Department of Medical Genetics, Faculty of Medical Sciences, State University of Campinas, Campinas, Brazil.
McKusick-Nathans Institute of Genetic Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Eur J Hum Genet. 2018 May;26(5):669-675. doi: 10.1038/s41431-017-0055-5. Epub 2018 Feb 16.
Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a severe disease characterized by functional obstruction in the urinary and gastrointestinal tract. The molecular basis of this condition started to be defined recently, and the genes related to the syndrome (ACTG2-heterozygous variant in sporadic cases; and MYH11 (myosin heavy chain 11), LMOD1 (leiomodin 1) and MYLK (myosin light chain (MLC) kinase)-autosomal recessive inheritance), encode proteins involved in the smooth muscle contraction, supporting a myopathic basis for the disease. In the present article, we described a family with two affected siblings with MMIHS born to consanguineous parents and the molecular investigation performed to define the genetic etiology. Previous whole exome sequencing of the affected child and parents did not identify a candidate gene for the disease in this family, but now we present a reanalysis of the data that led to the identification of a homozygous deletion encompassing the last exon of MYL9 (myosin regulatory light chain 9) in the affected individual. MYL9 gene encodes a regulatory myosin MLC and the phosphorylation of this protein is a crucial step in the contraction process of smooth muscle cell. Despite the absence of human or animal phenotype related to MYL9, a cause-effect relationship between MYL9 and the MMIHS seems biologically plausible. The present study reveals a strong candidate gene for autosomal recessive forms of MMIHS, expanding the molecular basis of this disease and reinforces the myopathic basis of this condition.
巨膀胱-小肠-肠蠕动不良综合征（MMIHS）是一种严重的疾病，其特征为泌尿道和胃肠道的功能性阻塞。该病症的分子基础最近才开始被定义，与该综合征相关的基因（散发性病例中的 ACTG2-杂合变异；以及常染色体隐性遗传的 MYH11（肌球蛋白重链 11）、LMOD1（leiomodin 1）和 MYLK（肌球蛋白轻链激酶）），编码参与平滑肌收缩的蛋白，支持该疾病的肌病基础。在本文中，我们描述了一个由近亲父母所生的患有 MMIHS 的两例受影响同胞的家族，以及为确定遗传病因而进行的分子研究。先前对受影响儿童及其父母进行的全外显子组测序并未在该家族中发现该疾病的候选基因，但现在我们重新分析了数据，结果确定了受影响个体中包含 MYL9（肌球蛋白调节轻链 9）最后一个外显子的纯合缺失。MYL9 基因编码调节肌球蛋白的 MLC，该蛋白的磷酸化是平滑肌细胞收缩过程中的关键步骤。尽管与 MYL9 相关的人类或动物表型不存在，但 MYL9 与 MMIHS 之间的因果关系在生物学上似乎是合理的。本研究揭示了常染色体隐性 MMIHS 的一个强有力的候选基因，扩展了该疾病的分子基础，并进一步证实了该疾病的肌病基础。
