Smith Amanda C, Mears Alan J, Bunker Ryan, Ahmed Afsana, MacKenzie Malcolm, Schwartzentruber Jeremy A, Beaulieu Chandree L, Ferretti Emanuela, Majewski Jacek, Bulman Dennis E, Celik Fatma Cakmak, Boycott Kym M, Graham Gail E
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
McGill University and Genome Quebec Innovation Centre, Montréal, Quebec, Canada.
J Med Genet. 2014 Jul;51(7):470-4. doi: 10.1136/jmedgenet-2013-102218. Epub 2014 Apr 4.
Sedaghatian-type spondylometaphyseal dysplasia (SSMD) is a neonatal lethal form of spondylometaphyseal dysplasia characterised by severe metaphyseal chondrodysplasia with mild limb shortening, platyspondyly, cardiac conduction defects, and central nervous system abnormalities. As part of the FORGE Canada Consortium we studied two unrelated families to identify the genetic aetiology of this rare disease.
Whole exome sequencing of a child affected with SSMD and her unaffected parents identified two rare variants in GPX4. The first (c.587+5G>A) was inherited from the mother, and the second (c.588-8_588-4del) was de novo (NM_001039848.1); both were predicted to impact splicing of GPX4. In vitro studies confirmed the mutations spliced out part of exon 4 and skipped exon 5, respectively, with both resulting in a frameshift and premature truncation of GPX4. Subsequently, a second child with SSMD was identified; although DNA from the child was not available, the two unaffected parents were found by Sanger sequencing to each carry the same heterozygous stop mutation in exon 3 of GPX4, c.381C>A, p.Tyr127* (NM_001039848.1).
Our identification of truncating mutations in GPX4 in two families affected with SSMD supports the pathogenic role of mutated GPX4 in this very rare disease. GPX4 is a member of the glutathione peroxidase family of antioxidant defence enzymes and protects cells against membrane lipid peroxidation. GPX4 is essential for early embryo development, regulating anti-oxidative and anti-apoptotic activities. Our findings highlight the importance of this enzyme in development of the cardiac, nervous, and skeletal systems.
塞达加蒂安型脊椎干骺端发育不良（SSMD）是脊椎干骺端发育不良的一种新生儿致死形式，其特征为严重的干骺端软骨发育不良，伴有轻度肢体缩短、椎体扁平、心脏传导缺陷和中枢神经系统异常。作为加拿大罕见病基因组探索联盟（FORGE Canada Consortium）的一部分，我们研究了两个无血缘关系的家族，以确定这种罕见疾病的遗传病因。
对一名患有SSMD的患儿及其未患病的父母进行全外显子组测序，在GPX4基因中发现了两个罕见变异。第一个变异（c.587+5G>A）遗传自母亲，第二个变异（c.588-8_588-4del）为新发突变（NM_001039848.1）；两者均被预测会影响GPX4的剪接。体外研究证实，这两个突变分别导致外显子4的部分序列被剪接掉和外显子5跳跃，均导致GPX4移码和过早截断。随后，又鉴定出一名患有SSMD的患儿；虽然无法获取该患儿的DNA，但通过桑格测序发现其两名未患病的父母在GPX4基因外显子3中均携带相同的杂合性终止突变，即c.381C>A，p.Tyr127*（NM_001039848.1）。
我们在两个患有SSMD的家族中鉴定出GPX4基因的截断突变，支持了突变的GPX4在这种极为罕见的疾病中的致病作用。GPX4是抗氧化防御酶谷胱甘肽过氧化物酶家族的成员，可保护细胞免受膜脂质过氧化的影响。GPX4对早期胚胎发育至关重要，可调节抗氧化和抗凋亡活性。我们的研究结果凸显了这种酶在心脏、神经和骨骼系统发育中的重要性。
