ACVRL1 – Pulmonary Arterial Hypertension

Activin receptor-like kinase-1 (ACVRL1) is an endothelial type I TGF-β/BMP receptor encoded by HGNC:175. Heterozygous loss-of-function variants in ACVRL1 cause hereditary hemorrhagic telangiectasia (HHT2) and, less commonly, manifest as autosomal dominant pulmonary arterial hypertension (PAH) with reduced penetrance. PAH due to ACVRL1 is characterized by progressive elevation of pulmonary vascular resistance, right ventricular strain, and clinical features such as exertional dyspnea and, in some cases, concomitant epistaxis reflecting overlapping HHT.

Multiple case-series and cohort studies have identified ACVRL1 variants in PAH cohorts. In a pediatric PAH series (n = 21), ACVRL1 mutations were detected in 5 probands (3 familial, 2 idiopathic) (PMID:18159113), while targeted exome capture in 80 unrelated PAH patients revealed 4 ACVRL1 missense variants (5%) (PMID:27316748). Genetic counselling of 529 sporadic and 94 familial PAH cases found ACVRL1 mutations in 9 sporadic and 3 familial patients (PMID:26699722). A Chinese IPAH/HPAH cohort (n = 106) reported 12 ACVRL1 mutation carriers with younger age at diagnosis and high mortality (PMID:34966542). Familial segregation was shown in a pedigree with three affected members carrying c.595G>C (p.Ala199Pro), with two additional relatives demonstrating co-segregation in severe portopulmonary and heritable PAH (PMID:29799317). One recurrent pathogenic allele, c.1450C>T (p.Arg484Trp), has been observed in multiple unrelated PAH pedigrees.

Functional assays support a haploinsufficiency mechanism: ACVRL1 missense mutants exhibit defective cell-surface trafficking, endoplasmic reticulum retention, markedly reduced BMP9-induced SMAD1/5 phosphorylation, and impaired luciferase reporter activity in NIH-3T3 cells (PMID:27316748). In vitro studies of kinase-domain mutations demonstrate both null and dominant-negative effects on receptor signaling, corroborating loss-of-function in HHT2 and PAH (PMID:16282348).

No major conflicting data have emerged to dispute ACVRL1’s role in PAH; phenotypic variability likely reflects modifier genes and environmental factors. While ACVRL1 is more recognized for HHT2, robust genetic and experimental concordance over >15 years establishes its causal link to PAH.

In summary, ACVRL1 harbors autosomal dominant, haploinsufficient variants in >30 unrelated PAH probands, with segregation in multi-member families and consistent functional deficits in BMP9/ALK1 signaling. This multifaceted evidence supports a Definitive ClinGen clinical validity classification, Strong genetic evidence, and Moderate experimental evidence for ACVRL1–PAH association.

Key Take-home: ACVRL1 genetic screening should be considered in PAH patients, especially those with HHT features, to enable early diagnosis, family counseling, and targeted management.

References

• Circulation Journal • 2008 • Implications of mutations of activin receptor-like kinase 1 gene (ALK1) in addition to bone morphogenetic protein receptor II gene (BMPR2) in children with pulmonary arterial hypertension. PMID:18159113
• Clinical Science • 2016 • Identification of multiple ACVRL1 mutations in patients with pulmonary arterial hypertension by targeted exome capture. PMID:27316748
• European Respiratory Journal • 2016 • Genetic counselling in a national referral centre for pulmonary hypertension. PMID:26699722
• Pulmonary Circulation • 2021 • Clinical characteristics and prognosis analysis of idiopathic and hereditary pulmonary hypertension patients with ACVRL1 gene mutations. PMID:34966542
• Pulmonary Circulation • 2018 • Different forms of pulmonary hypertension in a family with clinical and genetic evidence for hereditary hemorrhagic teleangectasia type 2. PMID:29799317
• 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

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