A novelCOL4A1frameshift mutation in familial kidney disease: the importance of the C-terminal NC1 domain of type IV collagen

Abstract

BackgroundHereditary 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.MethodsWe used genome-wide linkage analysis, whole exome sequencing and cosegregation analyses.ResultsWe 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.ConclusionsMissense 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.

Bioinformatics analysis suggests that COL4A1 may play an important role in gastric carcinoma recurrence

“…COL4A1 is an important member of the collagen family and it is a key structural component of the extracellular matrix that is found in most connective and embryonic tissues . COL4A1 mutations have been reported to be implicated in several vessel diseases, including familial kidney disease, brain stroke, myocardial infarction, and chronic kidney disease . Moreover, COL4A1 mutations resulted in an excess of the apoptosis of endothelial cells contributing to primary endothelial cell defects and COL4A1 ‐related myopathy in mice .…”

Alport syndrome: facts and opinions

“…GBM thinning may also be found in patients with hematuria who have no detectable pathological alterations in COL4A3, COL4A4, or COL4A5 48 . Other genetic loci for hematuria associated with GBM thinning have yet to be identified, although a recent report described a COL4A1 frameshift mutation in a family with autosomal dominant hematuria, GBM thinning, kidney cysts, and progressive kidney disease 49 . Thus, TBMN is a pathological description that does not, in and of itself, allow accurate prediction of prognosis or inheritance in an individual patient.…”

The highly expressed COL4A1 genes contributes to the proliferation and migration of the invasive ductal carcinomas

“…so the COL4A1 was tightly associated with the cell proliferation, it was reported that COL4A1 knockdown led to reduced cell viability and cell cycle arrest [ 15 ], and clinical performance associated with mutations of COL4A1 include perinatal cerebral hemorrhage and porencephaly [ 16 ], hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC) [ 17 ], ocular dysgenesis, myopathy and Walker-Warburg syndrome [ 18 ]. the latest reports identify the truncation of C-terminal NC1 domain of type IV collagen 1 by frameshift mutation tightly 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 [ 19 ].…”