Pathogenic variants in the survival of motor neurons complex gene GEMIN5 cause cerebellar atrophy

Clin Genet. 2021 Dec;100(6):722-730. doi: 10.1111/cge.14066. Epub 2021 Oct 7.

Abstract

Cerebellar ataxia is a genetically heterogeneous disorder. GEMIN5 encoding an RNA-binding protein of the survival of motor neuron complex, is essential for small nuclear ribonucleoprotein biogenesis, and it was recently reported that biallelic loss-of-function variants cause neurodevelopmental delay, hypotonia, and cerebellar ataxia. Here, whole-exome analysis revealed compound heterozygous GEMIN5 variants in two individuals from our cohort of 162 patients with cerebellar atrophy/hypoplasia. Three novel truncating variants and one previously reported missense variant were identified: c.2196dupA, p.(Arg733Thrfs*6) and c.1831G > A, p.(Val611Met) in individual 1, and c.3913delG, p.(Ala1305Leufs*14) and c.4496dupA, p.(Tyr1499*) in individual 2. Western blotting analysis using lymphoblastoid cell lines derived from both affected individuals showed significantly reduced levels of GEMIN5 protein. Zebrafish model for null variants p.(Arg733Thrfs*6) and p.(Ala1305Leufs*14) exhibited complete lethality at 2 weeks and recapitulated a distinct dysplastic phenotype. The phenotypes of affected individuals and the zebrafish mutant models strongly suggest that biallelic loss-of-function variants in GEMIN5 cause cerebellar atrophy/hypoplasia.

Keywords: GEMIN5; SMN; cerebellar atrophy; cerebellar hypoplasia; zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / abnormalities
  • Brain / diagnostic imaging
  • Cerebellar Ataxia / diagnosis*
  • Cerebellar Ataxia / genetics*
  • Disease Models, Animal
  • Exome Sequencing
  • Facies
  • Genetic Association Studies* / methods
  • Genetic Predisposition to Disease*
  • Humans
  • Loss of Function Mutation
  • Magnetic Resonance Imaging
  • Models, Molecular
  • Motor Neurons / metabolism
  • Mutation*
  • Nonsense Mediated mRNA Decay
  • Pedigree
  • Phenotype*
  • Protein Conformation
  • SMN Complex Proteins / chemistry
  • SMN Complex Proteins / genetics*
  • Structure-Activity Relationship
  • Zebrafish

Substances

  • GEMIN5 protein, human
  • SMN Complex Proteins