Bi-allelic CCDC47 Variants Cause a Disorder Characterized by Woolly Hair, Liver Dysfunction, Dysmorphic Features, and Global Developmental Delay
Bi-allelic CCDC47 Variants Cause a Disorder Characterized by Woolly Hair, Liver Dysfunction, Dysmorphic Features, and Global Developmental Delay
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DOI：
10.1016/j.ajhg.2018.09.014
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发表时间：
2018-11-01
影响因子：
9.8
通讯作者：
Malicdan, May Christine V.
中科院分区：
文献类型：
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作者：
Morimoto, Marie;Waller-Evans, Helen;Malicdan, May Christine V.
Ca2+信号对各种细胞过程至关重要，包括突触囊泡胞吐、肌肉收缩、分泌调节、基因转录和细胞增殖。内质网（ER）是细胞内最大的Ca2+储存，内质网Ca2+信号和稳态的失调有助于各种复杂疾病和孟德尔病特征的发病机制。我们描述了四个不相关的个体与复杂的多系统疾病的特点是毛茸茸的头发，肝功能障碍，瘙痒，畸形特征，张力低下，和整体发育迟缓。通过全外显子组测序和基于家族的基因组学，我们在CCDC47中发现了编码Ca2+结合ER跨膜蛋白CCDC47的双等位基因变异。CCDC47，也被称为钙蛋白，已被证明以低亲和力和高容量结合Ca2+。在小鼠中，Ccdc47的缺失会导致胚胎死亡，这表明Ccdc47对早期发育至关重要。来自具有预测的可能有害等位基因的个体的细胞表征显示CCDC47 mRNA表达和蛋白水平降低。体外细胞实验显示，总ER Ca2+储存减少，IP3R Ca2+释放通道介导的Ca2+信号传导受损，通过存储操作的Ca2+进入减少ER Ca2+再填充。这些结果，加上之前描述的CCDC47在Ca2+信号传导和发育中的作用，表明CCDC47的双等位基因功能丧失变体是这种多系统疾病的发病机制的基础。
Ca2+ signaling is vital for various cellular processes including synaptic vesicle exocytosis, muscle contraction, regulation of secretion, gene transcription, and cellular proliferation. The endoplasmic reticulum (ER) is the largest intracellular Ca2+ store, and dysregulation of ER Ca2+ signaling and homeostasis contributes to the pathogenesis of various complex disorders and Mendelian disease traits. We describe four unrelated individuals with a complex multisystem disorder characterized by woolly hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and global developmental delay. Through whole-exome sequencing and family-based genomics, we identified bi-allelic variants in CCDC47 that encodes the Ca2+-binding ER transmembrane protein CCDC47. CCDC47, also known as calumin, has been shown to bind Ca2+ with low affinity and high capacity. In mice, loss of Ccdc47 leads to embryonic lethality, suggesting that Ccdc47 is essential for early development. Characterization of cells from individuals with predicted likely damaging alleles showed decreased CCDC47 mRNA expression and protein levels. In vitro cellular experiments showed decreased total ER Ca2+ storage, impaired Ca2+ signaling mediated by the IP3R Ca2+ release channel, and reduced ER Ca2+ refilling via store-operated Ca2+ entry. These results, together with the previously described role of CCDC47 in Ca2+ signaling and development, suggest that bi-allelic loss-of-function variants in CCDC47 underlie the pathogenesis of this multisystem disorder.