CACNA1D – Primary Aldosteronism

Primary aldosteronism (PA) is the most common form of secondary hypertension, driven in many cases by aldosterone-producing adenomas (APAs). Recurrent somatic missense mutations in the L-type calcium channel gene CACNA1D have been identified in APAs, and de novo germline CACNA1D variants cause a syndromic form of PA with seizures and hypotonia (PASNA). Together, these data support CACNA1D as a bona fide PA gene.

Somatic heterozygous CACNA1D mutations occur in 9.3% of 474 APAs (44/474) across multi-center cohorts ([PMID:24866132]). These variants cluster in the pore-forming and voltage-sensor domains and are mutually exclusive of KCNJ5, ATP1A1, and ATP2B3 mutations. In APAs, CACNA1D mutations correlate with smaller tumor size and distinct clinical-biochemical profiles in comparison to other genotypes.

Germline de novo CACNA1D missense mutations have been reported in unrelated patients presenting with congenital hyperinsulinemic hypoglycemia, primary hyperaldosteronism, muscle hypotonia, and aortic regurgitation. A novel de novo variant, c.812T>A (p.Leu271His), was identified by trio exome sequencing in a female infant with PASNA, confirming CACNA1D haploinsufficiency as a cause of early-onset PA ([PMID:32336187]). Additional de novo mutations (e.g., c.1220+678G>A) replicate this phenotype ([PMID:28318089]).

The variant spectrum includes both germline de novo and somatic changes: for example, the somatic APA hotspot c.1207G>C (p.Gly403Arg) has been found in multiple patients ([PMID:28368480]). Across studies, CACNA1D mutations involve missense changes that alter channel gating, and rare intronic or deep-intronic mutations affecting splicing.

Functional assays in heterologous systems demonstrate gain-of-function of mutant Cav1.3 channels. De novo mutations shift voltage-dependence of activation by ~15 mV toward more negative potentials and slow inactivation, increasing Ca2+ influx ([PMID:25620733]). Somatic APA mutants likewise enhance channel open probability, thereby driving aldosterone synthase expression in adrenal cells.

No compelling evidence refutes the role of CACNA1D in PA; neither population data nor familial studies have identified common polymorphisms with protective effects. The concordance of genetic recurrence, segregation (de novo), and robust functional data establishes CACNA1D as a PA gene.

In summary, both somatic and germline CACNA1D gain-of-function variants cause aldosterone excess via enhanced Ca2+ entry through Cav1.3, providing diagnostic and therapeutic opportunities. Key take-home: CACNA1D mutation screening should be incorporated into the genetic workup of APAs and PASNA, and patients may benefit from L-type calcium channel blockers.

References

• Hypertension • 2014 • Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma PMID:24866132
• Channels (Austin, Tex.) • 2020 • A de novo CACNA1D missense mutation in a patient with congenital hyperinsulinism, primary hyperaldosteronism and hypotonia PMID:32336187
• Pediatric Diabetes • 2017 • A CACNA1D mutation in a patient with persistent hyperinsulinaemic hypoglycaemia, heart defects, and severe hypotonia PMID:28318089
• The Journal of Clinical Endocrinology & Metabolism • 2017 • Genetic and Histopathologic Intertumor Heterogeneity in Primary Aldosteronism PMID:28368480
• Biological Psychiatry • 2015 • CACNA1D de novo mutations in autism spectrum disorders activate Cav1.3 L-type calcium channels PMID:25620733

Evidence Based Scoring (AI generated)