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

• DOI: 10.1007/s00467-015-3067-9
• Publication Date: 2015-03-04T17:41:50Z
• Authors: Rachel Lennon; Helen M. Stuart; Agnieszka Bierzynska; Michael J. Randles; Bronwyn Kerr; Katherine A. Hillman; Gauri Batra; Joanna Campbell; Helen Storey; Frances A. Flinter; Ania Koziell; Gavin I. Welsh; Moin A. Saleem; Nicholas J. A. Webb; Adrian S. Woolf
• Keywords: Alport syndrome; Glomerulosclerosis; Nephrology

Mutations in podocyte and basement membrane genes are associated with a growing spectrum of glomerular disease affecting adults children. Investigation familial cases has helped to build understanding both normal physiology disease. We investigated consanguineous family wide clinical phenotype using clinical, histological, new genetic studies. report striking variability severity nephropathy within an X-linked Alport syndrome (XLAS) family. Four siblings each carried mutant COL4A5 allele, p.(Gly953Val) p.(Gly1033Arg). Two boys had signs limited hematuria mild/moderate proteinuria. In contrast, sister presented end-stage renal (ESRD) at 8 years age infant brother nephrotic syndrome, progressing ESRD by 3 age. Both were subsequently found have homozygous variants MYO1E, p.(Lys118Glu) p.(Thr876Arg). MYO1E is gene implicated focal segmental glomerulosclerosis it encodes podocyte-expressed non-muscle myosin. Bioinformatic modeling demonstrated that the collagen IV-alpha3,4,5 extracellular network connected via known protein–protein interactions intracellular myosin 1E. mutations may summate perturb common signaling pathways, resulting more severe than anticipated independently. suggest screening for other non-COL4 'podocyte gene' XLAS when expected individual's sex.