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Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production

The result's identifiers

  • Result code in IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00179906%3A_____%2F23%3A10465919" target="_blank" >RIV/00179906:_____/23:10465919 - isvavai.cz</a>

  • Alternative codes found

    RIV/00216208:11150/23:10465919

  • Result on the web

    <a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=t2ae_Qw9QU" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=t2ae_Qw9QU</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1038/s41588-023-01403-0" target="_blank" >10.1038/s41588-023-01403-0</a>

Alternative languages

  • Result language

    angličtina

  • Original language name

    Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production

  • Original language description

    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.

  • Czech name

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • OECD FORD branch

    30101 - Human genetics

Result continuities

  • Project

  • Continuities

Others

  • Publication year

    2023

  • Confidentiality

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Data specific for result type

  • Name of the periodical

    Nature Genetics

  • ISSN

    1061-4036

  • e-ISSN

    1546-1718

  • Volume of the periodical

    55

  • Issue of the periodical within the volume

    6

  • Country of publishing house

    US - UNITED STATES

  • Number of pages

    13

  • Pages from-to

    1009-1021

  • UT code for WoS article

    001004549100003

  • EID of the result in the Scopus database

    2-s2.0-85161401185