Format

Send to

Choose Destination
Nephrol Dial Transplant. 2016 Nov;31(11):1908-1914. Epub 2016 Apr 8.

A novel COL4A1 frameshift mutation in familial kidney disease: the importance of the C-terminal NC1 domain of type IV collagen.

Author information

1
UCL Centre for Nephrology, University College, London, UK.
2
Nephrology Department, Nicosia State Hospital, Nicosia, North Cyprus.
3
Department of Nephrology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
4
Department of Pediatrics, Nicosia State Hospital, Nicosia, North Cyprus.
5
West London Renal and Transplant Institute, Imperial College, London, UK.
6
South West Thames Institute for Renal Research, St Helier Hospital, Carshalton, UK.
7
School of Clinical Medicine, Cambridge University, Cambridge, UK.

Abstract

BACKGROUND:

Hereditary microscopic haematuria often segregates with mutations of COL4A3, COL4A4 or COL4A5 but in half of families a gene is not identified. We investigated a Cypriot family with autosomal dominant microscopic haematuria with renal failure and kidney cysts.

METHODS:

We used genome-wide linkage analysis, whole exome sequencing and cosegregation analyses.

RESULTS:

We identified a novel frameshift mutation, c.4611_4612insG:p.T1537fs, in exon 49 of COL4A1. This mutation predicts truncation of the protein with disruption of the C-terminal part of the NC1 domain. We confirmed its presence in 20 family members, 17 with confirmed haematuria, 5 of whom also had stage 4 or 5 chronic kidney disease. Eleven family members exhibited kidney cysts (55% of those with the mutation), but muscle cramps or cerebral aneurysms were not observed and serum creatine kinase was normal in all individuals tested.

CONCLUSIONS:

Missense mutations of COL4A1 that encode the CB3 [IV] segment of the triple helical domain (exons 24 and 25) are associated with HANAC syndrome (hereditary angiopathy, nephropathy, aneurysms and cramps). Missense mutations of COL4A1 that disrupt the NC1 domain are associated with antenatal cerebral haemorrhage and porencephaly, but not kidney disease. Our findings extend the spectrum of COL4A1 mutations linked with renal disease and demonstrate that the highly conserved C-terminal part of the NC1 domain of the α1 chain of type IV collagen is important in the integrity of glomerular basement membrane in humans.

KEYWORDS:

COL4A1; familial nephropathy; genetic renal disease; glomerular basement membrane; type IV collagen

Comment in

PMID:
27190376
PMCID:
PMC5091614
DOI:
10.1093/ndt/gfw051
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center