Nephrology Dialysis Transplantation, Vol 12, Issue 8 1595-1599, Copyright © 1997 by Oxford University Press
J Jefferson, H Lemmink, A Hughes, C Hill, H Smeets, C Doherty and A Maxwell
Background: Alport syndrome is a hereditary nephritis
that may lead to end-stage renal disease (ERSD) in young adult life and is
often associated with sensorineural deafness and/or ocular abnormalities.
The majority of families are X-linked due to mutations in the COL4A5 gene
at X122. Autosomal forms of the disease are also recognized with recessive
disease, having been shown to be due to mutations in the COL4A3 and COL4A4
genes on chromosome 2. Familial benign haematuria has also been mapped to
this region in some families.Subjects and methods: We
describe a large family with autosomal dominant Alport syndrome in which
males and females are equally severely affected and one member with a mild
sensorineural deafness reached ESRD aged 35 years. Renal biopsy in four
affected patients demonstrated characteristic thickened and split
glomerular basement membranes on electron-microscopy.
Results: Genetic linkage analysis using markers on
chromosome 2q demonstrated co-segregation of the disease with the markers
D2S351 and D2S401 with a maximum lod score of 3.4 at zero recombination.
Linkage to the COL4A4 gene was confirmed using an intragenic COL4A4
polymorphism. Mutation analysis has revealed a missense Leu36Pro mutation
in exon 5 of the adjacent COL4A3 gene in the unaffected mother, which may
lead to a more severe phenotype in affected family members carrying this
mutation. Conclusion: Mutations in the COL4A3 and
COL4A4 cause a spectrum of glomerular basement membrane disease ranging
from autosomal recessive Alport syndrome to autosomal dominant Alport
syndrome and familial benign haematuria. Keywords:
familial benign haematuria; hereditary nephritis; type IV collagen
ORIGINAL ARTICLES
Autosomal dominant Alport syndrome linked to the type IV collage &agr;3 and &agr;4 genes (COL4A3 and COL4A4)
Departments of Medical Genetics and Pathology, Queen's University, Belfast, UK; Department of Human genetics, University Hospital Nijmegen, The Netherlands; Corresponding author at: Department of Nephrology, Level 11 South, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland, UK
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