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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2006  |  Volume : 17  |  Issue : 3  |  Page : 320-325
Autosomal Dominant Alport's syndrome: Study of a Large Tunisian Family

1 Department of Nephrology, H Chaker Hospital, Sfax, Tunisia
2 Department of Pathology, H Bourguiba Hospital, Sfax, Tunisia
3 Laboratory of Genetics, University Medical, Sfax, Tunisia
4 INSERM, Necker Enfants Malades Hospital, Paris, France

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Alport's syndrome is a hereditary nephritis that may lead to end-stage renal disease (ESRD) in early adult life. It is a clinically and genetically heterogeneous nephropathy. Alport's syndrome is often associated with sensorineural deafness and/or ocular abnormalities. In contrast with the well-known X-linked phenotype, very little is known about the autosomal dominant form caused by mutations in COL4A3 and COL4A4 in the chromosome region 2q35-q37. We describe a Tunisian family with autosomal dominant Alport's syndrome in which males and females were equally affected. Two members reached ESRD at age 40 and 53 years, respectively. Three members experienced isolated microhematuria and one member experienced sensorineural deafness. No eye abnormalities were observed. Immunohistochemical studies showed a normal distribution of the α5 (type IV collagen) chain in the epidermal basement membrane. Genetic analysis demonstrated that a common haplotype co-segregated with the disease in the heterozygous state in all affected patients, thereby, confirming an autosomal dominant mode of inheritance. The same haplotype was observed in two asymptomatic children. We conclude that autosomal dominant Alport's syndrome, follows a rare mode of inheritance and exhibits a milder phenotype than usually observed in classic X-linked Alport's syndrome. The frequency of this mode of inheritance should be confirmed by a larger study.

Keywords: Hereditary nephritis, Alport′s syndrome, Autosomal dominant.

How to cite this article:
Kharrat M, Makni S, Makni K, Kammoun K, Charfeddine K, Azaeiz H, Jarraya F, Hmida M B, Gubler M C, Ayadi H, Hachicha J. Autosomal Dominant Alport's syndrome: Study of a Large Tunisian Family. Saudi J Kidney Dis Transpl 2006;17:320-5

How to cite this URL:
Kharrat M, Makni S, Makni K, Kammoun K, Charfeddine K, Azaeiz H, Jarraya F, Hmida M B, Gubler M C, Ayadi H, Hachicha J. Autosomal Dominant Alport's syndrome: Study of a Large Tunisian Family. Saudi J Kidney Dis Transpl [serial online] 2006 [cited 2022 Dec 7];17:320-5. Available from: https://www.sjkdt.org/text.asp?2006/17/3/320/35763

   Introduction Top

Alport's syndrome, a type IV collagen disorder, is a progressive hereditary nephro­pathy characterized by persistent hematuria that may evolve to end-stage renal disease (ESRD). [1] This syndrome is associated with ultrastructural lesions of the glomerular base­ment membrane (GBM), sensorineural hearing loss and/or ocular abnormalities (anterior lenticonus, macular or peripheral flecks). [2]

Alport's syndrome is clinically heterogeneous and several phenotypes have been described according to the rate of progression to ESRD, the presence or absence of deafness and/ or other extra-renal abnormalities. [3]

In 1988, the first Alport's locus was mapped to Xq22 and mutations were found in the COL4A5 gene [4] with an inheritance of nearly 85%. [3],[5] Nearly fourteen percent of Alport's syndrome segregated as an autosomal trait and several mutations in COL4A3 and COL4A4 on chromosome 2q35-q37 have been described in families with autosomal recessive Alport's syndrome. [6],[7] Less than 1% of Alport's syndrome cases have an autosomal dominant pattern of inheritance. [8]

In the present study, we describe a large Tunisian family with autosomal dominant Alport's syndrome in comparison with four other families presenting with Alport's syndrome with other modes of inheritance.

   Patients and Methods Top

In this study, we describe a large Tunisian family with progressive hematuric nephropathy and sensorineural hearing loss. Eleven members of this family were studied. Each person was subjected to a physical examination and qualitative urinalysis to determine the presence of microhematuria and proteinuria. Quantitative urinalysis and renal function tests were performed when microscopic hematuria was discovered by dipstick urinalysis. Hematological tests, ophthalmologic examination, hearing test, cholesterol monitoring and genetic analysis were also performed on all studied subjects.

Members of the family were considered affected, only if he/she had microscopic hematuria after exclusion of urinary infection and renal tumor.

