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Abstract：
Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a congenital disorder characterized by loss of smooth muscle contraction in the bladder and intestine. To date, three genes are known to be involved in MMIHS pathogenesis: ACTG2, MYH11, and LMOD1. However, for approximately 10% of affected individuals, the genetic cause of the disease is unknown, suggesting that other loci are most likely involved. Here, we report on three MMIHS-affected subjects from two consanguineous families with no variants in the known MMIHS-associated genes. By performing homozygosity mapping and whole-exome sequencing, we found homozygous variants in myosin light chain kinase (MYLK) in both families. We identified a 7 bp duplication (c.3838_3844dupGAAAGCG [p.Glu1282_Glyfs∗51]) in one family and a putative splice-site variant (c.3985+5C>A) in the other. Expression studies and splicing assays indicated that both variants affect normal MYLK expression. Because MYLK encodes an important kinase required for myosin activation and subsequent interaction with actin filaments, it is likely that in its absence, contraction of smooth muscle cells is impaired. The existence of a conditional-Mylk-knockout mouse model with severe gut dysmotility and abnormal function of the bladder supports the involvement of this gene in MMIHS pathogenesis. In aggregate, our findings implicate MYLK as a gene involved in the recessive form of MMIHS, confirming that this disease of the visceral organs is heterogeneous with a myopathic origin.
摘要：
巨结肠小结肠肠蠕动综合征（MMIHS）是一种先天性疾病，其特征是膀胱和肠道平滑肌收缩丧失。迄今为止,已知MMIHS发病机制涉及三个基因:ACTG2、MYH11和LMOD1。然而,对于大约10%的受影响个体，这种疾病的遗传原因是未知的，表明其他基因座最有可能参与其中。这里,我们报道了来自两个近亲家庭的3名MMIHS患者,已知MMIHS相关基因没有变异.通过进行纯合性作图和全外显子组测序，我们在两个家族中都发现了肌球蛋白轻链激酶(MYLK)的纯合变体.我们确定了一个7bp的重复（c.3838_3844dupGAAAGCG[p。Glu1282_Glyfs*51]）在一个家族中，在另一个家族中推定剪接位点变体（c.39855C>A）。表达研究和剪接测定表明两种变体都影响正常的MYLK表达。因为MYLK编码肌球蛋白激活和随后与肌动蛋白丝相互作用所需的重要激酶，很可能在它缺席的情况下，平滑肌细胞的收缩受损。具有严重肠动力障碍和膀胱功能异常的条件Mylk敲除小鼠模型的存在支持该基因参与MMIHS发病机理。总的来说,我们的发现暗示MYLK是一个涉及MMIHS隐性形式的基因，证实内脏器官的这种疾病与肌病起源是异质的。
