. Milder disease phenotypes, including occa­sional remission of proteinuria, in spite of characteristic CNF renal histology, have been reported. The oligonucleotide ligation assay coupled with PCR has been used to detect NPHS1 mutation in CNF patients. [33]

NPHS2 maps to chromosome 1q25 - 1q31. Its protein product, podocin, is a 42kDa trans­membrane protein, a member of the band-7 stomatin family that is expressed exclusively in the podocytes. Its mutations have been associated with a very specific type of auto­somal recessive focal segmental glomerulos­clerosis (FSGS) [34] as well as with autosomal recessive steroid-resistant nephrotic syn­drome. [35] In addition to autosomal recessive FSGS, NPHS2 mutations have been detected in sporadic cases of FSGS in childhood and adults. The gene, however, has been ruled out as a candidate for familial steroid-sensitive nephrotic syndrome. Podocin appears to participate in membrane associated proteolytic complexes, binds to nephrin and may augment nephrin-induced stimulation of mitogen-acti­vated protein kinases. There is evidence of a functional interrelationship between these two proteins. Genotype/phenotype correlations for NPHS1 and NPHS2 suggest that co­existing mutations in both genes may result in a clinical spectrum from mild nephrotic syndrome to severe CNF and even conge­nital FSGS. Mutation detection for these diseases by direct DNA analysis has been reported in research laboratories.

Nail-Patella Syndrome (NPS) is a rare autosomal dominant disorder characterized by nail dysplasia, patellar aplasia or hypo­plasia, iliac horns, elbow dysplasia, and often glaucoma and progressive nephropathy. [36] Mutations in the LMX1B gene (chromosome 9q34), a LIM-homeodomain transcription factor that may play a role in podocyte diffe­rentiation and in the regulation of collagen IV expression, is responsible for NPS. Col4A4 and Col4A3 are the first downstream target genes for LMX1B. Nearly 100 heterozygous mutations of LMX1B have been described in NPS so far. Prenatal diagnosis by DNA analysis has been reported in isolated cases. [37]

   Genetic Hematuric Syndromes Top

Alport syndrome and thin basement membrane disease. Alport syndrome is a progressive renal disease characterized by microhematuria and often sensorineural deaf­ness and anterior lenticonus. The pattern of inheritance for Alport syndrome is ~80% X­linked, ~15% autosomal recessive and ~ 5% autosomal dominant. The X-linked form of the disease is caused by mutations in the COL4A5 gene encoding the α5-chain of type IV-collagen. [38] Affected males have persistent microhematuria from early childhood, and go on to develop proteinuria and eventually progressive renal insufficiency. The vast majority of affected females have micro­scopic hematuria. Males and females with autosomal recessive Alport syndrome have persistent microhematuria. Mutations of COL4A3 and COL4A4 have been reported both in autosomal dominant and autosomal recessive Alport syndrome, as well as in benign familial hematuria. [39],[40] About half of the carriers of a COL4A3 or COL4A4 mutation also have persistent or intermittent microhematuria. Most affected individuals progress to ESRD before 30 years of age, though the pace is slower than for autosomal dominant Alport syndrome.

The diagnosis of Alport syndrome rests upon history and physical examination, including audiologic and ophthalmic evaluation with a detailed family history and possibly urinalyses on first- and second-degree relatives; immuno­histochemical analysis of type IV collagen expression in basement membranes of skin and/or renal biopsy specimens; and exa­mination of renal biopsy specimens by electron microscopy. Mutation analysis of the COL4A5 gene exons implicated in X­linked Alport syndrome by PCR-SSCP analysis is available on a research basis and has been reported to yield a mutation dete­ction rate of 69% in families who clearly demonstrated X-linked inheritance. [41] A multiplex genomic PCR-SSCP method was reported to yield a 79% rate of detection of COL4A5 mutations. [42] Direct sequencing of COL4A5 identifies about 80% of mutations in these patients. [43]

Molecular genetic testing of COL4A3 and COL4A4 implicated in autosomal recessive Alport syndrome and autosomal dominant Alport syndrome is also available on a rese­arch basis. The rate of detection of COL4A3 and COL4A4 mutations by PCR-SSCP appears to be about 50%. [44],[45] Molecular testing for Alport syndrome is obviously complicated by the fact that three genes (COL4A3, COL4A4, and COL4A5) cause the disease, the fact that the genes are large, and that they harbor an extremely large number of distinct mutations. In instances in which a disease-causing mutation of the COL4A5 gene is not identified in an affected family member, linkage analysis can be used for genetic counseling in families with multiple family members with X-linked Alport syn­drome. Since the markers used for X-linked Alport syndrome are highly informative and very tightly linked to the COL4A5 locus, they can be used in more than 50% of affected families with 99% accuracy. However, about 10% of families have a member with hema­turia, hearing loss, or renal disease that is not due to Alport syndrome and this can confound analysis. Currently, linkage analysis for auto­somal recessive Alport syndrome is available only in research laboratories.

