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


Colin E., Cong E. H. , Mollet G., Guichet A., Gribouval O., Arrondel C., ...Daha Fazla

AMERICAN JOURNAL OF HUMAN GENETICS, cilt.95, ss.637-648, 2014 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Cilt numarası: 95 Konu: 6
  • Basım Tarihi: 2014
  • Doi Numarası: 10.1016/j.ajhg.2014.10.011
  • Dergi Adı: AMERICAN JOURNAL OF HUMAN GENETICS
  • Sayfa Sayıları: ss.637-648

Özet

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.