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

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 a...

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Bibliographic Details
Published in:	BMC medical genetics Vol. 21; no. 1; p. 38
Main Authors:	Iqbal, Nida S, Jascur, Thomas A, Harrison, Steven M, Edwards, Angelena B, Smith, Luke T, Choi, Erin S, Arevalo, Michelle K, Chen, Catherine, Zhang, Shaohua, Kern, Adam J, Scheuerle, Angela E, Sanchez, Emma J, Xing, Chao, Baker, Linda A
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 21-02-2020 BioMed Central BMC
Subjects:	Abdomen Actin Adult Bladder Cell adhesion & migration Cytogenetics Deoxyribonucleic acid DNA Filamins - genetics FLNA Gastroesophageal reflux Gene expression Gene mutation Genes Genes, X-Linked - genetics Genetic aspects Genetic Diseases, X-Linked - genetics Genetic Diseases, X-Linked - physiopathology Genetic disorders Genetic Predisposition to Disease Genomes Genotype Hemizygote Humans Integrins Kidney diseases Male Males Middle Aged Missense mutation Morbidity Muscle proteins Mutation Mutation, Missense - genetics Myosin Ostomy Pediatrics Pedigree Phenotype Polymer crosslinking Premature birth Prune belly syndrome Prune Belly Syndrome - genetics Prune Belly Syndrome - physiopathology Sequencing Skeletal muscle Smooth muscle Transplants & implants Undescended testes Urogenital system Whole Exome Sequencing United States Prune belly syndrome FLNA Sequencing
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1471-2350 1471-2350
DOI:	10.1186/s12881-020-0973-x