   Genetic Glomerulosclerosis Disorders Top

Wilm's Tumor Suppressor Gene (WT1)­related Diseases. The WT1 gene located on chromosome 11p13 is a tumor suppressor gene that also plays an important role in nephrogenesis. In the mature kidney, WT1 expression appears to be necessary for normal podocyte function. WT1 gene mutations have been associated with Wilms' tumor (<15% patients) and, more consistently, with a spe­ctrum of glomerulopathies characterized by defective podocyte function and glomerulo­sclerosis. These diseases include the Denys­Drash Syndrome, incomplete Denys-Drash Syndrome, isolated diffuse mesangial scle­rosis, and Frasier Syndrome. Denys-Drash Syndrome and Frasier Syndrome are chara­cterized by male pseudohermaphroditism, a progressive glomerulopathy, and the develop­ment of genitourinary tumors. Patients with incomplete Denys-Drash Syndrome typically present with nephropathy and Wilms' tumor and without genital anomaly. The nephropathy of Denys-Drash Syndrome patients is typi­cally diffuse mesangial sclerosis, whereas FSGS occurs in Frasier Syndrome patients. [46] Loss-of-function mutations in WT1 exon 8 or 9 encoding zinc finger 2 or zinc finger 3, respectively, with a hot spot (R394W) in exon 9 have been found in the majority of Denys­Drash Syndrome patients studied, as well as in cases of isolated diffuse mesangial sclerosis and in cases of incomplete Denys-Drash Syndrome. Reduced WT1 gene expression may also explain, at least, in part, the reported progressive sclerosis renal failure noted in children nephrectomized for Wilm's tumor and in WAGR patients who have a deleted, allele. Podocalyxin and nephrin, two proteins that are highly expressed by podocytes and play a crucial role in the structure and function of the epithelial cell foot processes are downstream targets of WT1. At present, genetic testing for these diseases by direct DNA analysis is available at several research laboratories.

   Genetic Lysosomal and Peroxisomal Disorders Resulting in Renal Disease Top

Fabry Disease is an X-linked inborn error of metabolism due to mutations in the gene encoding the lysosomal enzyme α-galacto­sidase A. The enzymatic defect leads to the systemic accumulation of neutral glycosphin­golipids in plasma and tissues, particularly in endothelial cells, resulting in severe small vessel disease. Affected hemizygous males exhibit angiokeratoma, autonomic dysfun­ction, debilitating pain, renal failure, and vasculopathy of the heart and brain. [47] The definitive diagnosis of the disease in affected individuals is demonstration of a-galactosidase A deficiency in leukocytes or plasma. Most female carriers are clinically asymptomatic, but because of random X-chromosomal inactivation, enzymatic detection of carriers is often inconclusive. For accurate genetic counseling, molecular testing of possible carriers is required. The GLA gene on chromosome Xq22.1 has been cloned and more than 200 mutations have been identi­fied. Complete sequencing of the GLA gene is available clinically. Nearly all affected males have an identifiable mutation, and detection of a mutation in one GLA allele identified female carriers. [48] Prenatal testing is also available. Management for Fabry disease has until very recently been restricted to sym­ptomatic treatment, with renal transplantation or dialysis available for patients experiencing end-stage renal failure. Recombinant (x­galactosidase A has recently received FDA approval for treatment of this disorder. [49]

arises from defective cystine transport across the lysosomal membrane, resulting in its intracellular accumulation. Homozygous mutation results in infantile nephropathic cystinosis characterized by severe Fanconi syndrome, early-onset progre­ssive renal failure, and growth retardation. The cystinosis gene, (CTNS), maps to chromo­some 17p13, and encodes the lysosomal membrane protein cystinosin. Mutations in this gene cause all three types of cystinosis. [50] Late-onset cystinosis (juvenile; adolescent type) occurs less commonly, presents later, and has less severe clinical features. Non­nephropathic cystinosis is characterized solely by photophobia.

All clinical diagnoses of cystinosis should be confirmed by measurement of leucocyte cystine, which is best performed using the cystine binding protein assay. PCR amplifica­tion across this deletion allows for molecular diagnosis of homozygotes as well as hetero­zygotes, and clinical molecular diagnosis is available. In the United States and northern European populations, the majority of patients with nephropathic cystinosis are homozygous for a ~65-kb deletion that encompasses the first 9 exons and introns of CTNS and interrupts exon 10. [50],[51] A rapid PCR-based assay that detects both homozygous and heterozygous deletions has been developed and has been used to show that the ~65-kb deletion is present in either the homozygous or the heterozygous state in 76% of cystinotic patients of European origin. [52] This mutation, apparently representing a founder effect, has not been found outside of patients of European heritage.

Primary hyperoxaluria. The primary hyper­oxalurias are a group of inherited disorders of endogenous oxalate overproduction in which excessive oxalates are excreted by the kidneys, resulting in renal dysfunction ranging from renal failure in infancy to nephrolithiasis in late adulthood. Diagnosis of the two best­characterized disorders, primary hyperoxaluria (PH) types 1 and 2 is achieved by sequential measurement of alanine: glyoxylate amino­transferase and glyoxylate reductase enzyme activity in a single needle liver biopsy. Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disease caused by a deficiency of the liver-specific peroxisomal enzyme alanine: glyoxylate aminotransferase encoded by the AGXT gene. Studies to determine whether mutation analysis could replace enzymatic analysis for the diagnosis of PH1 indicated a sensitivity of mutation detection of only 47% in those patients with enzymologically confirmed Type 1 disease. However, genetic methods (mutation and linkage analysis) for diagnosing PH1 in other family members and for prenatal diagnosis and carrier testing may be of value [53],[54] PH2 is the result of mutations in the GRHPR gene encoding the enzyme glyoxylate reductase/ hydroxypyru­vate reductase. [55]

