Pathogenic variants in the survival of motor neurons complex gene GEMIN5 cause cerebellar atrophy.
Clin Genet
; 100(6): 722-730, 2021 12.
Article
in En
| MEDLINE
| ID: mdl-34569062
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phenotype
/
Cerebellar Ataxia
/
Genetic Predisposition to Disease
/
SMN Complex Proteins
/
Genetic Association Studies
/
Mutation
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Clin Genet
Year:
2021
Document type:
Article
Affiliation country: