Primary aldosteronism associated with a germline variant inCACNA1H

Abstract

The CACNA1H gene encodes the pore-forming α1 subunit of the T-type voltage-dependent calcium channel CaV3.2, expressed abundantly in the adrenal cortex. Mutations in CACNA1H are associated with various forms of primary aldosteronism (PA), including familial hyperaldosteronism type 4 (FH4). We describe a patient with refractory hypokalaemia and elevated aldosterone secretion independent of renin activity. Despite the absence of overt hypertension in this patient, the laboratory evaluation was consistent with a diagnosis of PA. Whole-exome sequencing revealed a de novo missense variant, R890H, in the voltage sensing domain of CACNA1H. Expression of the variant channel in cells resulted in decreased whole-cell current, consistent with a loss-of-function. We hypothesise this variant is the genetic cause of pathological aldosterone secretion in this patient, and thereby expand the current understanding of the genetic basis of FH4.

Genetics of Primary Aldosteronism

“…The pathogenicity of additional variants is less certain. 73 , 74 CACNA1H mutations lead to gain of channel function, with increased calcium influx and aldosterone production. 72 , 75 …”

“…The pathogenicity of additional variants is less certain. 73,74 CACNA1H mutations lead to gain of channel function, with increased calcium influx and aldosterone production. 72,75 A complex syndrome comprising PA, seizures, and neurological abnormalities was described in 2 individuals with de novo heterozygous gain-of-function CACNA1D mutations.…”

Voltage-Gated Ca2+-Channel α1-Subunit de novo Missense Mutations: Gain or Loss of Function – Implications for Potential Therapies

“…Like Cav1.3, Cav3.2 is important for mediating depolarization-induced aldosterone production. As a consequence, inherited ( Familial Hyperaldosteronism Type 4 ) and de novo germline GOF missense mutations S196L, M1549I, M1549V ( Figures 3 , 4 ), P2083L (not illustrated) ( Scholl et al, 2015 ; Daniil et al, 2016 ) and R890H ( Figure 4 , Wulczyn et al, 2019 ) cause hyperaldosteronism. Neurodevelopmental symptoms (such as mild ID, social skills alterations and learning) were also reported in carriers of the M1549 variants ( Daniil et al, 2016 ).…”

“…Unlike other mutations, R890H caused a pronounced LOF phenotype when expressed in HEK-293 cells ( Wulczyn et al, 2019 ), a puzzling finding considering the Ca 2+ -dependence of aldosterone secretion and the other disease-causing GOF mutations in CACNA1D and CACNA1H . However, a GOF in this mutation may again be due to the induction of gating-pore currents.…”

Molecular Mechanisms of Primary Aldosteronism

“…CACNA1H encodes for the pore-forming subunit alpha 1H of the T-type calcium channel Ca v 3.2 that is expressed in the zona glomerulosa cells [7883] and is activated by depolarizing changes in the membrane potential [84]. The disease presentation varied in patients carrying different mutation, but most mutations are gain-of-function to some degree (although, see [85]) and augmented aldosterone production [787985]. Several patients harbored mutations in Met1549 located in the repeat domain III of Ca v 3.2 that is a part of a conserved methionine-phenylalanine-valine (MFV) motif that is necessary for channel inactivation [86].…”