MUTATIONS IN THE TYPE-IV COLLAGEN ALPHA-3 (COL4A3) GENE IN AUTOSOMAL RECESSIVE ALPORT SYNDROME

A group of 22 unrelated patients with sporadic or non-X-linked Alport syndrome were screened for mutations in the non-collagenous domain of the type IV collagen (alpha 3 (COL4A3) chain gene. The five 3'-exons o f this gene, located on chromosome 2qter, were tested by single strand conformation polymorphism analysis and direct sequencing. One patient was heterozygous and another homozygous (Mochizuki et al., Nature Gen etics, in press) for a deletion of five nucleotides. A third patient a ppeared to be a compound heterozygote for two different nonsense mutat ions. In two patients and the father of a deceased patient we found a heterozygous substitution of an evolutionary conserved leucine by prol ine. However, segregation data of the mutation and a COL4A3/COL4A4 CA- repeat marker in their families argued against a causative role of the missense mutation. Even drastic changes of strongly conserved amino a cids, as in the Leu36Pro case, may not be significant. Autosomal reces sive inheritance due to pathogenic COL4A3 mutations accounts for at le ast 13% of Alport syndrome cases in this sample. It is concluded that COL4A3 is a major gene in the genetically and clinically heterogeneous Alport syndrome.