Pathogenic variants in the survival of motor neurons complex gene GEMIN5 cause cerebellar atrophy.
Animals
Brain
/ abnormalities
Cerebellar Ataxia
/ diagnosis
Disease Models, Animal
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
Structure-Activity Relationship
Exome Sequencing
Zebrafish
GEMIN5
SMN
cerebellar atrophy
cerebellar hypoplasia
zebrafish
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
revised:
05
09
2021
received:
07
06
2021
accepted:
24
09
2021
pubmed:
28
9
2021
medline:
19
2
2022
entrez:
27
9
2021
Statut:
ppublish
Résumé
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.
Substances chimiques
GEMIN5 protein, human
0
SMN Complex Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
722-730Subventions
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP21ek0109486
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP21ek0109549
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP21ek0109493
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP20ek0109484s0201
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP19H03621
Organisme : JSPS KAKENHI
ID : JP20K07907
Informations de copyright
© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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