Loss-of-function Mutations in WDR73 Are Responsible for Microcephaly and Steroid-Resistant Nephrotic Syndrome: Galloway-Mowat Syndrome

Am J Hum Genet. 2014 Dec 4;95(6):637-48. doi: 10.1016/j.ajhg.2014.10.011. Epub 2014 Nov 13.

Abstract

Galloway-Mowat syndrome is a rare autosomal-recessive condition characterized by nephrotic syndrome associated with microcephaly and neurological impairment. Through a combination of autozygosity mapping and whole-exome sequencing, we identified WDR73 as a gene in which mutations cause Galloway-Mowat syndrome in two unrelated families. WDR73 encodes a WD40-repeat-containing protein of unknown function. Here, we show that WDR73 was present in the brain and kidney and was located diffusely in the cytoplasm during interphase but relocalized to spindle poles and astral microtubules during mitosis. Fibroblasts from one affected child and WDR73-depleted podocytes displayed abnormal nuclear morphology, low cell viability, and alterations of the microtubule network. These data suggest that WDR73 plays a crucial role in the maintenance of cell architecture and cell survival. Altogether, WDR73 mutations cause Galloway-Mowat syndrome in a particular subset of individuals presenting with late-onset nephrotic syndrome, postnatal microcephaly, severe intellectual disability, and homogenous brain MRI features. WDR73 is another example of a gene involved in a disease affecting both the kidney glomerulus and the CNS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Brain / physiopathology
  • Cell Line
  • Cell Survival
  • Child
  • Child, Preschool
  • Cytosol / metabolism
  • Exome / genetics
  • Hernia, Hiatal / genetics*
  • Hernia, Hiatal / physiopathology
  • Homozygote
  • Humans
  • Intellectual Disability / genetics*
  • Kidney Glomerulus / physiopathology
  • Male
  • Microcephaly / genetics*
  • Microcephaly / physiopathology
  • Microtubules / metabolism
  • Mitosis
  • Models, Molecular
  • Mutation
  • Nephrosis / genetics*
  • Nephrosis / physiopathology
  • Nephrotic Syndrome / genetics*
  • Nephrotic Syndrome / physiopathology
  • Podocytes
  • Protein Transport
  • Proteins / genetics*
  • Proteins / metabolism
  • Spindle Poles / metabolism

Substances

  • Proteins
  • WDR73 protein, human

Supplementary concepts

  • Galloway Mowat syndrome