SMAD9 – Heritable Pulmonary Arterial Hypertension

Rare heterozygous variants in SMAD9, a receptor‐regulated SMAD of the BMP signaling pathway, have been implicated in autosomal dominant heritable pulmonary arterial hypertension (HPAH). In a large review of HPAH genetics, SMAD9 was nominated alongside BMPR2, ACVRL1, ENG, CAV1, and KCNK3 as a contributor to vascular remodeling and elevated pulmonary vascular resistance (PMID:27770446).

Genetic evidence is limited to two unrelated HPAH probands carrying distinct SMAD9 variants: a nonsense mutation c.606C>A (p.Cys202Ter) identified in an index case and her affected father (PMID:19211612), and a missense variant c.127A>G (p.Lys43Glu) found in a PAH cohort of 324 patients (PMID:21898662). Functional assays demonstrated that p.Cys202Ter abolishes SMAD9 phosphorylation by ALK1/ALK3 and fails to interact with SMAD4, while p.Lys43Glu reduces BMP‐responsive transcriptional activity, consistent with a loss‐of‐function mechanism. The modest number of probands and segregation in a single family support a Limited genetic classification.

Key Take-home: SMAD9 haploinsufficiency via rare truncating or missense variants can underlie autosomal dominant HPAH, but further cohort screening and segregation studies are needed to establish a more definitive clinical validity.

References

• The Journal of Pathology • 2017 • The role of genetics in pulmonary arterial hypertension. PMID:27770446
• Journal of Medical Genetics • 2009 • A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension. PMID:19211612
• Human Mutation • 2011 • Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension. PMID:21898662

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