Somatic mutations in arteriovenous malformations in hereditary hemorrhagic telangiectasia support a bi-allelic two-hit mutation mechanism of pathogenesis.

Autor:	DeBose-Scarlett E; Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA., Ressler AK; Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA., Gallione CJ; Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA., Sapisochin Cantis G; Abdominal Transplant and HPB Surgical Oncology, Toronto General Hospital and Princess Margaret Cancer Center, University Health Network, University of Toronto, Toronto, ON PMB-11-175, Canada., Friday C; Cure HHT, Monkton, MD 21111, USA., Weinsheimer S; Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94110, USA., Schimmel K; Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Stanford University, Stanford, CA 94305, USA., Spiekerkoetter E; Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Stanford University, Stanford, CA 94305, USA., Kim H; Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94110, USA., Gossage JR; Department of Medicine, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA., Faughnan ME; Division of Respirology, Department of Medicine, University of Toronto, Toronto, ON M5S 3H2, Canada; Toronto HHT Centre, St. Michael's Hospital and Li Ka Shing Knowledge Institute, Toronto, ON M5B 1W8, Canada., Marchuk DA; Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: douglas.marchuk@duke.edu.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2024 Oct 03; Vol. 111 (10), pp. 2283-2298. Date of Electronic Publication: 2024 Sep 18.
DOI:	10.1016/j.ajhg.2024.08.020
Abstrakt:	Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder of vascular malformations characterized by mucocutaneous telangiectases and arteriovenous malformations (AVMs) in internal organs. HHT is caused by inheritance of a loss of function mutation in one of three genes. Although individuals with HHT are haploinsufficient for one of these genes throughout their entire body, rather than exhibiting a systemic vascular phenotype, vascular malformations occur as focal lesions in discrete anatomic locations. The inconsistency between genotype and phenotype has provoked debate over whether haploinsufficiency or a different mechanism gives rise to the vascular malformations. We previously showed that HHT-associated skin telangiectases develop by a two-hit mutation mechanism in an HHT gene. However, somatic mutations were identified in only half of the telangiectases, raising the question whether a second-hit somatic mutation is a necessary (required) event in HHT pathogenesis. Here, we show that another mechanism for the second hit is loss of heterozygosity across the chromosome bearing the germline mutation. Secondly, we investigate the two-hit mutation mechanism for internal organ AVMs, the source of much of the morbidity of HHT. Here, we identified somatic molecular genetic events in eight liver telangiectases, including point mutations and a loss of heterozygosity event. We also identified somatic mutations in one pulmonary AVM and two brain AVMs, confirming that mucocutaneous and internal organ vascular malformations undergo the same molecular mechanisms. Together, these data argue that bi-allelic loss of function in an HHT gene is a required event in the pathogenesis of HHT-associated vascular malformations. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024. Published by Elsevier Inc.)
Databáze:	MEDLINE
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