Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog and canonical Wnt signaling

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00027162%3A_____%2F20%3AN0000214" target="_blank" >RIV/00027162:_____/20:N0000214 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/67985904:_____/20:00536280 RIV/00216224:14110/20:00114425 RIV/00159816:_____/20:00073506

Výsledek na webu

<a href="https://www.embopress.org/doi/full/10.15252/emmm.201911739" target="_blank" >https://www.embopress.org/doi/full/10.15252/emmm.201911739</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.15252/emmm.201911739" target="_blank" >10.15252/emmm.201911739</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog and canonical Wnt signaling

Popis výsledku v původním jazyce

Mutations in genes affecting primary cilia cause ciliopathies, a diverse group of disorders often affecting skeletal development. This includes Jeune syndrome or asphyxiating thoracic dystrophy (ATD), an autosomal recessive skeletal disorder. Unraveling the responsible molecular pathology helps illuminate mechanisms responsible for functional primary cilia. We identified two families with ATD caused by loss-of-function mutations in the gene encoding adrenergic receptor kinase 1 (ADRBK1 or GRK2). GRK2 cells from an affected individual homozygous for the p.R158* mutation resulted in loss of GRK2, and disrupted chondrocyte growth and differentiation in the cartilage growth plate. GRK2 null cells displayed normal cilia morphology, yet loss of GRK2 compromised cilia-based signaling of Hedgehog (Hh) pathway. Canonical Wnt signaling was also impaired, manifested as a failure to respond to Wnt ligand due to impaired phosphorylation of the Wnt co-receptor LRP6. We have identified GRK2 as an essential regulator of skeletogenesis and demonstrate how both Hh and Wnt signaling mechanistically contribute to skeletal ciliopathies.

Název v anglickém jazyce

Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog and canonical Wnt signaling

Popis výsledku anglicky

Mutations in genes affecting primary cilia cause ciliopathies, a diverse group of disorders often affecting skeletal development. This includes Jeune syndrome or asphyxiating thoracic dystrophy (ATD), an autosomal recessive skeletal disorder. Unraveling the responsible molecular pathology helps illuminate mechanisms responsible for functional primary cilia. We identified two families with ATD caused by loss-of-function mutations in the gene encoding adrenergic receptor kinase 1 (ADRBK1 or GRK2). GRK2 cells from an affected individual homozygous for the p.R158* mutation resulted in loss of GRK2, and disrupted chondrocyte growth and differentiation in the cartilage growth plate. GRK2 null cells displayed normal cilia morphology, yet loss of GRK2 compromised cilia-based signaling of Hedgehog (Hh) pathway. Canonical Wnt signaling was also impaired, manifested as a failure to respond to Wnt ligand due to impaired phosphorylation of the Wnt co-receptor LRP6. We have identified GRK2 as an essential regulator of skeletogenesis and demonstrate how both Hh and Wnt signaling mechanistically contribute to skeletal ciliopathies.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

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OECD FORD obor

30101 - Human genetics

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2020

Kód důvěrnosti údajů

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

Název periodika

EMBO Molecular Medicine

ISSN

1757-4676

e-ISSN

1757-4684

Svazek periodika

12

Číslo periodika v rámci svazku

11

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

20

Strana od-do

"e11739"

Kód UT WoS článku

000577616000001

EID výsledku v databázi Scopus

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