   Genetic Disorders Affecting Renal Tubular Function Top

Bartter's syndrome represents a group of autosomal recessive tubulopathies characte­rized by hypokalemia with renal potassium and salt wasting, metabolic alkalosis, and normal or low blood pressure despite hyper­reniemia and secondary hyperaldosteronism. Three subclasses of the disease have been identified, though no subclassification of Bartter's syndromes fits all cases (reviewed in reference 56). Antenatal Bartter syndrome is a severe form often presenting with maternal polyhydramnios, prematurity, postnatal poly­uria and dehydration, and hyposthenuria. Hypercalciuria with normal serum magnesium concentrations and nephrocalcinosis are typically evident. Defective Na + reabsorption resulting from mutations in the (SLC12A1) gene encoding the bumetanide-sensitive Na­K-2Cl cotransporter (NKCC2) or the KCNJ1 gene encoding the inwardly-rectifying K + channel ROMK residing in the thick ascen­ding limb of the loop of Henle give rise to this syndrome. Classical Bartter's syndrome often presents in infancy with dehydration, and is associated with hypomagnesemia in about 25% of cases and normal or increased calciuria. This form appears to be related to loss-of-function mutations of CLCNKB gene encoding the voltage-gated chloride channel CLC-Kb in the thick ascending limb of Henle, impairing chloride reabsorption. Patients with Gitelman's syndrome additionally exhibit renal magnesium wasting and hypocalciuria. Gitelman's syndrome patients are often recog­nized by chance or present in childhood or adolescence with muscular weakness, consti­pation, or tetany resulting from hypokalemia and hypomagnesemia. The disease has been linked to mutations in the SLC12A3 gene encoding the thiazide-sensitive Na-Cl cotrans­porter (NCCT) in the distal convoluted tubule. Gitelman syndrome patients typically present at older ages without overt hypo­volemia, whereas true Bartter patients usually present in childhood with signs of volume depletion.

Liddle syndrome is an autosomal dominant disorder with variable penetrance characte­rized by early, and often severe, hyperten­sion associated with hypokalemic metabolic alkalosis, low plasma renin activity, and sup­pressed aldosterone secretion. Liddle syndrome can result from constitutive activation of the renal epithelial sodium channel due to muta­tion in either the β subunit (SCNN1B) or γ subunit (SCNN1G) of this channel resulting in their prolonged retention in the plasma membrane. [57],[58] Amiloride, an inhibitor of the renal epithelial sodium channel, is therapeutic in this disease. A large number of hypertensive patients have been screened for SCNN1B and SCNN1G mutations, and molecular variants in the coding regions, all of which have been missense mutations, and promoter regions of the genes have been identified. Molecular genetic testing for Liddle syndrome is currently available only on a research basis.

Pseudohypoaldosteronism type 1 (PHA-1) is a syndrome characterized by urinary sodium wasting and reduced potassium excretion despite elevated aldosterone levels. The autosomal recessive form of this disorder may be associated with severe, and even fatal, episodes of hyponatremia, hyperkalemia, and hypotension. Mutations in each of the three ENaC subunits that result in reduced channel activity have been identified in several affected individuals. [59] Detection of mutation is available in a few research laboratories.

Hereditary hypomagnesemia Several heritable forms of hypomagnesemia have been described (reviewed by Konrad and Weber [56] and references therein), and molecular genetic testing is available for these disorders in a few research laboratories. Familial hypomag­nesemia with hypercalciuria and nephroca­lcinosis (FHHNC) is an autosomal recessive disorder characterized by impaired tubular reabsorption of magnesium and calcium in the thick ascending limb of Henle's loop, the result of mutations in the claudin 16 gene (CLDN16, chromosome 3q27-29), which encodes a renal tight junction protein that regulates paracellular Mg 2+ transport in the loop of Henle. The disorder typically presents in early childhood with polyuria, polydipsia, isosthenuria, recurrent urinary tract infections, and renal stones. Isolated Autosomal Domi­nant Hypomagnesemia, characterized by iso­lated renal magnesium wasting with resultant symptomatic hypomagnesemia, results from mutations in the FXYD2 gene (chromosome 11q23) encoding the Na-K-ATPase γ subunit, which result in its misrouting. Hypomag­nesemia with Secondary Hypocalciuria is an autosomal recessive disease presenting in early life with neurologic symptoms from hypomagnesemia and hypocalcemia. Muta­tions in the TRPM6 gene (chromosome 9q12-22.2), which encodes a putative ion channel belonging to the transient receptor potential (TRP) channel family, have been identified in some kindreds.

