Title :

CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking

Author(s) :

Wilson, Matthew P [Auteur]
Center for Human Genetics, University of Leuven School of Medicine
Durin, Zoe [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Unal, Özlem [Auteur]
Ng, Bobby G [Auteur]
Sanford Burnham Prebys Medical Discovery Institute
Marrecau, Thomas [Auteur]
Center for Human Genetics, University of Leuven School of Medicine
Keldermans, Liesbeth [Auteur]
Center for Human Genetics, University of Leuven School of Medicine
Souche, Erika [Auteur]
Center for Human Genetics, University of Leuven School of Medicine
Rymen, Daisy [Auteur]
Center for Human Genetics, University of Leuven School of Medicine
Gündüz, Mehmet [Auteur]
Köse, Gülşen [Auteur]
Sturiale, Luisa [Auteur]
Garozzo, Domenico [Auteur]
Freeze, Hudson H [Auteur]
Sanford Burnham Prebys Medical Discovery Institute
Jaeken, Jaak [Auteur]
Catholic University of Leuven = Katholieke Universiteit Leuven [KU Leuven]
Foulquier, Francois [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Matthijs, Gert [Auteur]
Center for Human Genetics, University of Leuven School of Medicine

Journal title :

HUMAN MOLECULAR GENETICS

Volume number :

31

Pages :

2571-2581

Publisher :

Oxford University Press (OUP)

Publication date :

2022-03-09

ISSN :

0964-6906

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

The transmembrane domain recognition complex (TRC) pathway is required for the insertion of C-terminal tail-anchored (TA) proteins into the lipid bilayer of specific intracellular organelles such as the endoplasmic reticulum ...
Show more >The transmembrane domain recognition complex (TRC) pathway is required for the insertion of C-terminal tail-anchored (TA) proteins into the lipid bilayer of specific intracellular organelles such as the endoplasmic reticulum (ER) membrane. In order to facilitate correct insertion, the recognition complex (consisting of BAG6, GET4 and UBL4A) must first bind to TA proteins and then to GET3 (TRC40, ASNA1), which chaperones the protein to the ER membrane. Subsequently, GET1 (WRB) and CAML form a receptor that enables integration of the TA protein within the lipid bilayer. We report an individual with the homozygous c.633 + 4A>G splice variant in CAMLG, encoding CAML. This variant leads to aberrant splicing and lack of functional protein in patient-derived fibroblasts. The patient displays a predominantly neurological phenotype with psychomotor disability, hypotonia, epilepsy and structural brain abnormalities. Biochemically, a combined O-linked and type II N-linked glycosylation defect was found. Mislocalization of syntaxin-5 in patient fibroblasts and in siCAMLG deleted Hela cells confirms this as a consistent cellular marker of TRC dysfunction. Interestingly, the level of the v-SNARE Bet1L is also drastically reduced in both of these models, indicating a fundamental role of the TRC complex in the assembly of Golgi SNARE complexes. It also points towards a possible mechanism behind the hyposialylation of N and O-glycans. This is the first reported patient with pathogenic variants in CAMLG. CAMLG-CDG is the third disorder, after GET4 and GET3 deficiencies, caused by pathogenic variants in a member of the TRC pathway, further expanding this novel group of disorders.Show less >

Language :

Anglais

Audience :

Internationale

Popular science :

Non

European Project :

ERA-Net for research programmes on rare diseases

Administrative institution(s) :

Université de Lille
CNRS

Collections :

• Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Research team(s) :

Mécanismes moléculaires de la N-glycosylation et pathologies associées

Submission date :

2022-09-21T12:21:18Z
2022-09-23T08:32:56Z
2022-09-23T08:39:27Z