Abstract
BackgroundMutations 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.MethodsWe investigated a consanguineous family with a wide clinical phenotype of glomerular disease using clinical, histological, and new genetic studies.ResultsWe 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.
Highlights
In 1927, Cecil Alport described an inherited nephropathy [1] with the teenage male proband having Ban attack of influenza followed by a large increase of blood and albumin in the urine^
MYO1E is a gene implicated in focal segmental glomerulosclerosis and it encodes a podocyte-expressed non-muscle myosin
We suggest screening for MYO1E and other non-COL4 ‘podocyte gene’ mutations in X-linked Alport syndrome (XLAS) when clinical nephropathy is more severe than expected for an individual’s age and sex
Summary
In 1927, Cecil Alport described an inherited nephropathy [1] with the teenage male proband having Ban attack of influenza followed by a large increase of blood and albumin in the urine^. The disease was called X-linked Alport syndrome (XLAS). Affected individuals have glomerular basement membrane (GBM) ultrastructural defects. Mutations of COL4A5 encoding the alpha-5 chain of collagen IV, a GBM component, cause XLAS [3]. A minority of AS individuals have mutations of autosomal genes encoding collagen IV alpha-3 or alpha-4 chains [4], which form heterotrimers with alpha-5. The generally less aggressive course of XLAS nephropathy in women is explained by the fact that they carry both a normal and mutant COL4A5 allele versus males who have only the mutated allele [5]. 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
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