Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production
Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1 . Independent whole exo...
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Veröffentlicht in: | Nature genetics 2023-06, Vol.55 (6), p.1009-1021 |
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Zusammenfassung: | Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene
CADM1
. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total,
n
= 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was
CYP11B2
(aldosterone synthase), and biological rhythms were the most differentially expressed process.
CADM1
knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased
CYP11B2
similarly to
CADM1
mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of
CADM1
cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production.
Recurrent somatic mutations altering residues in the transmembrane domain of
CADM1
are identified in aldosterone-producing adenomas. Follow-up studies implicate a role of gap junction communication in regulating aldosterone production. |
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ISSN: | 1061-4036 1546-1718 1546-1718 |
DOI: | 10.1038/s41588-023-01403-0 |