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  Novel pathogenic EIF2S3 missense variants causing clinically variable MEHMO syndrome with impaired eIF2γ translational function, and literature review

Kotzaeridou, U., Young-Baird, S. K., Suckow, V., Thornburg, A. G., Wagner, M., Harting, I., et al. (2020). Novel pathogenic EIF2S3 missense variants causing clinically variable MEHMO syndrome with impaired eIF2γ translational function, and literature review. Clinical Genetics: an international journal of genetics in medicine, 98(5), 507-514. doi:10.1111/cge.13831.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0007-817C-C Version Permalink: http://hdl.handle.net/21.11116/0000-0007-AD7F-9
Genre: Journal Article

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 Creators:
Kotzaeridou, Urania , Author
Young-Baird, Sara K. , Author
Suckow, Vanessa1, Author              
Thornburg, Alexis G., Author
Wagner, Matias , Author
Harting, Inga, Author
Christ, Stine, Author
Strom, Tim, Author
Dever, Thomas E. , Author
Kalscheuer, Vera M.1, Author              
Affiliations:
1Chromosome Rearrangements and Disease (Vera Kalscheuer), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385702              

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Free keywords: EIF2S3; MEHMO; X-linked; eIF2gamma; intellectual disability
 Abstract: Rare pathogenic EIF2S3 missense and terminal deletion variants cause the X-linked intellectual disability (ID) syndrome MEHMO, or a milder phenotype including pancreatic dysfunction and hypopituitarism. We present two unrelated male patients who carry novel EIF2S3 pathogenic missense variants (p.(Thr144Ile) and p.(Ile159Leu)) thereby broadening the limited genetic spectrum and underscoring clinically variable expressivity of MEHMO. While the affected male with p.(Thr144Ile) presented with severe motor delay, severe microcephaly, moderate ID, epileptic seizures responsive to treatments, hypogenitalism, central obesity, facial features, and diabetes, the affected male with p.(Ile159Leu) presented with moderate ID, mild motor delay, microcephaly, epileptic seizures resistant to treatment, central obesity, and mild facial features. Both variants are located in the highly conserved guanine nucleotide binding domain of the EIF2S3 encoded eIF2γ subunit of the heterotrimeric translation initiation factor 2 (eIF2) complex. Further, we investigated both variants in a structural model and in yeast. The reduced growth rates and lowered fidelity of translation with increased initiation at non-AUG codons observed for both mutants in these studies strongly support pathogenicity of the variants.

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Language(s): eng - English
 Dates: 2020-08-162020-09-042020-11
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1111/cge.13831.
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Title: Clinical Genetics: an international journal of genetics in medicine
  Other : Clin. Genet.
Source Genre: Journal
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Publ. Info: Copenhagen : Munksgaard
Pages: 8 Volume / Issue: 98 (5) Sequence Number: - Start / End Page: 507 - 514 Identifier: ISSN: 0009-9163
CoNE: https://pure.mpg.de/cone/journals/resource/954925391292