X‐linked Alport syndrome in Hellenic families: Phenotypic heterogeneity and mutations near interruptions of the collagen domain in COL4A5

Abstract

The X-linked Alport syndrome (ATS) is caused by mutations in COL4A5 and exhibits a widely variable expression. Usually ATS is heralded with continuous microhematuria which rapidly progresses to proteinuria, hypertension and chronic or end-stage renal disease (ESRD) by adolescence, frequently accompanied by sensorineural deafness and ocular complications. Milder forms of ATS also exist. We studied 42 patients (19M, 23F) of nine Hellenic families suspected clinically of X-linked ATS who presented with marked phenotypic heterogeneity. We identified mutations in COL4A5 in six families. Two males with nonsense mutation E228X reached ESRD by ages 14 and 18. Frameshift mutation 2946delT followed the same course with early onset renal involvement and deafness. However, two males with the milder missense mutation G624D, reached ESRD after 39 years and one patient showed thin basement membrane nephropathy (TBMN). Another 5/8 affected males with missense mutation P628L also developed ESRD between 30 and 57 years, while three exhibit only mild chronic renal failure (CRF). The data support previous findings that certain mutations are associated with milder phenotypes and confirm that mutation G624D may be expressed as TBMN with familial hematuria. Similar conclusions apply for missense mutation P628L. Interestingly, mutations G624D and P628L are near the 12th natural interruption of COL4A5 triple helical domain, which may explain the milder phenotype.

The Power of Molecular Genetics in Establishing the Diagnosis and Offering Prenatal Testing: The Case for Alport Syndrome

“…At the same time the EM studies do not show the classical thickening and lamellation of the usual X-linked Alport but extensive thinning of the GBM. Our findings agree with data presented in previous publications that identified this mutation in families from other populations [10][11][12][13] . However, the uncertainty and anxiety that accompany at-risk members belonging to families with conditions like this cannot always be dealt adequately clinically.…”

“…A renal biopsy in one patient established the presence of TBMN, thereby suggesting different explanations. Interestingly, the pedigree structure could not give a clear-cut information for X-linked or autosomal inheritance, considering that some females had symptoms of the disease 10 . The symptoms in six female carriers included microscopic hematuria while two of them exhibited additional non-nephrotic proteinuria.…”

“…We then engaged into re-sequencing the COL4A5 gene in patient II-1 by amplifying and sequencing all exons, including the splicing junctions and around 100 bp of flanking intronic regions. This sequencing revealed several polymorphic sites as well as a collagen mutation at position 624 that resulted in substitution of glycine by aspartic acid, G624D 10 . This mutation had been previously reported by three other groups and it was known to be associated with a milder Alport Syndrome phenotype, something that supported the mild presentation in our family [11][12][13] .…”

Effect of Shenkang granules on the progression of chronic renal failure in 5/6 nephrectomized rats

“…A significant observation of the present study was the marked improvement effect of SKG on renal pathological damage, through inhibition of the relative area of renal glomerulosclerosis and tubulointerstitial fibrosis, particularly in the SKGL and SKGM groups. Since the magnitude of fibrosis has been shown to indicate the degree and progression of renal failure (37), the antifibrotic effect of SKG may be relevant to the attenuation of renal disease progression. The effect of SKG in ameliorating renal pathological damage may be directly associated with a reduction in the synthesis of major ECM components (38,39), as demonstrated by the diminished production of collagen I and III in the kidney tissues of the SKG-treated 5/6 Nx rats .…”

Approach to Familial Hematuric Diseases: Review

“…KBY ve SDBY'ye gidiş klasik AS'li hastalardan daha geç dönemde olur. 16,17 Ekstrarenal tutulum nadirdir. EM olarak bakıldığında bulgular ince GBM hastalı-ğından ayırt edilemez.…”