Milder clinical aspects of X-linked Alport syndrome in men positive for the collagen IV α5 chain

X-linked Alport syndrome is caused by mutations in the COL4A5 gene encoding the type IV collagen alpha 5 chain (alpha 5(IV)). Complete absence of alpha 5(IV) in the renal basal membrane is considered a pathological characteristic in male patients; however, positive alpha 5(IV) staining has been found in over 20% of patients. We retrospectively studied 52 genetically diagnosed male X-linked Alport syndrome patients to evaluate differences in clinical characteristics and renal outcomes between 15 alpha 5(IV)-positive and 37 alpha 5(IV)-negative patients. Thirteen patients in the alpha 5(IV)-positive group had non-truncating mutations consisting of nine missense mutations, three in-frame deletions, and one splice-site mutation resulting in small in-frame deletions of transcripts. The remaining two showed somatic mutations with mosaicism. Missense mutations in the alpha 5(IV)-positive group were more likely to be located before exon 25 compared with missense mutations in the alpha 5(IV)-negative group. Furthermore, urinary protein levels were significantly lower and the age at onset of end-stage renal disease was significantly higher in the positive group than in the negative group. These results help to clarify the milder clinical manifestations and molecular characteristics of male X-linked Alport syndrome patients expressing the alpha 5(IV) chain.