Department of Urology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
BMC Med Genet. 2020 Feb 21;21(1):38. doi: 10.1186/s12881-020-0973-x.
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.
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.
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).
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.
普拉德-威利综合征（PBS）是一种罕见的多系统先天性肌病，主要影响男性，其遗传特征描述较差。表型上，其发病率从轻度到致死性不等，但所有孤立的 PBS 病例均表现出三个主要的病理特征：1）皱缩的松弛下腹壁伴骨骼肌缺乏，2）尿路扩张伴收缩性差的平滑肌，3）腹腔内未降睾丸。尽管有遗传基础的证据，但以前报道的 PBS 常染色体候选基因仅占一个近亲家庭和单个病例。
我们对 2 例综合征性 PBS（PBS+耳-腭-指综合征[OPDSD]）的母子半兄弟进行了全外显子组测序（WES），对 2 例无关的孤立性 PBS 个体进行了进一步的功能验证。
我们在 2 例相关病例和 2 例无关的散发性个体中发现了 X 染色体基因细丝蛋白 A（FLNA）中的 3 个未报道的半合子错义点突变（c.4952C>T(p.A1448V)，c.6727C>T(p.C2160R)，c.5966G>A(p.G2236E)）。这 3 个 PBS 突变中的 2 个位于 FLNA 的高度调节、伸展感应 Ig19-21 区域，并增强了与跨膜受体β-整合素 1（ITGβ1）的细胞内尾巴的结合。
FLNA 是一种调节肌动蛋白交联的蛋白，在平滑肌细胞中作为机械感觉分子支架发挥作用，通过结合蛋白将来自肌动球蛋白运动单位和细胞骨架的力信号传递到细胞外基质。这是首次在多个无关个体中发现 X 连锁的 PBS 原因，并扩展了男性中与 FLNA 相关的表型谱，甚至在成年后仍能存活。