Disorders of the Ca 2+ /Mg 2+ -Sensing Receptor (CASR). Activating mutations of the CASR gene (chromosome 3q13.3-q21) have been described in patients with autosomal dominant hypocalcemia, [60] who manifest hypocalcemia, hypercalciuria, polyuria, and often hypomagnesemia. Inactivating mutations of the CASR gene give rise to familial hypo­calciuric hypercalcemia and neonatal severe hyperparathyroidism. [61]

Renal Tubular Acidosis. Autosomal recessive distal renal tubular acidosis (dRTA) is an early-onset disease characterized by severe hyperchloremic metabolic acidosis, hypoka­lemia, decreased urinary calcium solubility, and impaired skeletal physiology and growth. Two clinically similar types of this disorder have been distinguished based on the presence or absence of progressive deafness. Mutations in genes encoding two different subunits of the apical H + -ATPase of the a-intercalated cell cause this disorder. β subunit gene ATP6V1B1 mutations are associated with deafness, whereas mutations in the α 4 subunit gene ATP6V0A4 are associated with preserved hearing. [62] Hereditary proximal renal tubular acidosis may be associated with ocular abnormalities, such as caused by mutations in the kidney type Na + /HCO3­ cotransporter gene SLC4A4, or associated with osteopetrosis, cerebral calcification, and mental retardation, as occurs with mutations in the carbonic anhydrase II gene. [63]

Dent's Disease. This X-linked disorder characterized by low-molecular weight pro­teinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, rickets and eventual renal failure, is the result of inactivating mutations in the renal epithelial voltage-gated chloride channel, hCLC-5. [64] Detection of mutation has been pursued in research laboratories.

Nephrogenic Diabetes Insipidus (NDI) is characterized by inability to concentrate the urine, which results in polyuria and poly­dipsia. The clinical diagnosis of NDI relies upon the demonstration of subnormal ability to concentrate the urine despite the presence of arginine vasopressin. NDI is most commonly inherited in an X-linked recessive manner (~90% of patients). NDI can also be inherited in an autosomal recessive manner (~10% of patients) and in an autosomal dominant manner (~1% of patients). The arginine vasopressin type 2 receptor gene AVPR2 (chromosomal locus Xq28) is the only gene known to be associated with X-linked NDI, whereas the aquaporin-2 AQP2 gene (chromo­somal locus 12q13) is the only gene known to be associa-ted with autosomal recessive and autosomal dominant NDI. [65] Molecular genetic testing of the AVPR2 gene detects >97% of disease-causing mutations in individuals with X-linked NDI; molecular genetic testing of the AQP2 gene detects about >97% of disease-causing mutations in individuals with autosomal recessive NDI. [66] Such testing is clinically available.

   Genetic Forms of ThromboticMicroangiopathies Top

Hemolytic Uremic Syndrome (HUS). Factor H is a multifunctional, multidomain, glycopro­tein that controls C3 convertase activity. Loss of function of Factor H is associated with HUS and membranoproliferative glomerulo­nephritis (MPGN) type ll. Point mutations of the Factor H gene have been associated with familial and sporadic cases of HUS. [67] Penetrance is variable and phenotypic expression ranges from healthy carriers to severe predisposition to HUS. Mutation detection is available in several research laboratories.

Thrombotic Thrombocytopenic Purpura (TTP). Deficiency of a von Willebrand­cleaving protease ADAMTS13 due to muta­tions in the ADAMTS13 gene (chromosome 9q34) or inhibitory autoantibodies has been demonstrated to be a cause of TTP. [68] Hereditary deficiency of ADAMTS13 is responsible for the Schulman-Upshaw syn­drome and cases of chronic relapsing HUS characterized by very low ADAMT13 levels. Diagnosis remains clinical and biochemical. Assay of ADAMTS13 activity distinguishes TTP (deficient activity) from HUS and other types of thrombotic microangiopathy (preserved activity). To avoid misdiagnosis related to variation in ADAMTS13 assay results among laboratories, low protease values should be corroborated by indepen­dent evidence of reduced VWF proteolysis, and the presence of inhibitors or deficiency in the family members. [68] Molecular diag­nostic testing by direct DNA analysis is available on a research basis.

   Genetic Disorders Associated with Renal Tumors Top

von Hippel-Lindau (VHL) Syndrome is a rare autosomal dominant disorder characte­rized by the development of specific benign and malignant tumors. VHL is caused by point mutations or deletions in a tumor suppressor gene, the VHL gene at chromosomal locus 3q25. [69] Additionally, silencing of the gene by promoter hypermethylation has been observed in 20% of the tumors. The VHL gene product, pVHL forms a complex with elongin B and C, cullin (cul-2), NEDD8 and Rbx1, which acts as an E3 ubiquitin ligase. Mutations at the elongin-binding site of pVHL result in degradation of the complex by the proteasome. Other reported functions of pVHL include roles in cell cycle exit control, fibronectin and ECM binding and post-transcriptional regulation of target genes through mRNA stability effects. 70 With new diagnostic methods, mutations are detected in virtually all cases of VHL. Molecular genetic tests are now standard practice in the evaluation of patients with VHL. Germline testing for VHL gene mutations is available commercially (OncorMed, Gaithersburg, Maryland) and at the University of Pennsyl­vania. Genotype-phenotype correlation studies are primarily used to counsel regarding the risk of pheochromocytoma. Even where there is no family history of VHL, prognostic coun­seling based on genetic tests is valuable. Carriers of mutations among family members can be identified and closely monitored, for early detection of disease. Conversely, family members without mutations do not need to be monitored and can be reassured. NIH group recommendations have been developed. Pre-symptomatic screening of family members is available and more individuals are availing themselves of this.

