Recessive MYF5 Mutations Cause External Ophthalmoplegia, Rib, and Vertebral Anomalies
Recessive MYF5 Mutations Cause External Ophthalmoplegia, Rib, and Vertebral Anomalies
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DOI：
10.1016/j.ajhg.2018.05.003
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发表时间：
2018-07-05
影响因子：
9.8
通讯作者：
Engle, Elizabeth C.
中科院分区：
文献类型：
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作者：
Di Gioia, Silvio Alessandro;Shaaban, Sherin;Engle, Elizabeth C.
MYF5 是 Myc 样碱性螺旋-环-螺旋转录因子家族的成员，与其他肌生成调节因子 MYOD 和 MYF5 合作，是肌生成早期的关键调节因子。在这里，我们报告了三个具有 MYF5 双等位基因纯合功能丧失突变的近亲家族，他们定义了一种临床疾病，其特征是先天性眼肌麻痹伴脊柱侧凸以及椎骨和肋骨异常。临床表型与几种 Myf5 敲除小鼠模型中报道的临床表型惊人地重叠。两个家族的受影响成员共享一个半相合区域，该区域在 MYF5 的外显子 1 (c.23_32delAGTTCTCACC [p.GIn8Leufs*86]) 中包含纯合 10 移码突变，预计会经历无义介导的衰变。第三个家族的受影响成员在 MYF5 的外显子 1 中存在纯合错义变化 (c.283C>T [p.Arg95Cys])。使用体外测定，我们表明这种错义突变通过损害 MYF5 DNA 结合和核定位而充当功能丧失等位基因。我们对一名患有移码突变的受影响个体进行了全基因组测序，并且没有在半相合区域中发现其他罕见的变异，这些变异可能是家庭之间严重程度差异的原因。这些数据支持 MYF5 在人类肋骨、脊柱和眼外肌形成中的直接作用。
MYF5 is member of the Myc-like basic helix-loop-helix transcription factor family and, in cooperation with other myogenic regulatory factors MYOD and MYF5, is a key regulator of early stages of myogenesis. Here, we report three consanguineous families with biallelic homozygous loss-of-function mutations in MYF5 who define a clinical disorder characterized by congenital ophthalmoplegia with scoliosis and vertebral and rib anomalies. The clinical phenotype overlaps strikingly with that reported in several Myf5 knockout mouse models. Affected members of two families share a haploidentical region that contains a homozygous 10 by frameshift mutation in exon 1 of MYF5 (c.23_32delAGTTCTCACC [p.GIn8Leufs*86]) predicted to undergo nonsense-mediated decay. Affected members of the third family harbor a homozygous missense change in exon 1 of MYF5 (c.283C>T [p.Arg95Cys]). Using in vitro assays, we show that this missense mutation acts as a loss-of-function allele by impairing MYF5 DNA binding and nuclear localization. We performed whole-genome sequencing in one affected individual with the frameshift mutation and did not identify additional rare variants in the haploidentical region that might account for differences in severity among the families. These data support the direct role of MYF5 in rib, spine, and extraocular muscle formation in humans.