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

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Novel pathogenic EIF2S3 missense variants causing clinically variable MEHMO syndrome with impaired eIF2γ translational function, and literature review.
Clinical Genetics ( IF 2.9 ) Pub Date : 2020-08-16 , DOI: 10.1111/cge.13831
Urania Kotzaeridou ₁ , Sara K Young-Baird _{2,

3} , Vanessa Suckow ₄ , Alexis G Thornburg ₂ , Matias Wagner _{5,

6,

7} , Inga Harting ₈ , Stine Christ ₁ , Tim Strom ₅ , Thomas E Dever ₂ , Vera M Kalscheuer ₄

Affiliation

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.

中文翻译：

新的致病性 EIF2S3 错义变异导致 eIF2γ 翻译功能受损的临床可变 MEHMO 综合征，以及文献综述。

罕见的致病性EIF2S3错义和末端缺失变异导致 X 连锁智力障碍 (ID) 综合征 MEHMO，或包括胰腺功能障碍和垂体功能减退在内的较温和表型。我们介绍了两名携带新型EIF2S3的无关男性患者致病性错义变异（p.（Thr144Ile）和 p.（Ile159Leu））从而拓宽了有限的遗传谱并强调了 MEHMO 的临床可变表达性。患有 p.(Thr144Ile) 的受影响男性表现出严重的运动迟缓、严重的小头畸形、中度 ID、对治疗有反应的癫痫发作、性功能减退、中心性肥胖、面部特征和糖尿病，而患有 p.(Ile159Leu) 的受影响男性表现出中度 ID、轻度运动迟缓、小头畸形、难治性癫痫发作、中心性肥胖和轻度面部特征。两种变体都位于EIF2S3的高度保守的鸟嘌呤核苷酸结合域编码异源三聚体翻译起始因子 2 (eIF2) 复合物的 eIF2γ 亚基。此外，我们研究了结构模型和酵母中的两种变体。在这些研究中观察到两种突变体的生长速率降低和翻译保真度降低，以及在非 AUG 密码子处的起始增加，有力地支持了变体的致病性。

更新日期：2020-10-21

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