A form of muscular dystrophy associated with pathogenic variants in JAG2
A form of muscular dystrophy associated with pathogenic variants in JAG2
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DOI：
10.1016/j.ajhg.2021.03.020
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发表时间：
2021-05-06
影响因子：
9.8
通讯作者：
Kang, Peter B.
中科院分区：
文献类型：
--
作者：
Coppens, Sandra;Barnard, Alison M.;Kang, Peter B.
JAG2编码Notch配体Jagged2。保守的Notch信号通路有助于多种组织的发育和动态平衡，包括骨骼肌。我们研究了来自13个无关家系的23名遗传未解决的肌营养不良症患者的国际队列。全外显子测序在所有13个家系中发现了罕见的纯合子或复合杂合子JAG2变异体。已鉴定的双等位基因变异包括10个扰乱高度保守氨基酸的错义变异，一个无义变异，两个移码变异，一个框架内缺失，以及一个围绕JAG2的微缺失。从婴儿期到成年期，都会出现肌肉无力。血清肌酸激酶(CK)水平正常或轻度升高。肌肉组织学主要表现为营养不良。下肢MRI显示明显的、轻微不对称的肌肉受累模式，股四头肌和胫前肌的保留和受累肌肉的核心，在某些情况下类似于POGLUT1相关性肌营养不良的模式。对两名参与者肌肉组织的转录组分析表明，包括PAX7在内的参与肌肉发生的基因调控不当。在补充性研究中，Jag2在小鼠成肌细胞中的下调导致Notch途径的多个组成部分下调，包括MEGF10。对果蝇的研究表明，Serrate和Drpr之间存在相互作用，它们分别是JAG1/JAG2和MEGF10的果蝇同源基因。在计算机分析中预测，许多Jagged2错义变体与结构变化和蛋白质错误折叠有关。综上所述，我们描述了一例与JAG2致病变异相关的肌营养不良症，并有证据表明与Notch途径功能障碍有关的疾病机制。
JAG2 encodes the Notch ligand Jagged2. The conserved Notch signaling pathway contributes to the development and homeostasis of multiple tissues, including skeletal muscle. We studied an international cohort of 23 individuals with genetically unsolved muscular dystrophy from 13 unrelated families. Whole-exome sequencing identified rare homozygous or compound heterozygous JAG2 variants in all 13 families. The identified bi-allelic variants include 10 missense variants that disrupt highly conserved amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. Onset of muscle weakness occurred from infancy to young adulthood. Serum creatine kinase (CK) levels were normal or mildly elevated. Muscle histology was primarily dystrophic. MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy. Transcriptome analysis of muscle tissue from two participants suggested misregulation of genes involved in myogenesis, including PAX7. In complementary studies, Jag2 downregulation in murine myoblasts led to downregulation of multiple components of the Notch pathway, including Megf10. Investigations in Drosophila suggested an interaction between Serrate and Drpr, the fly orthologs of JAG1/JAG2 and MEGF10, respectively. In silico analysis predicted that many Jagged2 missense variants are associated with structural changes and protein misfolding. In summary, we describe a muscular dystrophy associated with pathogenic variants in JAG2 and evidence suggests a disease mechanism related to Notch pathway dysfunction.