Tuberous Sclerosis Complex (TSC) is inhe­rited as an autosomal dominant trait arising from mutations in the TSC1 and TSC2 genes. TSC1 encodes harmatin and maps to 9q34.3, while TSC2 encodes tuberin and maps to 16q13.3. Both conditions are clinically indistinguishable except for the occurrence of renal cysts almost exclusively in TSC2. Some TSC2 patients have renal cystic disease so severe as to be indistinguishable from ADPKD, with progression to renal failure. Harmatin binds to proteins of the ezrin-radixin-moesin family, which cross-link cortical actin filaments to the plasma mem­brane, and act as substrates for the tyrosine kinase of the epidermal growth factor receptor. Tuberin shows homology with the GTPase-activating protein of Rap1 and Rap5 members of the Ras family, which may be involved in cell division. It was recently shown that functional localization of polycys­tin-1 at the basolateral membrane is defective in TSC2 mutant cells. Angiomyolipomas are formed in the kidneys of 67% of TSC patients at autopsy. Both the protein trun­cation test and DGGE have been used to detect mutations. [71],[72],[73]

Familial Renal Cell Carcinoma. Recently chromosome 3 translocations have been des­cribed in a number of families with familial renal cell carcinoma. Positional cloning of the familial t(2;3)(35;q21) translocation revealed that the translocation disrupts a novel gene DIRC2 (disrupted in renal cancer 2). [74] The gene encodes a predicted transmembrane protein that represents a new member of the major facilitator superfamily (MFS) of trans­porters. This protein is expressed in proximal tubule cells where it may act as an anion­cation transporter involved in the secretion of xenobiotics. Disruption of the DIRC2 gene may result in reduced or defective transit of these molecules across the renal proximal tubular epithelium and their accumulation within the cell. Periodic ultrasound screening and genetic counseling is already actively pursued in some of the "at risk" families allowing the possibility of early detection of renal cell carcinoma and early surgical inter­vention. Germline mutations in the MET gene on chromosome 7 have been identified in a hereditary form of papillary renal cell carcinoma. MET is a transmembrane receptor for the hepatocyte growth factor. Germline mutation analysis by DHPLC followed by genomic sequencing is probably warranted in patients with papillary renal cell carcinoma only if additional evidence for a genetic pre­disposition (positive family history, unusual age at onset, bilateral disease) is apparent. [74]

   Conclusion Top

At the present time, molecular diagnostic tests are mostly applicable to symptomatic individuals with family histories of rare monogenic diseases and to population-based screening, such as newborn screening pro­grams and carrier testing of ethnic groups at high risk. Diagnostic testing and detection of disease susceptibility for the common complex diseases, such as hypertension, athe­rosclerosis, stroke, diabetes mellitus, and cancer, comprise only 5% of current genetic testing. Pharmacogenomic testing will also be very useful in predicting adverse drug reactions and also in predicting responsiveness to certain therapies, for example angiotensin converting enzyme inhibitors.

The rapidly increasing availability of new genetic tests and their commercialization will bring pressure to apply the tests. This pressure, however, should not obviate the careful consideration of the risks and benefits of each test, cost-benefit considerations, sensitivity, specificity, predictive values, and effective­ness of the specific tests, and the legal, ethical and psychosocial issues involved.

Risk or susceptibility may not be precisely measurable especially in conditions that may have a much-delayed onset, so that a heavy psychological burden may be imposed on the individual and on family members.

Some of the ethical and legal issues include: privacy, stigmatization, denial or increased cost of health and life insurance, employment discrimination and loss of employment, and the cost and availability of testing to all. There is also an ethical question regarding the testing for risk in a condition where there are no effective or palatable preventive measures. All of the considerations notwith­standing, it is anticipated that molecular genetic testing will become an increasingly powerful and utilized tool for the detection of hereditary renal diseases and associated disorders.

   Acknowledgements Top

Work in the authors' laboratories is suppor­ted by NIH grants RO1 DK-50745 and P50 GM-20529 (BCK), the "DREAMS" Center Grant from the Department of Defense (BCK), and endowment funds from The James T. and Nancy B. Wilkerson Chair (BCK).

