Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene
| Autor: | Erin S. Choi, Chao Xing, Nida S. Iqbal, Thomas A. Jascur, Linda A. Baker, Michelle K. Arevalo, Emma Sanchez, Adam J. Kern, Angela E. Scheuerle, Catherine Chen, Steven M. Harrison, Angelena Edwards, Luke T. Smith, Shaohua Zhang |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Adult Male Candidate gene lcsh:Internal medicine lcsh:QH426-470 Genotype Filamins 030232 urology & nephrology Mutation Missense Biology Filamin 03 medical and health sciences 0302 clinical medicine Prune belly syndrome Genes X-Linked Exome Sequencing Genetics medicine FLNA Missense mutation Humans Prune Belly Syndrome Sequencing Genetic Predisposition to Disease lcsh:RC31-1245 Genetics (clinical) Exome sequencing Hemizygote Point mutation Genetic Diseases X-Linked Middle Aged medicine.disease Congenital myopathy Pedigree lcsh:Genetics 030104 developmental biology Phenotype Research Article |
| Zdroj: | BMC Medical Genetics BMC Medical Genetics, Vol 21, Iss 1, Pp 1-16 (2020) |
| ISSN: | 1471-2350 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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