Autosomal dominant Alport syndrome linked to the type IV collage a3 and a4 genes (COL4A3 and COL4A4)

Introduction Background. Alport syndrome is a hereditary nephritis that may lead to end-stage renal disease (ESRD) in Alport syndrome is a progressive hereditary nephroyoung adult life and is often associated with sensorineupathy associated with characteristic ultrastructural ral deafness and/or ocular abnormalities. The majority abnormalities of the glomerular basement membrane of families are X-linked due to mutations in the (GBM ). The majority of families demonstrate X-linked COL4A5 gene at Xq22. Autosomal forms of the disease transmission of the disease [1]. Classically males are also recognized with recessive disease, having been develop haematuria and deafness at a young age and shown to be due to mutations in the COL4A3 and progress to ESRD in their early 20s. Other associated COL4A4 genes on chromosome 2. Familial benign features include eye signs [2] (anterior lenticonus, haematuria has also been mapped to this region in perimacular flecks), leiomyomatosis [3 ], and possibly some families. macrothrombocytopathia. Females tend to be less Subjects and methods. We describe a large family with severely a ected. Renal biopsy of patients with Alport autosomal dominant Alport syndrome in which males syndrome often shows minimal abnormality on lightand females are equally severely a ected and one microscopy and standard immunofluorescence. Elecmember with a mild sensorineural deafness reached tron-microscopy, however, shows typical changes with ESRD aged 35 years. Renal biopsy in four a ected thickening and splitting of the glomerular basement patients demonstrated characteristic thickened and membrane [4]. split glomerular basement membranes on electronIn 1988 the Alport locus was mapped to Xq22 [5] microscopy. and when the COL4A5 gene was cloned and mapped Results. Genetic linkage analysis using markers on to the same region [6 ] it became a very strong candidate chromosome 2q demonstrated co-segregation of the as the Alport gene. This was confirmed in 1990 by the disease with the markers D2S351 and D2S401 with a finding of mutations in the COL4A5 gene in three maximum lod score of 3.4 at zero recombination. kindreds with Alport syndrome [7]. Since then more Linkage to the COL4A4 gene was confirmed using an than 200 mutations in the gene have been described intragenic COL4A4 polymorphism. Mutation analysis [8,9]. Autosomal forms of Alport syndrome are also has revealed a missense Leu36Pro mutation in exon 5 known to occur and in 1993 mutations in COL4A3 of the adjacent COL4A3 gene in the una ected mother, and COL4A4 were described in families with which may lead to a more severe phenotype in a ected autosomal recessive Alport syndrome who had a very family members carrying this mutation. similar phenotype to the X-linked disease [10,11]. Conclusion. Mutations in the COL4A3 and COL4A4 Autosomal dominant disease is also described but is genes can cause a spectrum of glomerular basement much less common [12]. membrane disease ranging from autosomal recessive In this study we performed genetic linkage analysis Alport syndrome to autosomal dominant Alport synon a large family with autosomal dominant Alport drome and familial benign haematuria syndrome using intragenic markers and microsatellite markers on 2q flanking the COL4A3/COL4A4 loci.