   References Top

1.Shi MM. Bleavins MR, de la iglesia FA. Technologies for individual genotyping: detection of genetic polymorphisms in drug targets and disease genes. Am J Pharmaco­genomics. 2002;2:197-205.  Back to cited text no. 1    
2.Altmuller J, Palmer LJ, Fischer G, Scherb H, Wjst M. Genomewide scans of complex human diseases: true linkage is hard to find. Am J Hum Genet. 2001;69:936-50.  Back to cited text no. 2    
3.Kristensen VN, Kelefiotis D, Kristensen T, Borresen-Dale AL. High-throughput methods for detection of genetic variation. Biotech­niques. 2001;30:318-22, 324, 326 passim.  Back to cited text no. 3    
4.Kiechle FL. DNA technology, the clinical laboratory, and the future. Arch Pathol Lab Med. 2001;125:72-6.  Back to cited text no. 4    
5.Fodde R, Losekoot M. Mutation detection by denaturing gradient gel electrophoresis (DGGE). Hum Mutat. 1994;3:83-94.  Back to cited text no. 5    
6.Andersen PS, Jespersgaard C, Vuust J, Christiansen M, Larsen LA. Capillary electrophoresis-based single strand DNA conformation analysis in high-throughput mutation screening. Hum Mutat. 2003; 21:455-65.  Back to cited text no. 6    
7.Lilleberg SL. In-depth mutation and SNP discovery using DHPLC gene scanning. Curr Opin Drug Discov Devel. 2003;6:237-52.  Back to cited text no. 7    
8.Smooker PM, Cotton RG. The use of chemical reagents in the detection of DNA mutations. Mutat Res 1993;288:65-77.  Back to cited text no. 8    
9.Goldrick MM. RNase cleavage-based methods for mutation/SNP detection, past and present. Hum Mutat. 2001;18:190-204.  Back to cited text no. 9    
10.Den Dunnen JT, Van Ommen GJ. The protein truncation test: A review. Hum Mutat. 1999;14:95-102.  Back to cited text no. 10    
11.Hacia JG, Brody LC, Collins FS. Applications of DNA chips for genomic analysis. Mol Psychiatry. 1998;3:483-92. 12.  Back to cited text no. 11    
12.Griffin TJ, Smith LM. Single-nucleotide polymorphism analysis by MALDI-TOF mass spectrometry. Trends Biotechnol. 2000;18:77-84.  Back to cited text no. 12    
13.Tsuchihashi Z, Dracopoli NC. Progress in high throughput SNP genotyping methods. Pharmacogenomics J. 2002;2:103-10.  Back to cited text no. 13    
14.Ravine D. Automated mutation analysis. J Inherit Metab Dis. 1999;22:503-18.  Back to cited text no. 14    
15.Wu G, Somlo S. Molecular genetics and mechanism of autosomal dominant polycystic kidney disease. Mol Genet Metab. 2000;69:1-15.  Back to cited text no. 15    
16.Harris PC. Molecular basis of polycystic kidney disease: PKD1, PKD2 and PKHD1. Curr Opin Nephrol Hypertens. 2002; 11:309-14.  Back to cited text no. 16    
17.Rossetti S, Strmecki L, Gamble V, et al. Mutation analysis of the entire PKD1 gene: genetic and diagnostic implications. Am J Hum Genet. 2001;68:46-63.  Back to cited text no. 17    
18.Rossetti S, Burton S, Strmecki L, et al. The position of the polycystic kidney disease 1 (PKD1) gene mutation correlates with the severity of renal disease. J Am Soc Nephrol. 2002;13:1230-7.  Back to cited text no. 18    
19.Rossetti S, Chauveau D, Walker D, et al. A complete mutation screen of the ADPKD genes by DHPLC. Kidney Int. 2002; 61:1588-99.  Back to cited text no. 19    
20.Bergmann C, Senderek J, Sedlacek B, et al. Spectrum of Mutations in the Gene for Autosomal Recessive Polycystic Kidney Disease (ARPKD/PKHD1). J Am Soc Nephrol. 2003;14:76-89.  Back to cited text no. 20    
21.Onuchic LF, Furu L, Nagasawa Y, et al. PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats. Am J Hum Genet. 2002;70:1305-17.  Back to cited text no. 21    
22.Ward CJ, Hogan MC, Rossetti S, et al. The gene mutated in autosomal recessive poly­cystic kidney disease encodes a large, receptor­like protein. Nat Genet. 2002;30:259-69.  Back to cited text no. 22    
23.Onuchic LF, Mrug M, Hou X, et al. Refinement of the autosomal recessive polycystic kidney disease (PKHD1) interval and exclusion of an EF hand-containing gene as a PKHD1 candidate gene. Am J Med Genet. 2002;110:346-52.  Back to cited text no. 23    
24.Scolari F, Viola BF, Prati E, et al. Medullary cystic kidney disease: past and present. Contrib Nephrol. 2001;(136):68-78.  Back to cited text no. 24    
25.Stavrou C, Koptides M, Tombazos C, et al. Autosomal-dominant medullary cystic kidney disease type 1: clinical and molecular findings in six large Cypriot families. Kidney Int. 2002;62:1385-94.  Back to cited text no. 25    
26.Auranen M, Ala-Mello S, Turunen JA, Jarvela I. Further evidence for linkage of autosomal-dominant medullary cystic kidney disease on chromosome 1q21. Kidney Int 2001;60:1225-32.  Back to cited text no. 26    
27.Scolari F, Puzzer D, Amoroso A,et al. Identification of a new locus for medullary cystic disease, on chromosome 16p12. Am J Hum Genet. 1999;64:1655-60.  Back to cited text no. 27    