One patient had renal biopsy with light and immunofluorescence microscopy examination. Another patient had an immunohistological study of epidermal basement membranes using monoclonal mouse antibodies anti α25 (CFT­45325, - Shigei Medical Research Institute). For genetic analysis, DNA was extracted from patient whole blood and healthy controls. Microsatellite markers were used such as DXS456, DXS1191 and DXS1106 to test linkage to chromosome X and D2S351, D2S159, D2S401 for COL4A3 and COL4A4 on chromosome 2, and intragenic COL4A3 microsatellite. Genotyping was performed using a radioactive detection system. The amplification of the polymorphic markers was undertaken by the polymerase chain reaction (PCR). PCR was performed in a 50 µl reaction volume with 10 ng genomic DNA, 20µMole (M) of each primer, and PCR buffer contain­ing 50 mM KCl, 10 mM tris HCl (pH 9.5); 1.5 mM MgCl 2 ; 1.25 mM each of dATP, dGTP, dTTP, and dCTP, and 1 U Taq DNA polymerase. Reaction mixtures were heated to 94°C for denaturation and then were cycled 35 times as follows: 45s at 94°C for denatu­ration, with annealing at 55°C for 45s and 45s at 72°C, followed by a final elongation step at 72°C for 5min. The reaction products were denatured at 96°C for 10 min and resolved on 6% denaturing sequencing gels with 8.3 M urea. After transfer onto hybond N+ membrane, the separated bands were detected by autoradiography after exposure to Kodak XAR-5 film for 2-48 H at -70°C.

   Results Top

Eleven members of this family were studied. The index case (III2) was a 40-year-old man with chronic renal failure, mild proteinuria and microhematuria. He quickly progressed to ESRD. His hearing test and ophthalmologic examination were normal. His sister (III3) had chronic renal failure with proteinuria, microhematuria and deafness at the age of 53. A second sister (III5) only had microhematuria at 36 years. His third sister (III6) experienced microhematuria since the age of 24 without proteinuria. Her blood pressure and renal function were normal. Renal biopsy was performed on her at the age of 30 and showed an absence of lesions by light microscopy. Electron microscopy was not performed. Her hearing test showed high frequency sensorineural deafness and no ocular lesions were found. Their mother died with chronic renal failure.

The niece (IV10) had isolated microhematuria at the age of 12 years. On renal biopsy, the immunohistochemical study showed a normal distribution of the 0 5 (type IV collagen) chain in the epidermal basement membrane of patient III2.

The pedigree could be compatible with the most common X-linked form, but involve­ment of the COL4A5 locus was excluded by linkage analysis.

Autosomal recessive Alport's syndrome was also excluded because a morbid haplotype was found in the heterozygous state in all the patients.

No hypercholesterolemia, leukocyte inclusions, or macrothrombocytopenia was observed in these subjects. Clinical features of the patients and healthy controls are displayed in [Table - 1] and pedigree in [Figure - 1].

   Discussion Top

Alport's syndrome is a genetically and phenotypically heterogeneous disease. [1] X­linked Alport's syndrome is the most common form, [9] but autosomal recessive and autosomal dominant forms have also been described and are responsible for 15% of inheritance cases. [10],[11] In accordance with the Feingold et al [12] criteria for Alport's syndrome diagnosis, our study family had three affected generations. Of the affected family members, two experienced hematuria, one experienced sensorineural deafness and one progressed to renal failure. [12] Furthermore, these manifestations are consistent with the third form of Grawfurd classification. [13]

The X-linked and autosomal recessive patterns of inheritance were excluded by linkage analysis. A morbid haplotype was found in the heterozygous state in all patients. This finding confirms the autosomal dominant mode of inheritance. The same allele was also found in two asymptomatic children (IV7, IV8). The absence of microhematuria in these two children can be explained by the intermittent nature of hematuria in children described in the original case of Alport's syndrome [14] or the in-complete penetrance of inheritance. Pescucci et al described an incomplete penetrance of about 95% in an autosomal dominant form of Alport's syndrome. [15] Jefferson et al studied a similar family and hypothesized that heterozygous mutations may lead to a less severe phenotype than the homozygous mutations as long as normal α3 and α4 type IV collagen chains are detected. [16] Furthermore, Heidet et al demonstrated the broad spectrum of phenotypes associated with COL4A3 heterozygous mutations, which can be completely asymptomatic or lead to hematuric nephropathies of variable severity. [17] Heterozygous COL4A3 and COL4A4 mutations cause thin basement membrane nephro­pathy (TBMN) as well as dominant Alport's syndrome. [18] Renal failure and hearing loss can be seen in Alport's syndrome, but not in TBMN.

Autosomal dominant Alport's syndrome families have a relatively mild phenotype indicated by a slower rate of progression to ESRD than most patients with X-linked Alport's syndrome,[8],[16] which correlates well with the findings in our patients.

Seen by electron microscopy, the typical lesion of Alport's syndrome involves a thickening of the GBM with splitting and fragmenting of the lamina densa into several strands forming a "basket wave" pattern. [19] However, GBM changes varied with age and gender from normal GBM to uniformly thin GBM. [19]

As observed in our patient (III3), the distri­bution of the α5 (type IV collagen) chain is usually normal in autosomal dominant Alport's syndrome.[10],[20] Moreover, the absence of ocular abnormalities in autosomal dominant Alport's syndrome has been cited by several authors.[11],[16],[21]

Finally, the combination of electron micro­scopic changes, molecular alteration and clinical outcome in relatives may eventually lead to the correct diagnosis.[17]

We conclude that autosomal dominant Alport's syndrome is a rare mode of inheritance. This form of inheritance displays a milder phenotype than what is usually observed in classic X­-linked Alport's syndrome. The frequency of this mode of inheritance must be confirmed by a larger study.

