A NONSENSE MUTATION IN THE COL4A5 COLLAGEN GENE IN A FAMILY WITH X-LINKED JUVENILE ALPORT SYNDROME

The X-linked form of Alport syndrome is associated with mutations in t he COL4A5 gene encoding the alpha 5-chain of type IV collagen. By usin g PCR-amplification and direct sequencing we identified a novel mutati on involving a deletion of the last two bases in the codon GGA for Gly cine-1479 in exon 47 of the COL4A5 gene in a patient with a juvenile f orm of X-linked Alport syndrome with deafness. This two base deletion caused a shift in the reading frame and introduced a premature stop co don which resulted in an alpha 5(IV)-chain shortened by 202 residues a nd lacking almost the entire NC1 domain. The mutation was found to co- segregate with the disease in the family. The information of the seque nce variation in this family was used to perform carrier detection and prenatal diagnosis by allele-specific oligonucleotide hybridization a nalysis and direct sequencing of PCR amplified exon 47. Prenatal diagn osis on chorionic villi tissue, obtained from one of the female carrie rs in the family, revealed a male fetus hemizygous for the mutated all ele. A subsequent prenatal test in her next pregnancy revealed a norma l male fetus. Prenatal diagnosis of Alport syndrome has not previously been reported.