28.Hart TC, Gorry MC, Hart PS, et al. Mutations of the UMOD gene are res­ponsible for medullary cystic kidney disease 2 and familial juvenile hyper­uricaemic nephropathy. J Med Genet. 2002; 39:882-92.  Back to cited text no. 28    
29.Caridi G, Dagnino M, Gusmano R, et al. Clinical and molecular heterogeneity of juvenile nephronophthisis in Italy: insights from molecular screening. Am J Kidney Dis. 2000;35:44-51.  Back to cited text no. 29    
30.Heninger E, Otto E, Imm A, Caridi G, Hildebrandt F. Improved strategy for mole­cular genetic diagnostics in juvenile nephro­nophthisis. Am J Kidney Dis. 2001;37:1131-9.  Back to cited text no. 30    
31.Mollet G, Salomon R, Gribouval O, et al. The gene mutated in juvenile nephro­nophthisis type 4 encodes a novel protein that interacts with nephrocystin. Nat Genet. 2002;32:300-5.  Back to cited text no. 31    
32.Lenkkeri U, Mannikko M, McCready P, et al. Structure of the gene for congenital nephrotic syndrome of the finnish type (NPHS1) and characterization of mutations. Am J Hum Genet. 1999;64:51-61.  Back to cited text no. 32    
33.Romppanen EL. Oligonucleotide ligation assay: applications to molecular diagnosis of inherited disorders. Scand J Clin Lab Invest. 2001;61:123-9.  Back to cited text no. 33    
34.Koziell A, Grech V, Hussain S, et al. Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration. Hum Mol Genet. 2002;11:379-88.  Back to cited text no. 34    
35.Karle SM, Uetz B, Ronner V, Glaeser L, Hildebrandt F, Fuchshuber A. Novel muta­tions in NPHS2 detected in both familial and sporadic steroid-resistant nephrotic syndrome. J Am Soc Nephrol. 2002;13:388-93.  Back to cited text no. 35    
36.Bongers EM, Gubler MC, Knoers NV. Nail­patella syndrome. Overview on clinical and molecular findings. Pediatr Nephrol. 2002;17:703-12.  Back to cited text no. 36    
37.McIntosh I, Clough MV, Gak E, Frydman M. Prenatal diagnosis of nail-patella syndrome. Prenat Diagn. 1999;19:287-8.  Back to cited text no. 37    
38.Barker DF, Hostikka SL, Zhou J, et al. Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science. 1990;248:1224-7.  Back to cited text no. 38    
39.Longo I, Porcedda P, Mari F, et al. COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome. Kidney Int. 2002;61:1947-56.  Back to cited text no. 39    
40.Frasca GM, Onetti-Muda A, Renieri A. Thin glomerular basement membrane disease. J Nephrol. 2000;13:15-9.  Back to cited text no. 40    
41.Hertz JM, Juncker I, Persson U, et al. Detection of mutations in the COL4A5 gene by SSCP in X-linked Alport syndrome. Hum Mutat. 2001;18:141-8.  Back to cited text no. 41    
42.Barker DF, Denison JC, Atkin CL, Gregory MC. Efficient detection of Alport syndrome COL4A5 mutations with multiplex genomic PCR-SSCP. Am J Med Genet. 2001; 98:148-60.  Back to cited text no. 42    
43.Martin P, Heiskari N, Zhou J, et al. High mutation detection rate in the COL4A5 collagen gene in suspected Alport syndrome using PCR and direct DNA sequencing. J Am Soc Nephrol. 1998;9:2291-301.  Back to cited text no. 43    
44.Heidet L, Arrondel C, Forestier L, et al. Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome. J Am Soc Nephrol. 2001;12:97-106.  Back to cited text no. 44    
45.Boye E, Mollet G, Forestier L, et al. Determination of the genomic structure of the COL4A4 gene and of novel mutations causing autosomal recessive Alport syndrome. Am J Hum Genet. 1998;63:1329-40.  Back to cited text no. 45    
46.McTaggart SJ, Algar E, Chow CW, Powell HR, Jones CL. Clinical spectrum of Denys­Drash and Frasier syndrome. Pediatr Nephrol. 2001;16:335-9.  Back to cited text no. 46    
47.Ahlmen J, Hultberg B, Brynger H, Sjoblad S, Svalander C. Clinical and diagnostic consi­derations in Fabry's disease. Acta Med Scand 1982;211:309-12.  Back to cited text no. 47    
48.Branton MH, Schiffmann R, Sabnis SG, et al. Natural history of Fabry renal disease: influence of alpha-galactosidase A activity and genetic mutations on clinical course. Medicine (Baltimore). 2002;81:122-38.  Back to cited text no. 48    
49.Alpha-Galactosidase - Genzyme General. Fabrazyme, Agalsidase Beta, Recombinant Human alpha-Galactosidase A. Drugs R D. 2003;4:115-8.  Back to cited text no. 49    
50.Town M, Jean G, Cherqui S, et al. A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. Nat Genet. 1998;18:319-24.  Back to cited text no. 50    
51.Shotelersuk V, Larson D, Anikster Y, et al. CTNS mutations in an American-based population of cystinosis patients. Am J Hum Genet. 1998;63:1352-62.  Back to cited text no. 51    
52.Forestier L, Jean G, Attard M, et al. Molecular characterization of CTNS deletions in nephropathic cystinosis: development of a PCR-based detection assay. Am J Hum Genet. 1999;65:353-9.  Back to cited text no. 52    
53.Johnson SA, Rumsby G, Cregeen D, Hulton SA. Primary hyperoxaluria type 2 in children. Pediatr Nephrol. 2002;17:597-601.  Back to cited text no. 53    
