The homozygous variant c.797G>A/p.(Cys266Tyr) in PISD is associated with a Spondyloepimetaphyseal dysplasia with large epiphyses and disturbed mitochondrial function
The homozygous variant c.797G>A/p.(Cys266Tyr) in PISD is associated with a Spondyloepimetaphyseal dysplasia with large epiphyses and disturbed mitochondrial function
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DOI：
10.1002/humu.23693
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发表时间：
2019-03-01
期刊：
影响因子：
3.9
通讯作者：
Mortier, Geert
中科院分区：
文献类型：
--
作者：
Girisha, Katta M.;von Elsner, Leonie;Mortier, Geert
脊柱干骺端发育不良（SEMD）是一组以椎体异常和干骺端异常为特征的遗传异质性骨骼疾病。我们调查了两个具有新SEMD类型的家庭，每个家庭有一名先证者。他们表现出轻微的面部畸形，扁平椎体（扁平脊柱），大骨骺，干骺端发育不良和拇外翻作为常见的临床特征。通过三外显子组测序，纯合错义变体c.797G>A/p。PISD中的Cys 266 Tyr在两个受影响的个体中均被发现。基于纯合区域的外显子组数据分析，这两名患者在22号染色体上共享一个纯合区块，包括PISD，表明他们有远亲关系。PISD编码磷脂酰丝氨酸（PS）脱羧酶，其位于线粒体内膜中并催化PS在哺乳动物细胞中脱羧为磷脂酰乙醇胺（PE）。PE在线粒体膜中以高丰度发生。患者来源的成纤维细胞表现出线粒体碎片形态。用MG-132或星形孢菌素处理患者细胞以诱导内源性凋亡途径的活化，显示细胞活力显著降低，半胱天冬酶-3和半胱天冬酶-7活化增加。值得注意的是，乙醇胺（Etn）补充在很大程度上恢复了MG-132应激患者细胞的细胞活力并增强了细胞凋亡。我们的数据表明，双等位基因亚纯型PISD变体p。（Cys 266 Tyr）与一种新的SEMD形式有关，这种形式可以用Etn给药治疗。
Spondyloepimetaphyseal dysplasias (SEMD) are a group of genetically heterogeneous skeletal disorders characterized by abnormal vertebral bodies and epimetaphyseal abnormalities. We investigated two families with a new SEMD type with one proband each. They showed mild facial dysmorphism, flat vertebral bodies (platyspondyly), large epiphyses, metaphyseal dysplasia, and hallux valgus as common clinical features. By trio-exome sequencing, the homozygous missense variant c.797G>A/p.(Cys266Tyr) in PISD was found in both affected individuals. Based on exome data analyses for homozygous regions, the two patients shared a single homozygous block on chromosome 22 including PISD, indicating their remote consanguinity. PISD encodes phosphatidylserine (PS) decarboxylase that is localized in the inner mitochondrial membrane and catalyzes the decarboxylation of PS to phosphatidylethanolamine (PE) in mammalian cells. PE occurs at high abundance in mitochondrial membranes. Patient-derived fibroblasts showed fragmented mitochondrial morphology. Treatment of patient cells with MG-132 or staurosporine to induce activation of the intrinsic apoptosis pathway revealed significantly decreased cell viability with increased caspase-3 and caspase-7 activation. Remarkably, ethanolamine (Etn) supplementation largely restored cell viability and enhanced apoptosis in MG-132-stressed patient cells. Our data demonstrate that the biallelic hypomorphic PISD variant p.(Cys266Tyr) is associated with a novel SEMD form, which may be treatable with Etn administration.