BACKGROUND Prune belly syndrome (PBS) is a rare, multi-system congenital myopathy primarily affecting males that is poorly described genetically. Phenotypically, its morbidity spans from mild to lethal, however, all isolated PBS cases manifest three cardinal pathological features: 1) wrinkled flaccid ventral abdominal wall with skeletal muscle deficiency, 2) urinary tract dilation with poorly contractile smooth muscle, and 3) intra-abdominal undescended testes. Despite evidence for a genetic basis, previously reported PBS autosomal candidate genes only account for one consanguineous family and single cases. METHODS We performed whole exome sequencing (WES) of two maternal adult half-brothers with syndromic PBS (PBS + Otopalatodigital spectrum disorder [OPDSD]) and two unrelated sporadic individuals with isolated PBS and further functionally validated the identified mutations. RESULTS We identified three unreported hemizygous missense point mutations in the X-chromosome gene Filamin A (FLNA) (c.4952 C > T (p.A1448V), c.6727C > T (p.C2160R), c.5966 G > A (p.G2236E)) in two related cases and two unrelated sporadic individuals. Two of the three PBS mutations map to the highly regulatory, stretch-sensing Ig19-21 region of FLNA and enhance binding to intracellular tails of the transmembrane receptor β-integrin 1 (ITGβ1). CONCLUSIONS FLNA is a regulatory actin-crosslinking protein that functions in smooth muscle cells as a mechanosensing molecular scaffold, transmitting force signals from the actin-myosin motor units and cytoskeleton via binding partners to the extracellular matrix. This is the first evidence for an X-linked cause of PBS in multiple unrelated individuals and expands the phenotypic spectrum associated with FLNA in males surviving even into adulthood.

中文翻译：

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幸存男性的西梅综合症可能是由X连锁的Filamin A基因中的半合错义突变引起的。

背景技术修剪腹部综合症（PBS）是一种罕见的多系统先天性肌病，主要影响男性，但在遗传学上却鲜为人知。从表型上看，其发病率从轻度到致命，但是，所有孤立的PBS病例均表现出三个主要的病理特征：1）腹壁皱纹松弛，骨骼肌缺乏； 2）尿路扩张，平滑肌收缩差，以及3）腹部睾丸未降。尽管有遗传基础的证据，以前报道的PBS常染色体候选基因仅占一个近亲家族和单个病例。方法我们对两名患有综合症PBS（PBS +十指数字频谱疾病[OPDSD]）的成年同母异母兄弟和两名与分离的PBS无关的零星个体进行了全外显子组测序（WES），并在功能上进一步验证了所鉴定的突变。结果我们在X染色体基因Filamin A（FLNA）中鉴定出三个未报告的半合子错义点突变（c.4952 C> T（p.A1448V），c.6727C> T（p.C2160R），c.5966 G> A （p.G2236E））在两个相关的案例和两个不相关的零星个人中。这三个PBS突变中的两个映射到FLNA的高度调节，可拉伸感知的Ig19-21区，并增强了与跨膜受体β-整合素1（ITGβ1）的细胞内尾部的结合。结论FLNA是一种调节性肌动蛋白交联蛋白，在平滑肌细胞中起机械传感分子支架的作用，通过结合伴侣将肌动蛋白-肌球蛋白运动单位和细胞骨架的力信号传递至细胞外基质。这是在多个无关个体中PBS X连锁病因的第一个证据，并扩大了甚至存活至成年男性的与FLNA相关的表型谱。