Pathogenic FLNA variants affecting the hinge region of filamin A are associated with male survival.

Autor: Wade EM; Department of Women's and Children's Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand., Morgan T; Department of Women's and Children's Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand., Gimenez G; Department of Pathology, Dunedin School of Medicine, Otago University, Dunedin, New Zealand., Jenkins ZA; Department of Women's and Children's Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand., Titheradge H; Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK., O'Donnell M; Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK., Skidmore D; IWK Hospital, Dalhousie University, Halifax, Nova Scotia, Canada., Suri M; Clinical Genetics Service, City Hospital, Nottingham, UK., Robertson SP; Department of Women's and Children's Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part A [Am J Med Genet A] 2024 Oct; Vol. 194 (10), pp. e63779. Date of Electronic Publication: 2024 Jun 10.
DOI: 10.1002/ajmg.a.63779
Abstrakt: Pathogenic variants in FLNA cause a diversity of X-linked developmental disorders associated with either preserved or diminished levels of filamin A protein and are conceptualized dichotomously as relating to underlying gain- or loss-of-function pathogenic mechanisms. Hemizygosity for germline deletions or truncating variants in FLNA is generally considered to result in embryonic lethality. Structurally, filamin A is composed of an N-terminal actin-binding region, followed by 24 immunoglobulin-like repeat units. The repeat domains are separated into distinct segments by two regions of low-complexity known as hinge-1 and hinge-2. Hinge-1 is proposed to confer flexibility to the otherwise rigid protein and is a target for cleavage by calpain with the resultant filamin fragments mediating crucial cellular signaling processes. Here, three families with pathogenic variants in FLNA that impair the function of hinge-1 in males are described, leading to distinct clinical phenotypes. One large in-frame deletion that includes the hinge leads to frontometaphyseal dysplasia in affected males and females, while two germline truncating variants located within the exon encoding hinge 1 result in phenotypes in males that are explained by exon skipping and under-expression of a transcript that deletes hinge-1 from the resultant protein. These three variants affecting hinge-1 indicate that this domain does not mediate cellular functions that, when deficientresult in embryonic lethality in males and that germline truncating variants in this region of FLNA can result in viable phenotypes in males.
(© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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