The recurrent de novo c.2011C>T missense variant in MTSS2 causes syndromic intellectual disability.
The recurrent de novo c.2011C>T missense variant in MTSS2 causes syndromic intellectual disability.
复制标题
MTSS2 中反复出现的 c.2011C>T 错义变异会导致综合征性智力障碍。
DOI：
10.1016/j.ajhg.2022.08.011
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发表时间：
2022
影响因子：
9.8
通讯作者：
Kernohan,
中科院分区：
文献类型：
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作者：
Huang,Yan;Lemire,Gabrielle;Briere,LaurenC;Liu,Fang;Wessels,MarjaW;Wang,Xueqi;Osmond,Matthew;Kanca,Oguz;Lu,Shenzhao;High,FrancesA;Walker,MelissaA;Rodan,LanceH;UndiagnosedDiseasesNetwork;Care4RareCanadaConsortium;Kernohan,
MTSS2，也称为MTSS1L，与质膜结合并调节其弯曲。MTSS2在中枢神经系统（CNS）中高度表达，似乎参与活动依赖性突触可塑性。MTSS 2的变异体尚未与OMIM的人类表型相关。本文报道了5例MTSS2（GenBank：NM_138383.2：c.2011C>T [p.Arg671Trp]）基因的异源突变体。个体表现为全面发育迟缓、轻度智力残疾、眼科异常、小头畸形或相对小头畸形，并共有轻度面部畸形。来自两个受影响个体的成纤维细胞的免疫印迹显示，该变体不会显著改变MTSS2水平。我们在果蝇中模拟了该变异体，并表明果蝇转移中的直系亲属转移（mim）在CNS的大多数神经元和胶质细胞亚群中广泛表达。在成年果蝇中，失去mim会导致寿命缩短、运动行为受损和突触传递减少。人类MTSS2参考cDNA的表达挽救了他们的功能丧失（LoF）表型，而c.2011C>T变体的挽救能力与参考相比有所下降，表明它是一个部分LoF等位基因。然而，升高的表达的变体，而不是referenceMTSS2cDNA，导致类似的缺陷所观察到的mimLoF，这表明该变体是有毒的，并可能作为一个显性负等位基因时，在苍蝇中表达。总之，我们的研究结果支持mim对于适当的神经功能是重要的，MTSS2c.2011C>T变异体导致智力残疾的综合征形式。
MTSS2, also known as MTSS1L, binds to plasma membranes and modulates their bending.MTSS2is highly expressed in the central nervous system (CNS) and appears to be involved in activity-dependent synaptic plasticity. Variants inMTSS2have not yet been associated with a human phenotype in OMIM. Here we report five individuals with the same heterozygousde novovariant inMTSS2(GenBank: NM_138383.2: c.2011C>T [p.Arg671Trp]) identified by exome sequencing. The individuals present with global developmental delay, mild intellectual disability, ophthalmological anomalies, microcephaly or relative microcephaly, and shared mild facial dysmorphisms. Immunoblots of fibroblasts from two affected individuals revealed that the variant does not significantly alter MTSS2 levels. We modeled the variant inDrosophilaand showed that the fly orthologmissing-in-metastasis(mim) was widely expressed in most neurons and a subset of glia of the CNS. Loss ofmimled to a reduction in lifespan, impaired locomotor behavior, and reduced synaptic transmission in adult flies. Expression of the humanMTSS2reference cDNA rescued themimloss-of-function (LoF) phenotypes, whereas the c.2011C>T variant had decreased rescue ability compared to the reference, suggesting it is a partial LoF allele. However, elevated expression of the variant, but not the referenceMTSS2cDNA, led to similar defects as observed bymimLoF, suggesting that the variant is toxic and may act as a dominant-negative allele when expressed in flies. In summary, our findings support thatmimis important for appropriate neural function, and that theMTSS2c.2011C>T variant causes a syndromic form of intellectual disability.