PUBLICATION
Pathogenic variants in the SMN complex gene GEMIN5 cause cerebellar atrophy
- Authors
- Saida, K., Tamaoki, J., Sasaki, M., Haniffa, M., Koshimizu, E., Sengoku, T., Maeda, H., Kikuchi, M., Yokoyama, H., Sakamoto, M., Iwama, K., Sekiguchi, F., Hamanaka, K., Fujita, A., Mizuguchi, T., Ogata, K., Miyake, N., Miyatake, S., Kobayashi, M., Matsumoto, N.
- ID
- ZDB-PUB-210928-14
- Date
- 2021
- Source
- Clinical genetics 100(6): 722-730 (Journal)
- Registered Authors
- Kobayashi, Makoto, Tamaoki, Junya
- Keywords
- GEMIN5, SMN, cerebellar atrophy, cerebellar hypoplasia, zebrafish
- 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
- PubMed
- 34569062 Full text @ Clin. Genet.
Citation
Saida, K., Tamaoki, J., Sasaki, M., Haniffa, M., Koshimizu, E., Sengoku, T., Maeda, H., Kikuchi, M., Yokoyama, H., Sakamoto, M., Iwama, K., Sekiguchi, F., Hamanaka, K., Fujita, A., Mizuguchi, T., Ogata, K., Miyake, N., Miyatake, S., Kobayashi, M., Matsumoto, N. (2021) Pathogenic variants in the SMN complex gene GEMIN5 cause cerebellar atrophy. Clinical genetics. 100(6):722-730.
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. 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 individuals showed significantly reduced levels of GEMIN5 protein. Zebrafish model for 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 model strongly suggest that biallelic loss-of-function variants in GEMIN5 cause cerebellar atrophy.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping