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

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• 作者：Rachel Lennon ; Helen M. Stuart ; Agnieszka Bierzynska…
• 关键词：Alport syndrome ; Genetics ; COL4A5 ; MYO1E ; Nephrotic syndrome ; Whole exome sequencing
• 刊名：Pediatric Nephrology
• 出版年：2015
• 出版时间：September 2015
• 年：2015
• 卷：30
• 期：9
• 页码：1459-1465
• 全文大小：796 KB
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• 作者单位：Rachel Lennon (1) (2) (3)
  Helen M. Stuart (4)
  Agnieszka Bierzynska (5)
  Michael J. Randles (1) (2)
  Bronwyn Kerr (4)
  Katherine A. Hillman (6)
  Gauri Batra (7)
  Joanna Campbell (8)
  Helen Storey (8)
  Frances A. Flinter (9)
  Ania Koziell (10)
  Gavin I. Welsh (5)
  Moin A. Saleem (5)
  Nicholas J. A. Webb (3)
  Adrian S. Woolf (2) (3)
  
  1. Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Michael Smith Building, M13 9PT, Manchester, UK
  2. Institute of Human Development, Faculty of Human Sciences, University of Manchester, Manchester, UK
  3. Department of Paediatric Nephrology, Central Manchester University Hospitals NHS Foundation Trust (CMFT), Manchester Academic Health Science Centre (MAHSC), Manchester, UK
  4. Manchester Centre for Genomic Medicine, Manchester, UK
  5. Academic Renal Unit, University of Bristol, Bristol, UK
  6. Manchester Institute of Nephrology and Transplantation, CMFT, Manchester, UK
  7. Department of Paediatric Histopathology, CMFT, Manchester, UK
  8. Molecular Genetics, Viapath, Guy’s Hospital, London, UK
  9. Clinical Genetics Department, Guy’s and St Thomas-NHS Foundation Trust, London, UK
  10. Guy’s and St Thomas-NHS Foundation Trust and King’s College London, London, UK
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Pediatrics
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-198X

文摘

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.