NOTCH3 – Pulmonary Arterial Hypertension

Heterozygous missense variants in NOTCH3 have been identified in five unrelated patients with pulmonary arterial hypertension (PAH), including an adult case with c.5015G>A (p.Ser1672Asn) (PMID:38989243), two pediatric cases with c.2519G>A (p.Gly840Glu) and c.2698A>C (p.Thr900Pro) (PMID:24936512), and two Saudi Arabian patients with c.3548T>C (p.Val1183Ala) and c.3308T>C (p.Met1103Thr) (PMID:34377436). All variants are missense changes localized to conserved epidermal growth factor–like repeats. No segregation with disease has been reported. Functional studies using stable cell lines expressing mutant NOTCH3 demonstrated endoplasmic reticulum retention of the chaperone GRP78/BiP, nuclear translocation, increased smooth muscle cell proliferation, and impairment of NOTCH3–HES5 signaling, supporting a gain-of-function mechanism (PMID:24936512). Despite these findings, the small number of probands and absence of familial segregation data limit the current evidence.

References

• Pulmonary circulation • 2024 • An adult patient with pulmonary arterial hypertension, a NOTCH3 mutation, and leflunomide exposure. PMID:38989243
• Molecular genetics & genomic medicine • 2014 • Mutations of NOTCH3 in childhood pulmonary arterial hypertension. PMID:24936512
• Pulmonary circulation • 2021 • Genetic basis of pulmonary arterial hypertension: a prospective study from a highly inbred population. PMID:34377436

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