Tissue-specific distribution of an alternatively spliced COL4A5 isoform and non-random X chromosome inactivation reflect phenotypic variation in heterozygous X-linked Alport syndrome.

A novel type of hereditary transmission of COL4A5 in a Japanese family with X-linked Alport syndrome was detected through analysis of cDNA sequences and an X-chromosome inactivation assay. A female patient with moderately altered renal function, who was diagnosed with Alport syndrome by renal biopsy, and her mother, who was undergoing maintenance haemodialysis, showed similar tissue-specific expression of a truncated isoform of COL4A5, which was generated by alternative splicing without a splice-site mutation. Expression of the truncated isoform occurred in the renal specimen derived from the patient, but not in specimens from controls. Genomic analysis revealed two point mutations (c.4821 + 121, T>C; c.4822-151_150, ins T) in intron 49 of COL4A5 from the patient. The peripheral blood mononuclear cells of the patient and her mother showed non-random lyonization. While the females showed only renal impairment, an affected male in the same family suffered from severe renal insufficiency, visual defect and hearing disturbances. Hence, we suggest that this type of heredity COL4A5 presents with phenotypic variation in female heterozygous X-linked Alport syndrome patients.