Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene

Abstract

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 ) 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.

Case Report: Novel Copy Number Variant 16p11.2 Duplication Associated With Prune Belly Syndrome

“…Murray et al documented the deletion of HNF-1 β gene on chromosome 17 in a patient with PBS ( 18 ). Iqbal et al reported on PBS patients with mutations of X-linked filamin A gene ( 19 ).…”

Síndrome de Prune Belly en una paciente adolescente

“…8 En otro estudio se identificaron tres mutaciones del gen FLNA, implicado en la producción de la proteína filamina A, la cual regula la reticulación de actina que funciona en las células del músculo liso. 9 Además, se han propuesto teorías que implican alteraciones en diversas proteínas de contractilidad muscular visceral como resultado de mutaciones genéticas, incluyendo los genes ACTA2, ACTG2, MYH11, MYLK, MYOCD y HNF1B. 6 El diagnóstico precoz permite un tratamiento oportuno.…”

“…Algunas incluyen el origen genético heterogéneo, con la implicación de diversas proteínas de contractilidad muscular visceral o de alteraciones de los receptores muscarínicos colinérgicos M3, 6,7 o bien, que el modo de herencia está ligado al cromosoma X. 8,9 Otra propuesta describe que hay alteración en el desarrollo del mesodermo, lo cual explicaría las alteraciones morfológicas a nivel genitourinario, gastrointestinal y de otros sistemas. 10 El diagnóstico puede realizarse durante la gestación, a través de una ecografía obstétrica con evidencia de contornos irregulares en el abdomen asociado con un aumento de su circunferencia, anomalías del tracto urinario, oligohidramnios, ascitis fetal y uraco permeable.…”

Envisioning treating genetically-defined urinary tract malformations with viral vector-mediated gene therapy

“…Nevertheless, this field of genomic investigation of human urinary tract malformations is rapidly expanding, with variants in yet other genes reported every few months by research laboratories. Recent examples are: BNC2 [23], encoding the protein basonuclin 2 expressed in the urogenital sinus, with mutations causing urethral obstruction; FLNA, encoding filamin A, an actin crosslinking protein expressed in bladder smooth muscle and mutated in some cases of prune belly-like syndrome [24]; SLC20A1 [25], coding for sodium-dependent phosphate transporter 1 expressed in and around the urogenital sinus, with mutations associated with bladder extrophy; and EBF3, coding for the early B cell factor 3 transcription factor that when mutated causes dysfunctional voiding [26]. Probably, there will be many other genes implicated in this group of diseases and, as genetic testing becomes more widely adopted in the clinic, a greater proportion of all individuals with urinary tract malformations will be found to have a genetic cause.…”