EIF2S3 – MEHMO Syndrome

MEHMO syndrome is a rare X-linked intellectual disability disorder characterized by mental retardation, epilepsy, hypogenitalism, microcephaly, and obesity. Pathogenic variants in the gene encoding the γ subunit of eukaryotic initiation factor 2, EIF2S3, underlie this condition ([PMID:28055140]). Affected hemizygous males present in infancy with profound cognitive impairment, intractable seizures, micropenis or microgenitalism, progressive microcephaly, and early-onset obesity. Inheritance is X-linked recessive, supported by maternal transmission and absence of disease in heterozygous females. The core pathogenic mechanism involves impaired eIF2 complex assembly, translational initiation defects, and dysregulation of the integrated stress response.

Genetic evidence includes pathogenic EIF2S3 variants in eight unrelated male probands: three families harboring recurrent C-terminal frameshift mutations ([PMID:28055140], [PMID:29303605], [PMID:35765291]); two cousins with a novel missense c.820C>G (p.Leu274Val) ([PMID:34999262]); and single-patient missense p.Ser108Arg cases ([PMID:28055140]). Segregation analyses confirm maternal carrier status in multiple pedigrees. The variant spectrum comprises at least two frameshift and four distinct missense changes affecting critical domains of eIF2γ. No common founder allele beyond the recurrent frameshift has been established.

Functional studies demonstrate that EIF2S3 mutations disrupt eIF2 complex integrity and translational initiation. A missense p.Ile222Thr impairs eIF2β binding and start codon selection ([PMID:23063529]). The I259M substitution reduces Met-tRNAiMet binding in yeast and human cells, derepresses ATF4 translation, and is rescued by tRNA overexpression ([PMID:30517694]). Patient-derived iPS cells with C-terminal truncations exhibit reduced ternary-complex formation and increased stress-induced cell death, which is rescued by the small molecule ISRIB ([PMID:31836389]). Zebrafish CRISPR knockouts for novel missense variants recapitulate human microcephaly and reveal pancreatic endocrine defects ([PMID:33942450]). These concordant in vitro and in vivo assays support a loss-of-function mechanism.

The clinical spectrum extends beyond neurologic features to endocrinologic and immunologic involvement. Two probands with C-terminal frameshifts developed neonatal hypoglycemia, early-onset insulin-dependent diabetes, and hypopituitarism ([PMID:29303605]). Immunologic evaluation of a patient on immunoglobulin therapy showed a 54.5% reduction in infection frequency despite normal IgG/IgM levels ([PMID:32901502]), indicating secondary immune impairment. Additional reports describe hypertrichosis and glucose dysregulation, underscoring multisystem involvement.

A milder phenotype has been observed with the p.Pro432Ser variant in three related males presenting X-linked hypopituitarism, normal head circumference, and mild learning difficulties ([PMID:30878599]). This variant segregated with disease in a single kindred and impaired eIF2γ function in pancreatic cell and yeast assays. These findings expand the phenotypic spectrum beyond classical MEHMO, suggesting variant-specific hypomorphic effects.

Collectively, the genetic, segregation, and functional data robustly support a Strong clinical validity for EIF2S3 in MEHMO syndrome, with eight affected male probands, segregation in carrier females, and concordant mechanistic studies. Pathogenic variants act via loss of eIF2γ function causing translational initiation and stress-response dysregulation. Diagnostic sequencing of EIF2S3 is indicated in males with intellectual disability, epilepsy, microcephaly, hypogenitalism, and obesity. Functional assays, endocrine evaluation, and immunologic testing aid variant interpretation and management, and emerging therapies such as ISRIB and immunoglobulin replacement offer targeted intervention. Key Take-home: EIF2S3 loss-of-function causes X-linked MEHMO syndrome through impaired translational initiation and warrants gene-specific diagnostic and therapeutic strategies.

References

• Human Mutation • 2017 • EIF2S3 Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO PMID:28055140
• Physiological research • 2020 • Immunologic phenotype of a child with the MEHMO syndrome. PMID:32901502
• European journal of medical genetics • 2022 • mRNA analysis revealed a novel pathogenic EIF2S3 variant causing MEHMO syndrome. PMID:34999262
• Clinical case reports • 2022 • Expanding the phenotype of the recurrent truncating eIF2γ pathogenic variant p.(Ile465Serfs*4) identified in two brothers with MEHMO syndrome PMID:35765291
• Physiological research • 2018 • Neonatal hypoglycemia, early-onset diabetes and hypopituitarism due to the mutation in EIF2S3 gene causing MEHMO syndrome. PMID:29303605
• Molecular cell • 2012 • eIF2γ mutation that disrupts eIF2 complex integrity links intellectual disability to impaired translation initiation PMID:23063529
• Nucleic acids research • 2019 • MEHMO syndrome mutation EIF2S3-I259M impairs initiator Met-tRNAiMet binding to eukaryotic translation initiation factor eIF2. PMID:30517694
• Molecular cell • 2020 • Suppression of MEHMO Syndrome Mutation in eIF2 by Small Molecule ISRIB. PMID:31836389
• Human mutation • 2021 • Broadening the phenotypic spectrum and physiological insights related to EIF2S3 variants. PMID:33942450
• EBioMedicine • 2019 • Impaired EIF2S3 function associated with a novel phenotype of X-linked hypopituitarism with glucose dysregulation. PMID:30878599

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