POMK mutations disrupt muscle development leading to a spectrum of neuromuscular presentations
POMK mutations disrupt muscle development leading to a spectrum of neuromuscular presentations
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DOI：
10.1093/hmg/ddu296
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发表时间：
2014-11-01
影响因子：
3.5
通讯作者：
Manzini, M. Chiara
中科院分区：
文献类型：
--
作者：
Di Costanzo, Stefania;Balasubramanian, Anuradha;Manzini, M. Chiara
肌营养不良聚糖是一种跨膜糖蛋白，其与细胞外基质（ECM）的相互作用是正常肌肉和大脑发育所必需的，其功能的破坏导致肌营养不良聚糖病，一组先天性肌营养不良症显示出极端的遗传和临床异质性。与肌营养不良聚糖（α-肌营养不良聚糖）的细胞外部分结合的特异性聚糖介导ECM相互作用，并且大多数已知的肌营养不良聚糖病基因编码参与聚糖合成的糖基转移酶。POMK在两个肌营养不良聚糖病病例中发现突变，而是参与对ECM结合至关重要的聚糖磷酸化反应，但对POMK突变的临床表现或该蛋白在肌肉中的功能知之甚少。在这里，我们描述了两个家庭携带不同的截断等位基因，都删除POMK的激酶结构域，不同的临床表现，从沃克-沃伯格综合征，最严重的形式的肌营养不良症，以肢带型肌营养不良症与认知缺陷。我们探讨了POMK在胎儿和成人肌肉中的表达，并确定了主要在胎儿发育期间在肌细胞和间质细胞中的广泛表达，这表明该蛋白在早期肌肉分化期间的作用。对斑马鱼胚胎和幼体功能丧失的分析表明，pomk功能是正常肌肉发育所必需的，导致胚胎运动功能障碍和幼体肌营养不良的迹象。总之，我们定义了POMK突变后的各种临床表现，并表明该基因对早期肌肉发育是必要的。
Dystroglycan is a transmembrane glycoprotein whose interactions with the extracellular matrix (ECM) are necessary for normal muscle and brain development, and disruptions of its function lead to dystroglycanopathies, a group of congenital muscular dystrophies showing extreme genetic and clinical heterogeneity. Specific glycans bound to the extracellular portion of dystroglycan, alpha-dystroglycan, mediate ECM interactions and most known dystroglycanopathy genes encode glycosyltransferases involved in glycan synthesis. POMK, which was found mutated in two dystroglycanopathy cases, is instead involved in a glycan phosphorylation reaction critical for ECM binding, but little is known about the clinical presentation of POMK mutations or of the function of this protein in the muscle. Here, we describe two families carrying different truncating alleles, both removing the kinase domain in POMK, with different clinical manifestations ranging from Walker-Warburg syndrome, the most severe form of dystroglycanopathy, to limb-girdle muscular dystrophy with cognitive defects. We explored POMK expression in fetal and adult human muscle and identified widespread expression primarily during fetal development in myocytes and interstitial cells suggesting a role for this protein during early muscle differentiation. Analysis of loss of function in the zebrafish embryo and larva showed that pomk function is necessary for normal muscle development, leading to locomotor dysfuction in the embryo and signs of muscular dystrophy in the larva. In summary, we defined diverse clinical presentations following POMK mutations and showed that this gene is necessary for early muscle development.