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

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.

Fig. 1

Family pedigree. Black filled symbols represent individuals affected by end-stage renal disease (ESRD) and black filled symbols with a line through are those individuals who had ESRD as a cause of death. Hatched symbols represent individuals with hematuria and or proteinuria. Genotypes for COL4A5 are indicated above the symbols (blue) and for MYO1E the genotype is indicated below (red). Each filled semicircle represents a mutant allele. † indicates age of death

Fig. 2

Native renal biopsies (a–d). Transmission electron micrograph images from IV.3 (a, b) and IV.5 (c, d), with higher magnification images in the bottom row (b, d). In IV.3, the GBM was thin, with a diameter as low as 92 nm. There were also focal areas of lamination (black arrow in a). In IV.5, glomerular basement membranes extra cellular matrix (GBMs) were irregular, with thick and thin portions, with lamination (black arrow in c). There was extensive podocyte foot process fusion and a generalized increase in the mesangium

Fig. 3

Protein–protein interaction network for collagen IV and myosin 1E. This interaction network was created from a database of known protein–protein interactions. The direct (1-hop) interactors for collagen IV-α3,4,5 and myosin 1E were identified and arranged within the network. The circles (nodes) represent proteins within the interaction network. The lines (edges) represent known interactions. The size of the node represents the degree of connections and the color of the node represents the number of interactions. The network comprises 43 nodes and 151 edges. Network analysis was performed using Cytoscape (version 2.8.1) [12]. Collagen IV alpha-3,4,5 and myosin 1E were mapped onto a merged human interactome built from the Protein Interaction Network Analysis platform Homo sapiens network (release date, 28 June 2011) and Mus musculus network (release date, 28 June 2011) [13], the ECM interactions database MatrixDB (release date, 26 August 2010) [14] and a literature-curated database of integrin-based adhesion-associated proteins [15]. Topological parameters were computed using the NetworkAnalyzer plug-in [16]