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

Pediatr Nephrol. 2015 Sep;30(9):1459-65. doi: 10.1007/s00467-015-3067-9. Epub 2015 Mar 5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Child
  • Child, Preschool
  • Collagen Type IV / genetics*
  • Female
  • Humans
  • Infant
  • Inheritance Patterns / genetics
  • Kidney Glomerulus / pathology*
  • Male
  • Mutation
  • Myosin Type I / genetics*
  • Nephritis, Hereditary* / diagnosis
  • Nephritis, Hereditary* / genetics
  • Nephritis, Hereditary* / physiopathology
  • Pedigree
  • Severity of Illness Index
  • Siblings

Substances

  • COL4A5 protein, human
  • Collagen Type IV
  • MYO1E protein, human
  • Myosin Type I