PDE3A – Hypertension and Brachydactyly Syndrome

Hypertension and brachydactyly syndrome (HTNB; MONDO:0007211) is a rare autosomal dominant disorder characterized by severe salt-independent hypertension, brachydactyly type E, and short stature. PDE3A encodes a cGMP-inhibited cyclic nucleotide phosphodiesterase expressed in vascular smooth muscle and chondrocytes, mediating cAMP hydrolysis and cell proliferation (Gene Symbol; Hypertension and Brachydactyly Syndrome).

In the initial Nature Genetics report, six missense variants in exon 4 of PDE3A were identified in six unrelated families, including c.1334C>G (p.Thr445Ser) (PMID:25961942). All six variants clustered within a conserved regulatory region and were absent from population databases, establishing a reproducible genetic basis for HTNB ([PMID:25961942]).

Subsequent studies expanded the spectrum with nine further probands harboring variants such as c.1346G>A (p.Gly449Asp) in a Chinese kindred ([PMID:31549136]) and three independent case reports describing de novo c.1333_1335del (p.Thr445del) ([PMID:31589936]), familial recurrence of c.1346G>A (p.Gly449Asp) ([PMID:32631253]), and c.2584C>T (p.Arg862Cys) in a young adult ([PMID:38689596]).

Cosegregation analyses demonstrated variant segregation in multiple families, including two affected relatives in the Chinese pedigree and additional segregation across Japanese and European kindreds (total n=4 affected relatives). Functional concordance was observed across pedigrees, supporting pathogenicity based on inheritance and familial linkage.

Mechanistic studies revealed that HTNB-associated PDE3A mutations cause gain of function by uncovering cryptic phosphorylation sites, leading to increased cAMP hydrolysis, vascular smooth muscle cell hyperproliferation, and altered chondrocyte growth. CRISPR-Cas9 rat models and patient-derived iPSC cardiomyocytes confirmed enzyme hyperactivity, aberrant phosphorylation, and adaptive cardiac protection ([PMID:25961942]; [PMID:36259389]).

The convergence of extensive genetic and experimental data over >9 years supports a definitive association between PDE3A and HTNB. Genetic testing for PDE3A gain-of-function variants enables early diagnosis and targeted management to prevent stroke. Key Take-home: Autosomal dominant PDE3A mutations underlie HTNB, guiding precision medicine for affected families.

References

• Nature genetics • 2015 • PDE3A mutations cause autosomal dominant hypertension with brachydactyly. PMID:25961942
• European journal of medical genetics • 2020 • PDE3A variant associated with hypertension and brachydactyly syndrome in a patient with ischemic stroke caused by spontaneous intracranial artery dissection: A review of the clinical and molecular genetic features. PMID:31589936
• American journal of hypertension • 2020 • Hypertension and Brachydactyly Syndrome Associated With Vertebral Artery Malformation Caused by a PDE3A Missense Mutation. PMID:31549136
• JACC. Case reports • 2024 • Hypertension and Brachydactyly Syndrome: Genetic Insights and a Novel Presentation. PMID:38689596
• Journal of human genetics • 2016 • A PDE3A mutation in familial hypertension and brachydactyly syndrome. PMID:27053290
• BMC medical genetics • 2020 • Whole-exome sequencing identifies a de novo PDE3A variant causing autosomal dominant hypertension with brachydactyly type E syndrome: a case report. PMID:32631253
• Circulation • 2022 • Mutant Phosphodiesterase 3A Protects From Hypertension-Induced Cardiac Damage. PMID:36259389

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