54.Rumsby G. Biochemical and genetic diagnosis of the primary hyperoxalurias: a review. Mol Urol. 2000;4:349-54.  Back to cited text no. 54    
55.Cramer SD, Ferree PM, Lin K, Milliner DS, Holmes RP. The gene encoding hydroxy­pyruvate reductase (GRHPR) is mutated in patients with primary hyperoxaluria type II. Hum Mol Genet. 1999;8:2063-9.  Back to cited text no. 55    
56.Konrad M, Weber S. Recent advances in molecular genetics of hereditary magnesium­losing disorders. J Am Soc Nephrol. 2003;14:249-60.  Back to cited text no. 56    
57.Shimkets RA, Warnock DG, Bositis CM, et al. Liddle's syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell. 1994;79:407-14.  Back to cited text no. 57    
58.Hansson JH, Nelson-Williams C, Suzuki H, et al. Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome. Nat Genet. 1995;11:76-82.  Back to cited text no. 58    
59.Rossier BC, Pradervand S, Schild L, Hummler E. Epithelial sodium channel and the control of sodium balance: interaction between genetic and environmental factors. Annu Rev Physiol. 2002;64:877-97.  Back to cited text no. 59    
60.Okazaki R, Chikatsu N, Nakatsu M, et al. A novel activating mutation in calcium­sensing receptor gene associated with a family of autosomal dominant hypocalcemia. J Clin Endocrinol Metab. 1999;84:363-6.  Back to cited text no. 60    
61.Fuleihan Gel H. Familial benign hypo­calciuric hypercalcemia. J Bone Miner Res. 2002;17 Suppl 2:N51-6.  Back to cited text no. 61    
62.Stover EH, Borthwick KJ, Bavalia C, et al. Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss. J Med Genet. 2002;39:796-803.  Back to cited text no. 62    
63.Igarashi T, Sekine T, Watanabe H. Molecular basis of proximal renal tubular acidosis. J Nephrol. 2002;15 Suppl 5:S135-41.  Back to cited text no. 63    
64.Fisher SE, van Bakel I, Lloyd SE, et al. Cloning and characterization of CLCN5, the human kidney chloride channel gene impli­cated in Dent disease (an X-linked hereditary nephrolithiasis). Genomics. 1995;29:598-606.  Back to cited text no. 64    
65.Oksche A, Rosenthal W. The molecular basis of nephrogenic diabetes insipidus. J Mol Med. 1998;76:326-37.  Back to cited text no. 65    
66.Wildin RS, Cogdell DE. Clinical utility of direct mutation testing for congenital nephrogenic diabetes insipidus in families. Pediatrics. 1999;103:632-9.  Back to cited text no. 66    
67.Taylor CM. Complement factor H and the haemolytic uraemic syndrome. Lancet. 2001;358:1200-2.  Back to cited text no. 67    
68.Tsai HM. Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol. 2003;14:1072-81.  Back to cited text no. 68    
69.Ohh M, Kaelin WG Jr. VHL and kidney cancer. Methods Mol Biol 2003;222:167-83.  Back to cited text no. 69    
70.Zatyka M, da Silva NF, Clifford SC, et al. Identification of cyclin D1 and other novel targets for the von Hippel-Lindau tumor suppressor gene by expression array analysis and investigation of cyclin D1 genotype as a modifier in von Hippel-Lindau disease. Cancer Res. 2002;62:3803-11.  Back to cited text no. 70    
71.Dabora SL, Sigalas I, Hall F, Eng C, Vijg J, Kwiatkowski DJ. Comprehensive mutation analysis of TSC1 using two-dimensional DNA electrophoresis with DGGE. Ann Hum Genet. 1998;62 ( Pt 6):491-504.  Back to cited text no. 71    
72.Mayer K. Application of the protein truncation test (PTT) for the detection of tuberculosis sclerosis complex type 1 and 2 (TSC1 and TSC2) mutations. Methods Mol Biol. 2003;217:329-44.  Back to cited text no. 72    
73.Mayer K, Ballhausen W, Leistner W, Rott H. Three novel types of splicing aberrations in the tuberous sclerosis TSC2 gene caused by mutations apart from splice consensus sequences. Biochim Biophys Acta. 2000; 1502:495-507.  Back to cited text no. 73    
74.Bodmer D, Eleveld M, Kater-Baats E, et al. Disruption of a novel MFS transporter gene, DIRC2, by a familial renal cell carcinoma­associated t(2;3)(q35;q21). Hum Mol Genet. 2002;11:641-9.  Back to cited text no. 74    

Correspondence Address:
Bruce C Kone
Departments of Internal Medicine and of Integrative Biology and Pharmacology, The University of Texas, Medical School at Houston, 6431 Fannin, MSB 4.148, Houston, TX 77030
Login to access the Email id

Source of Support: None, Conflict of Interest: None

PMID: 17657098

Rights and PermissionsRights and Permissions


  [Table - 1]


    Similar in PUBMED
    Search Pubmed for
    Search in Google Scholar for
  Related articles
    Email Alert *
    Add to My List *
* Registration required (free)  

    Mutation Detecti...
    Genetic Polycyst...
    Genetic Proteinu...
    Genetic Hematuri...
    Genetic Glomerul...
    Genetic Lysosoma...
    Genetic Disorder...
    Genetic Forms of...
    Genetic Disorder...
    Article Tables

 Article Access Statistics
    PDF Downloaded559    
    Comments [Add]    

Recommend this journal