Journal article
Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene
BMC medical genetics, Vol.21(1), pp.38-38
02/21/2020
DOI: 10.1186/s12881-020-0973-x
PMCID: PMC7035669
PMID: 32085749
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 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.
Details
- Title: Subtitle
- Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene
- Creators
- Nida S. Iqbal - The University of Texas Southwestern Medical CenterThomas A. Jascur - The University of Texas Southwestern Medical CenterSteven M. Harrison - Broad InstituteAngelena B. Edwards - The University of Texas Southwestern Medical CenterLuke T. Smith - The University of Texas Southwestern Medical CenterErin S. Choi - The University of Texas Southwestern Medical CenterMichelle K. Arevalo - The University of Texas Southwestern Medical CenterCatherine Chen - The University of Texas Southwestern Medical CenterShaohua Zhang - The University of Texas Southwestern Medical CenterAdam J. Kern - The University of Texas Southwestern Medical CenterAngela E. Scheuerle - The University of Texas Southwestern Medical CenterEmma J. Sanchez - The University of Texas Southwestern Medical CenterChao Xing - The University of Texas Southwestern Medical CenterLinda A. Baker - The University of Texas Southwestern Medical Center
- Resource Type
- Journal article
- Publication Details
- BMC medical genetics, Vol.21(1), pp.38-38
- DOI
- 10.1186/s12881-020-0973-x
- PMID
- 32085749
- PMCID
- PMC7035669
- NLM abbreviation
- BMC Med Genet
- ISSN
- 1471-2350
- eISSN
- 1471-2350
- Publisher
- BioMed Central
- Grant note
- DK100483 / ;
- Language
- English
- Date published
- 02/21/2020
- Academic Unit
- Stead Family Department of Pediatrics; Urology
- Record Identifier
- 9984319991002771
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