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EIF2S3 Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO
Martina Skopkova1, Friederike Hennig2, Byung-Sik Shin3
1DIABGENE & Laboratory of Diabetes and Metabolic Disorders, Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
Human Mutation
|January 6, 2017
Summary
Genetic mutations in EIF2S3 cause MEHMO syndrome, a rare X-linked disorder. Impaired translation initiation and integrated stress response (ISR) activation are linked to the syndrome
Area of Science:
- Genetics and Molecular Biology
- Neurodevelopmental Disorders
- Cellular Stress Response
Background:
- MEHMO syndrome is a rare X-linked disorder with unknown genetic causes.
- Impaired translation initiation and integrated stress response (ISR) are implicated in multisystemic disorders.
Purpose of the Study:
- To identify the genetic etiology of MEHMO syndrome.
- To investigate the role of EIF2S3 gene mutations in MEHMO syndrome pathogenesis.
Main Methods:
- Genetic analysis of EIF2S3 in MEHMO syndrome families.
- Functional assays in patient-derived fibroblasts and yeast models.
- Assessment of integrated stress response (ISR) activation.
Main Results:
- Identified C-terminal frameshift mutation (Ile465Serfs) and missense variant (p.Ser108Arg) in EIF2S3.
- Confirmed increased ISR activation in patient fibroblasts with Ile465Serfs mutation.
- Demonstrated impaired eIF2γ function, with frameshift mutation causing greater dysfunction.
Conclusions:
- EIF2S3 mutations are the genetic cause of MEHMO syndrome.
- Mutation severity correlates with clinical phenotype severity.
- Dysregulation of translation initiation and ISR contributes to MEHMO syndrome.
Keywords:
EIF2S3MEHMO syndromeXLIDintegrated stress responsetranslation initiationunfolded-protein responseMore Related Videos
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