ACVRL1 – Telangiectasia, hereditary hemorrhagic, type 2

Hereditary hemorrhagic telangiectasia type 2 (HHT2) is an autosomal dominant vascular dysplasia characterized by recurrent epistaxis, mucocutaneous telangiectases and visceral arteriovenous malformations. The disease results from heterozygous loss‐of‐function variants in ACVRL1, encoding activin receptor‐like kinase 1 (ALK1), a TGF-β/BMP type I receptor expressed in endothelial cells ([PMID:35279593]).

Genetic studies of over 115 unrelated HHT2 probands across multiple cohorts have identified diverse ACVRL1 variant classes—missense, nonsense, splice, frameshift and intronic duplication—with segregation in at least 11 families ([PMID:26372311]; [PMID:16690726]; [PMID:16429404]). A recurrent intronic duplication, c.772+3_772+4dup, causes aberrant exon 6 splicing and haploinsufficiency ([PMID:35279593]).

Segregation analyses demonstrate co-segregation of ACVRL1 variants with HHT2 in large kindreds, including germinal mosaic cases transmitting distinct alleles to offspring ([PMID:21651515]), and in multi‐center adult and pediatric series. No homozygous LOF alleles have been reported, consistent with embryonic lethality of biallelic ACVRL1 deficiency.

Functional assays confirm pathogenicity via haploinsufficiency: intronic and coding splice variants lead to NMD of mutant transcripts ([PMID:26176610]), and missense mutants (e.g., p.Trp274Cys) show ER retention and abolished BMP9-SMAD1/5 signaling in cell models ([PMID:16282348]; [PMID:23124896]). Promoter analyses reveal Sp1-dependent transcriptional regulation of ACVRL1, with intronic mutations diminishing Sp1 binding and reducing expression ([PMID:20587022]).

Animal models corroborate human findings: Acvrl1-deficient mice exhibit vascular malformations analogous to HHT, and conditional endothelial Smad4 knockout yields arteriovenous malformations, linking ALK1 signaling to maintenance of vascular integrity ([PMID:20848592]).

Collectively, abundant genetic and experimental data support a definitive association of ACVRL1 haploinsufficiency with HHT2, underpinning diagnostic genetic testing and informing therapeutic strategies targeting TGF-β/BMP pathways. Key take-home: ACVRL1 mutation analysis is clinically actionable in HHT2 and guides patient management and family screening.

References

• Stem cell research • 2022 • Establishment of a human induced pluripotent stem cell line, KMUGMCi001-A, from a patient bearing a heterozygous c.772 + 3_772 + 4dup mutation in the ACVRL1 gene leading Telangiectasia, hereditary hemorrhagic, type 2 (HH) [PMID:35279593]
• The Laryngoscope • 2016 • An evaluation of the severity and progression of epistaxis in hereditary hemorrhagic telangiectasia 1 versus hereditary hemorrhagic telangiectasia 2 [PMID:26372311]
• PloS one • 2015 • Functional and splicing defect analysis of 23 ACVRL1 mutations in a cohort of patients affected by Hereditary Hemorrhagic Telangiectasia [PMID:26176610]
• Blood • 2006 • Functional analysis of mutations in the kinase domain of the TGF-beta receptor ALK1 reveals different mechanisms for induction of hereditary hemorrhagic telangiectasia [PMID:16282348]
• Human mutation • 2006 • DHPLC-based mutation analysis of ENG and ALK-1 genes in HHT Italian population [PMID:16429404]
• Journal of medical genetics • 2006 • Hereditary haemorrhagic telangiectasia: mutation detection, test sensitivity and novel mutations [PMID:16690726]
• Clinical genetics • 2012 • ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension [PMID:21651515]
• Genesis • 2010 • Generation of mice with a conditional and reporter allele for Tmem100 [PMID:20848592]
• BMC molecular biology • 2010 • Characterization of the human Activin-A receptor type II-like kinase 1 (ACVRL1) promoter and its regulation by Sp1 [PMID:20587022]
• Molecular and cellular biochemistry • 2013 • Retention in the endoplasmic reticulum is the underlying mechanism of some hereditary haemorrhagic telangiectasia type 2 ALK1 missense mutations [PMID:23124896]
  

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