Coinheritance of COL4A5 and MYO1E mutations accentuate the severity of kidney disease.
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.
Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Michael Smith Building, M13 9PT, Manchester, UK, rachel.lennon@manchester.ac.uk.
Rachel
R
Lennon
Helen M
HM
Stuart
Agnieszka
A
Bierzynska
Michael J
MJ
Randles
Bronwyn
B
Kerr
Katherine A
KA
Hillman
Gauri
G
Batra
Joanna
J
Campbell
Helen
H
Storey
Frances A
FA
Flinter
Ania
A
Koziell
Gavin I
GI
Welsh
Moin A
MA
Saleem
Nicholas J A
NJ
Webb
Adrian S
AS
Woolf
D000328:Adult; D002648:Child; D002675:Child, Preschool; D024141:Collagen Type IV / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D040582:Inheritance Patterns / Q000235:genetics; D007678:Kidney Glomerulus / Q000473:pathology*; D008297:Male; D009154:Mutation; D024461:Myosin Type I / Q000235:genetics*; D009394:Nephritis, Hereditary / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D010375:Pedigree; D012720:Severity of Illness Index; D035781:Siblings
C478159:COL4A5 protein, human; D024141:Collagen Type IV; C511011:MYO1E protein, human; D024461:Myosin Type I