Truncating Mutations of MAGEL2, a Gene within the Prader-Willi Locus, Are Responsible for Severe Arthrogryposis
Truncating Mutations of MAGEL2, a Gene within the Prader-Willi Locus, Are Responsible for Severe Arthrogryposis
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DOI：
10.1016/j.ajhg.2015.08.010
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发表时间：
2015-10-01
影响因子：
9.8
通讯作者：
Melki, Judith
中科院分区：
文献类型：
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作者：
Mejlachowicz, Dan;Nolent, Flora;Melki, Judith
先天性多发性关节退行性变(AMC)的特征是由于胎儿运动减少或缺失而导致的多发性关节痉挛。在这里，我们报告了两个受到致命性AMC影响的无关家庭。通过遗传作图和全外显子测序，在先证者中发现了一个MAGEL2杂合性截短突变，导致移码和提前终止密码子(c.1996delC，p.Gln666Serff*36)，并从父亲那里遗传。在另一个家系中，在患病个体中发现了导致MAGEL2等位基因移码(c.2118delT，p.Leu708Trpfs*7)和从头发生的截断杂合性突变。在这两个家族中，RNA分析仅在受影响的个体中发现了突变的父系MAGEL2转录本。MAGEL2是Prader-Willi综合征(PWS)基因座中父系表达的基因之一。PWS在不同程度上与胎儿活动能力降低、严重的婴儿低眼压、儿童期肥胖、性腺功能减退和智力障碍有关。最近有报道称，MAGEL2突变存在于具有类似PWS特征的患者中，称为Schaaf-Yang综合征。在这里，我们表明，父亲的MAGEL2突变也是致死性AMC的原因，总结了PWS的临床谱，并暗示MAGEL2是PWS的决定基因。
Arthrogryposis multiplex congenita (AMC) is characterized by the presence of multiple joint contractures resulting from reduced or absent fetal movement. Here, we report two unrelated families affected by lethal AMC. By genetic mapping and whole-exome sequencing in a multiplex family, a heterozygous truncating MAGEL2 mutation leading to frameshift and a premature stop codon (c.1996delC, p.Gln666Serfs*36) and inherited from the father was identified in the probands. In another family, a distinct heterozygous truncating mutation leading to frameshift (c.2118delT, p.Leu708Trpfs*7) and occurring de novo on the paternal allele of MAGEL2 was identified in the affected individual. In both families, RNA analysis identified the mutated paternal MAGEL2 transcripts only in affected individuals. MAGEL2 is one of the paternally expressed genes within the Prader-Willi syndrome (PWS) locus. PWS is associated with, to varying extents, reduced fetal mobility, severe infantile hypotonia, childhood-onset obesity, hypogonadism, and intellectual disability. MAGEL2 mutations have been recently reported in affected individuals with features resembling PWS and called Schaaf-Yang syndrome. Here, we show that paternal MAGEL2 mutations are also responsible for lethal AMC, recapitulating the clinical spectrum of PWS and suggesting that MAGEL2 is a PWS-determining gene.