Revising pathogenesis of AP1S1-related MEDNIK syndrome: a missense variant in the AP1S1 gene as a causal genetic lesion

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11130%2F24%3A10484975" target="_blank" >RIV/00216208:11130/24:10484975 - isvavai.cz</a>

Alternative codes found

RIV/00064203:_____/24:10484975

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=oa9v7hbCPk" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=oa9v7hbCPk</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1007/s00109-024-02482-0" target="_blank" >10.1007/s00109-024-02482-0</a>

Result language

angličtina

Original language name

Revising pathogenesis of AP1S1-related MEDNIK syndrome: a missense variant in the AP1S1 gene as a causal genetic lesion

Original language description

MEDNIK syndrome is a rare autosomal recessive disease characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma, and caused by variants in the adaptor-related protein complex 1 subunit sigma 1 (AP1S1) gene. This gene encodes the sigma 1A protein, which is a subunit of the adaptor protein complex 1 (AP-1), a key component of the intracellular protein trafficking machinery. Previous work identified three AP1S1 nonsense, frameshift and splice-site variants in MEDNIK patients predicted to encode truncated sigma 1A proteins, with consequent AP-1 dysfunction. However, two AP1S1 missense variants (c.269 T &gt; C and c.346G &gt; A) were recently reported in patients who presented with severe enteropathy but no additional symptoms of MEDNIK. This condition was described as a novel non-syndromic form of congenital diarrhea caused specifically by the AP1S1 missense variants. In this study, we report two patients with the same c.269 T &gt; C variant, who, contrary to the previous cases, presented as complete MEDNIK syndrome. These data substantially revise the presentation of disorders associated with AP1S1 gene variants and indicate that all the identified pathogenic AP1S1 variants result in MEDNIK syndrome. We also provide a series of functional analyses that elucidate the impact of the c.269 T &gt; C variant on sigma 1A function, contributing to a better understanding of the molecular pathogenesis of MEDNIK syndrome.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30109 - Pathology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2024

Confidentiality

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

Name of the periodical

Journal of Molecular Medicine

ISSN

0946-2716

e-ISSN

1432-1440

Volume of the periodical

102

Issue of the periodical within the volume

11

Country of publishing house

DE - GERMANY

Number of pages

11

Pages from-to

1343-1353

UT code for WoS article

001313280400001

EID of the result in the Scopus database

2-s2.0-85204157634