COL4A1 mutations as a potential novel cause of autosomal dominant CAKUT in humans.

TitleCOL4A1 mutations as a potential novel cause of autosomal dominant CAKUT in humans.
Publication TypeJournal Article
Year of Publication2019
AuthorsKitzler, TM, Schneider, R, Kohl, S, Kolvenbach, CM, Connaughton, DM, Dai, R, Mann, N, Nakayama, M, Majmundar, AJ, Wu, C-HW, Kari, JA, Desoky, SMEl, Senguttuvan, P, Bogdanovic, R, Stajić, N, Valivullah, Z, Lek, M, Mane, S, Lifton, RP, Tasic, V, Shril, S, Hildebrandt, F
JournalHum Genet
Date Published2019 Oct
KeywordsAlleles, Amino Acid Substitution, Collagen Type IV, Computational Biology, Congenital Abnormalities, Databases, Genetic, DNA Mutational Analysis, Evolution, Molecular, Female, Genetic Association Studies, Genetic Loci, Genomics, Heterozygote, Humans, Kidney, Kidney Diseases, Cystic, Male, Mutation, Nephrotic Syndrome, Phenotype, Urinary Tract, Web Browser, Whole Exome Sequencing

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease (~ 45%) that manifests before 30 years of age. The genetic locus containing COL4A1 (13q33-34) has been implicated in vesicoureteral reflux (VUR), but mutations in COL4A1 have not been reported in CAKUT. We hypothesized that COL4A1 mutations cause CAKUT in humans. We performed whole exome sequencing (WES) in 550 families with CAKUT. As negative control cohorts we used WES sequencing data from patients with nephronophthisis (NPHP) with no genetic cause identified (n = 257) and with nephrotic syndrome (NS) due to monogenic causes (n = 100). We identified a not previously reported heterozygous missense variant in COL4A1 in three siblings with isolated VUR. When examining 549 families with CAKUT, we identified nine additional different heterozygous missense mutations in COL4A1 in 11 individuals from 11 unrelated families with CAKUT, while no COL4A1 mutations were identified in a control cohort with NPHP and only one in the cohort with NS. Most individuals (12/14) had isolated CAKUT with no extrarenal features. The predominant phenotype was VUR (9/14). There were no clinical features of the COL4A1-related disorders (e.g., HANAC syndrome, porencephaly, tortuosity of retinal arteries). Whereas COL4A1-related disorders are typically caused by glycine substitutions in the collagenous domain (84.4% of variants), only one variant in our cohort is a glycine substitution within the collagenous domain (1/10). We identified heterozygous COL4A1 mutations as a potential novel autosomal dominant cause of CAKUT that is allelic to the established COL4A1-related disorders and predominantly caused by non-glycine substitutions.

Alternate JournalHum. Genet.
PubMed ID31230195
PubMed Central IDPMC6745245
Grant ListR01 DK088767 / DK / NIDDK NIH HHS / United States
n/a / / KRESCENT - Kidney Foundation of Canada, the Canadian Society of Nephrology, and the Canadian Institutes of Health Research /
T32-DK007726 / / Research Training in Pediatric Nephrology grant /
S10 OD018521 / OD / NIH HHS / United States
T32-GM007748 / / Research Training in Pediatric Nephrology grant /
HPF-206-674 / / Health Research Board, Ireland /
DK076683 / NH / NIH HHS / United States
F-KP-0003-17-00 / / Harvard Stem Cell Institute Kidney Inter-lab Fellowship Award at Harvard Medical School /
T32 DK007726 / DK / NIDDK NIH HHS / United States
T32 GM007748 / GM / NIGMS NIH HHS / United States
R01 DK076683 / DK / NIDDK NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States