AQP1 – Aquaporin-1 and Pulmonary Arterial Hypertension

Rare heterozygous variants in AQP1 have been reported in families with hereditary and associated forms of pulmonary arterial hypertension (PAH). In two unrelated pedigrees, c.376C>T (p.Arg126Cys) segregated with disease in three affected members of one family and was detected in a second proband ([PMID:35627312]). Whole-genome sequencing of 1 038 PAH index cases versus 6 385 controls demonstrated significant enrichment of rare AQP1 variants, including p.Arg195Trp, in PAH patients ([PMID:29650961]). The inheritance pattern is consistent with autosomal dominant transmission with incomplete penetrance.

Functional data for AQP1 in PAH remain limited and partly contradictory. Xenopus oocyte assays of loop D mutants show altered ion conductance, and structural studies of hydrogen-bond network mutants reveal misfolding, but none of these have been directly linked to pulmonary vascular remodeling. Overall, genetic segregation and case–control enrichment provide preliminary support for AQP1 as a PAH gene, but replication in larger cohorts and disease-relevant functional models is needed. Key Take-home: AQP1 variant screening may aid PAH diagnosis, but clinical interpretation requires additional validation.

References

• Nature communications • 2018 • Identification of rare sequence variation underlying heritable pulmonary arterial hypertension. PMID:29650961
• Unknown • 2022 • Identification of AQP1 variants in unrelated PAH families. PMID:35627312

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