   References Top

1.Gubler MC, Antignac C, Deschenes G, et al. Genetic, clinical and morphologic heterogeneity in Alport's's syndrome. Adv Nephrol Necker Hosp 1993;22:15-35.  Back to cited text no. 1    
2.Kashtan C E. Alport's syndrome: an inherited disorder of renal, ocular and cochlear basement membranes. Medicine 1999;78:338-60.  Back to cited text no. 2    
3.Jais J P, Knebelmann B, Giatras I, et al. X-linked Alport's syndrome: natural history in 195 families and genotype-phenotype correlations in males. J Am Soc Nephrol 2000;11:649-57.  Back to cited text no. 3    
4.Barker DF, Hostikka SL, Zhou J, et al. Identification of mutations in the COL4A5 collagen gene in Alport's syndrome. Science 1990;248:1224-7.  Back to cited text no. 4    
5.Tryggvason K, Zhou J, Hostikka SL, Shows TB. Molecular genetics of Alport's syndrome. Kidney Int 1993; 43: 38 - 44.  Back to cited text no. 5    
6.Mariyama M, Zheng K, Yang-feng TL, Reeders ST. Colocalization of the genes for the alpha3 (IV) and alpha4 (IV) chains of type IV collagen to chromosome 2 bands q35-q37. Genomics 1992;13:809-13.  Back to cited text no. 6    
7.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's syndrome. Am J Hum Genet 1998;63:1329-40.  Back to cited text no. 7    
8.Van Der Loop F, Heidet L, Timmer E, et al. Autosomal dominant Alport's syndrome caused by a COL4A3 splice site mutation. Kidney Int 2000;58:1870-5.  Back to cited text no. 8    
9.Atkin CL, Gregory MC, Border WA. Alport's syndrome. in, Schrier RW, Gosttschalk CW (eds): Diseases of the Kidney 4th Ed, Little Brown, Boston, 1988, 617-41.  Back to cited text no. 9    
10.Pirson Y. Making the diagnosis of Alport's's syndrome. Kidney Int 1999;56: 760-75.  Back to cited text no. 10    
11.Ciccarese M, Casu D, Ki Wong F, et al. Identification of a new mutation in the alpha4 (IV) collagen gene in a family with autosomal dominant Alport's syndrome and hypercholesterolaemia. Nephrol Dial Transplant 2001;16:2008-12.  Back to cited text no. 11    
12.Feingold J, Bois E, Chompret A, Broyer M, Gubler MC, Grunfeld JP. Genetic heterogeneity of Alport's syndrome. Kidney Int 1985;27:672-7.  Back to cited text no. 12    
13.Grawfurd MA. Alport's's syndrome. J Med Genet 1988;25:623-7.  Back to cited text no. 13    
14.Kashtan C E, Michael A F. Alport's syndrome: from bedside to genome to bedside. Am J Kidney Dis 1993;22:627-40.  Back to cited text no. 14    
15.Pescucci C, Mari F, Longo I, et al. Auto­somal-dominant Alport's syndrome: Natural history of a disease due to COL4A3 or COL4A4 gene. Kidney Int 2004;65:1598­-603.  Back to cited text no. 15    
16.Jefferson JA, Lemmink HH , Hughes AE, et al. Autosomal dominant Alport's syndrome linked to the type IV collagen alpha3 and alpha4 (COL4A3 and COL4A4). Nephrol Dial Transplant 1997;12:1595-9.  Back to cited text no. 16    
17.Heidet L , Arrondel C , Forestier L, et al. Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport's syndrome. J Am Soc Nephrol 2001;12:97-106.  Back to cited text no. 17    
18.Wang Y Y, Rana K, Tonna S, Lin T, Sinand L, Savige J. COL4A3 mutations and their clinical consequences in thin basement membrane nephropathy (TBMN). Kidney Int 2004;65:786-90.  Back to cited text no. 18    
19.Gubler MC, Heidet L, Antignac C. Alport's's syndrome, thin basement membrane nephropathy, nail-patella syndrome and type III collagen glomerulopathy, in Jennette J, Olson JL, Schwartz MM, Silva FG. Heptinstall's Pathology of the Kidney. 5th edition. Lippincott-Raven Publishers Philadelphia, 1207-30.  Back to cited text no. 19    
20.Barsotti P , Muda AO, Mazzucco G, et al. Distribution of alpha chains of type IV collagen in glomerular basement membranes with ultrastructural alterations suggestive of Alport's syndrome. Nephrol Dial Transplant 2001;16:94552.  Back to cited text no. 20    
21.Blaise P, Delanaye P, Martalo O, Pierard GE, Rorive G, Galand A. Anterior lenticonus: diagnostic aid in Alport's syndrome. J Fr Ophtalomol 2003;26(10):1075-82.  Back to cited text no. 21    

Correspondence Address:
M Kharrat
Department of Nephrology, H. Chaker hospital, 3029, Sfax
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Source of Support: None, Conflict of Interest: None

PMID: 16970251

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  [Figure - 1]

  [Table - 1]

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