Homozygous splicing mutation in NUP133 causes Galloway-Mowat syndrome

Ann Neurol. 2018 Dec;84(6):814-828. doi: 10.1002/ana.25370.

Abstract

Objective: Galloway-Mowat syndrome (GAMOS) is a neural and renal disorder, characterized by microcephaly, brain anomalies, and early onset nephrotic syndrome. Biallelic mutations in WDR73 and the 4 subunit genes of the KEOPS complex are reported to cause GAMOS. Furthermore, an identical homozygous NUP107 (nucleoporin 107kDa) mutation was identified in 4 GAMOS-like families, although biallelic NUP107 mutations were originally identified in steroid-resistant nephrotic syndrome. NUP107 and NUP133 (nucleoporin 133kDa) are interacting subunits of the nuclear pore complex in the nuclear envelope during interphase, and these proteins are also involved in centrosome positioning and spindle assembly during mitosis.

Methods: Linkage analysis and whole exome sequencing were performed in a previously reported GAMOS family with brain atrophy and steroid-resistant nephrotic syndrome.

Results: We identified a homozygous NUP133 mutation, c.3335-11T>A, which results in the insertion of 9bp of intronic sequence between exons 25 and 26 in the mutant transcript. NUP133 and NUP107 interaction was impaired by the NUP133 mutation based on an immunoprecipitation assay. Importantly, focal cortical dysplasia type IIa was recognized in the brain of an autopsied patient and focal segmental glomerulosclerosis was confirmed in the kidneys of the 3 examined patients. A nup133-knockdown zebrafish model exhibited microcephaly, fewer neuronal cells, underdeveloped glomeruli, and fusion of the foot processes of the podocytes, which mimicked human GAMOS features. nup133 morphants could be rescued by human wild-type NUP133 mRNA but not by mutant mRNA.

Interpretation: These data indicate that the biallelic NUP133 loss-of-function mutation causes GAMOS. Ann Neurol 2018;84:814-828.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / growth & development
  • Brain / metabolism
  • Brain / pathology
  • Child, Preschool
  • Family Health
  • Female
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Genetic Predisposition to Disease / genetics*
  • Hernia, Hiatal / diagnostic imaging
  • Hernia, Hiatal / genetics*
  • Hernia, Hiatal / pathology
  • Humans
  • Infant
  • Japan
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney / ultrastructure
  • Lymphocytes / metabolism
  • Lymphocytes / ultrastructure
  • Male
  • Microcephaly / diagnostic imaging
  • Microcephaly / genetics*
  • Microcephaly / pathology
  • Microtubule-Associated Proteins / metabolism
  • Minor Histocompatibility Antigens / genetics*
  • Minor Histocompatibility Antigens / ultrastructure
  • Morpholinos / administration & dosage
  • Mutagenesis, Site-Directed
  • Mutation / genetics*
  • Nephrosis / diagnostic imaging
  • Nephrosis / genetics*
  • Nephrosis / pathology
  • Nuclear Pore Complex Proteins / genetics*
  • Nuclear Pore Complex Proteins / ultrastructure
  • Phosphopyruvate Hydratase / metabolism
  • Young Adult
  • Zebrafish

Substances

  • MAP2 protein, human
  • Microtubule-Associated Proteins
  • Minor Histocompatibility Antigens
  • Morpholinos
  • NUP133 protein, human
  • Nuclear Pore Complex Proteins
  • Phosphopyruvate Hydratase

Supplementary concepts

  • Galloway Mowat syndrome