Skip to content

Coinheritance of COL4A5 and MYO1E mutations accentuate the severity of kidney disease

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)1459-65
Number of pages7
JournalPediatric Nephrology
Volume30
Issue number9
DOIs
DatePublished - Sep 2015

Abstract

BACKGROUND: Mutations in podocyte and basement membrane genes are associated with a growing spectrum of glomerular disease affecting adults and children. Investigation of familial cases has helped to build understanding of both normal physiology and disease.

METHODS: We investigated a consanguineous family with a wide clinical phenotype of glomerular disease using clinical, histological, and new genetic studies.

RESULTS: We report striking variability in severity of nephropathy within an X-linked Alport syndrome (XLAS) family. Four siblings each carried a mutant COL4A5 allele, p.(Gly953Val) and p.(Gly1033Arg). Two boys had signs limited to hematuria and mild/moderate proteinuria. In striking contrast, a sister presented with end-stage renal disease (ESRD) at 8 years of age and an infant brother presented with nephrotic syndrome, progressing to ESRD by 3 years of age. Both were subsequently found to have homozygous variants in MYO1E, p.(Lys118Glu) and p.(Thr876Arg). MYO1E is a gene implicated in focal segmental glomerulosclerosis and it encodes a podocyte-expressed non-muscle myosin. Bioinformatic modeling demonstrated that the collagen IV-alpha3,4,5 extracellular network connected via known protein-protein interactions to intracellular myosin 1E.

CONCLUSIONS: COL4A5 and MYO1E mutations may summate to perturb common signaling pathways, resulting in more severe disease than anticipated independently. We suggest screening for MYO1E and other non-COL4 'podocyte gene' mutations in XLAS when clinical nephropathy is more severe than expected for an individual's age and sex.

Documents

View research connections

Related faculties, schools or groups