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

Abstract

X-linked Alport syndrome is caused by mutations in the COL4A5 gene encoding the type IV collagen α5 chain (α5(IV)). Complete absence of α5(IV) in the renal basal membrane is considered a pathological characteristic in male patients; however, positive α5(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 α5(IV)-positive and 37 α5(IV)-negative patients. Thirteen patients in the α5(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 α5(IV)-positive group were more likely to be located before exon 25 compared with missense mutations in the α5(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 α5(IV) chain.

Genetic, Clinical, and Pathologic Backgrounds of Patients with Autosomal Dominant Alport Syndrome

“…Previous studies of large Greek Cypriot pedigrees led to the suggestion of a causal relationship between heterozygous COL4A3/COL4A4 mutations and FSGS (20,21 (4) showed normal expression in glomeruli in all patients in this study. We previously also showed normal expression of a5(4) in GBM in 29% of patients with XLAS and 20% of patients with ARAS (16,18). A normal distribution of a5(4) cannot, thus, be used to establish the inheritance mode for ADAS.…”

“…Blood samples were collected from patients and family members, and genomic DNA was isolated from peripheral blood leukocytes using the Quick Gene Mini 80 System (Fujifilm, Tokyo, Japan) according to the manufacturer's instructions. For genomic DNA analysis, all 52 specific exons of COL4A3 and 48 exons of COL4A4 were amplified by PCR as described previously (16). The PCR-amplified products were then purified and subjected to direct sequencing using a Dye Terminator Sequencing Kit (Amersham Biosciences, Piscataway, NJ) with an automatic DNA sequencer (model ABI Prism 3130; PerkinElmer, Waltham, MA).…”

A case of mild phenotype Alport syndrome caused by COL4A3 mutations

“…They showed less urinary protein and developed into end-stage renal failure at a later age than those without a5 chain expression. a5 chain expression in XLAS patients appears to be related to milder clinical manifestations [12]. Jais et al reported that there was a difference in the progression of renal impairment between missense mutations and nonsense mutations [13].…”

X-Linked Alport Syndrome Caused by Splicing Mutations in COL4A5

“…Recently, we reported that 29% of patients with XLAS showed a5(IV) expression on kidney glomeruli, and these patients displayed milder phenotypes (13). All of these patients positive for a5(IV) had nontruncating mutations, including in-frame deletions or in-frame mutations resulting from splice site mutations and exon skipping.…”