Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly

Nat Genet. 2017 Oct;49(10):1529-1538. doi: 10.1038/ng.3933. Epub 2017 Aug 14.

Abstract

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • CRISPR-Cas Systems
  • Carrier Proteins / genetics
  • Cell Movement
  • Cytoskeleton / ultrastructure
  • DNA Repair / genetics
  • Endoplasmic Reticulum Stress / genetics
  • Gene Knockout Techniques
  • Hernia, Hiatal / genetics*
  • Humans
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics
  • Metalloendopeptidases / deficiency
  • Metalloendopeptidases / genetics
  • Mice
  • Microcephaly / genetics*
  • Models, Molecular
  • Multiprotein Complexes / genetics*
  • Mutation*
  • Nephrosis / genetics*
  • Nephrotic Syndrome / genetics
  • Nephrotic Syndrome / pathology
  • Podocytes / metabolism
  • Podocytes / ultrastructure
  • Protein Conformation
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • RNA Processing, Post-Transcriptional / genetics
  • RNA, Transfer / metabolism
  • Telomere Homeostasis / genetics
  • Zebrafish
  • Zebrafish Proteins / deficiency
  • Zebrafish Proteins / genetics

Substances

  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • LAGE3 protein, human
  • Multiprotein Complexes
  • TPRKB protein, human
  • Zebrafish Proteins
  • RNA, Transfer
  • Protein-Serine-Threonine Kinases
  • TP53RK protein, human
  • Metalloendopeptidases
  • O-sialoglycoprotein endopeptidase

Supplementary concepts

  • Galloway Mowat syndrome