PNPLA1 defects in patients with autosomal recessive congenital ichthyosis and KO mice sustain PNPLA1 irreplaceable function in epidermal omega-O-acylceramide synthesis and skin permeability barrier

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F17%3A10364258" target="_blank" >RIV/00216208:11160/17:10364258 - isvavai.cz</a>

Result on the web

<a href="http://academic.oup.com/hmg/article/26/10/1787/3091202" target="_blank" >http://academic.oup.com/hmg/article/26/10/1787/3091202</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1093/hmg/ddx079" target="_blank" >10.1093/hmg/ddx079</a>

Result language

angličtina

Original language name

PNPLA1 defects in patients with autosomal recessive congenital ichthyosis and KO mice sustain PNPLA1 irreplaceable function in epidermal omega-O-acylceramide synthesis and skin permeability barrier

Original language description

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of monogenic genodermatoses that encompasses non-syndromic disorders of keratinization. The pathophysiology of ARCI has been linked to a disturbance in epidermal lipid metabolism that impaired the stratum corneum function, leading to permeability barrier defects. Functional characterization of some genes involved in ARCI contributed to the identification of molecular actors involved in epidermal lipid synthesis, transport or processing. Recently, PNPLA1 has been identified as a gene causing ARCI. While other members of PNPLA family are key elements in lipid metabolism, the function of PNPLA1 remained unclear. We identified 5 novel PNPLA1 mutations in ARCI patients, mainly localized in the putative active enzymatic domain of PNPLA1. To investigate Pnpla1 biological role, we analysed Pnpla1-deficient mice. KO mice died soon after birth from severe epidermal permeability defects. Pnpla1-deficient skin presented an important impairment in the composition and organization of the epidermal lipids. Quantification of epidermal ceramide species highlighted a blockade in the production of omega-O-acylceramides with a concomitant accumulation of their precursors in the KO. The virtually loss of omega-O-acylceramides in the stratum corneum was linked to a defective lipid coverage of the resistant pericellular shell encapsulating corneocytes, the so-called cornified envelope, and most probably disorganized the extracellular lipid matrix. Finally, these defects in omega-O-acylceramides synthesis and cornified envelope formation were also evidenced in the stratum corneum from PNPLA1-mutated patients. Overall, our data support that PNPLA1/Pnpla1 is a key player in the formation of omega-O-acylceramide, a crucial process for the epidermal permeability barrier function.

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

30104 - Pharmacology and pharmacy

Project

<a href="/en/project/GC16-25687J" target="_blank" >GC16-25687J: Interdependencies between Inflammatory Processes and Barrier Lipids in Diseased Skin</a><br>

Continuities

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

Publication year

2017

Confidentiality

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

Name of the periodical

Human Molecular Genetics

ISSN

0964-6906

e-ISSN

—

Volume of the periodical

26

Issue of the periodical within the volume

10

Country of publishing house

GB - UNITED KINGDOM

Number of pages

14

Pages from-to

1787-1800

UT code for WoS article

000402010500001

EID of the result in the Scopus database

2-s2.0-85020105719