Identification of a new mutation in the α4(IV) collagen gene in a family with autosomal dominant Alport syndrome and hypercholesterolaemia

Background. Alport syndrome (AS) is a hereditary disease of the glomerular basement membrane in the kidney characterized by progressive renal failure, sensorineural deafness, and/or ocular abnormalities. In contrast to the well‐known X‐linked phenotype, very little is known about the autosomal dominant form. Rare autosomal forms of AS have been described with mutations in COL4A3 and COL4A4 at chromosome region 2q35‐q37, but there have been no descriptions of dominant forms due to a mutation in COL4A4. Methods. We describe a Sardinian family with a classical AS‐phenotype plus hypercholesterolaemia, a clinical feature also present in Fechtner syndrome (FS), a disease that segregates as an autosomal dominant trait. Results. A suggestive linkage (LOD=2.7) between AS and the COL4A3/A4 locus at 2q35‐q37 was identified. Other candidate collagen genes encoding basement membrane collagen (COL4A1/A2 and COL4A5/A6) were excluded by linkage analysis (13q33‐q34 and Xq22), or by sequence (COL4A3). DNA sequence analysis of the COL4A4 gene revealed that the Lys325Asn mutation was present in all affected family members, but was absent in all unaffected members and in a random sample of the Sardinian population. A clear indication of a gene‐dosage effect was seen in the most severely affected family member, since she carried the mutation in the homozygous form. Conclusions. These data confirm the importance of collagen 4A4 as a component in the structural integrity of the glomerular basement membrane and confirm the phenotypic and genetic heterogeneity of collagen disorders.