De novo variants in

Axin Protein / genetics Child Child, Preschool Developmental Disabilities / genetics Face / abnormalities Female Genetic Predisposition to Disease HEK293 Cells Humans Infant Male Muscle Hypotonia / genetics Nuclear Proteins / genetics Proteolysis Ubiquitin-Protein Ligases / genetics Wnt Signaling Pathway / genetics beta Catenin / genetics
E3 ubiquitin ligase SIAH1 Wnt signaling exome sequencing

Journal

Journal of medical genetics
ISSN: 1468-6244
Titre abrégé: J Med Genet
Pays: England
ID NLM: 2985087R

Informations de publication

Date de publication:
03 2021
Historique:
received: 03 06 2019
revised: 25 03 2020
accepted: 03 04 2020
pubmed: 21 5 2020
medline: 4 9 2021
entrez: 21 5 2020
Statut: ppublish

Résumé

Ubiquitination has a central role in numerous biological processes, including cell development, stress responses and ageing. Perturbed ubiquitination has been implicated in human diseases ranging from cancer to neurodegenerative diseases. Trio exome sequencing followed by Sanger validation was undertaken in five individuals with syndromic developmental delay. Three-dimensional structural modelling was used to predict pathogenicity of affected residues. Wnt stimulatory activity was measured by luciferase reporter assays and Axin degradation assays in HEK293 cells transfected with wild-type and mutant SIAH1 expression plasmids. We report five unrelated individuals with shared features of developmental delay, infantile hypotonia, dysmorphic features and laryngomalacia, in whom exome sequencing identified de novo monoallelic variants in Our results lend support to

Sections du résumé

BACKGROUND
Ubiquitination has a central role in numerous biological processes, including cell development, stress responses and ageing. Perturbed ubiquitination has been implicated in human diseases ranging from cancer to neurodegenerative diseases.
METHODS
Trio exome sequencing followed by Sanger validation was undertaken in five individuals with syndromic developmental delay. Three-dimensional structural modelling was used to predict pathogenicity of affected residues. Wnt stimulatory activity was measured by luciferase reporter assays and Axin degradation assays in HEK293 cells transfected with wild-type and mutant SIAH1 expression plasmids.
RESULTS
We report five unrelated individuals with shared features of developmental delay, infantile hypotonia, dysmorphic features and laryngomalacia, in whom exome sequencing identified de novo monoallelic variants in
CONCLUSION
Our results lend support to

Identifiants

DOI: 10.1136/jmedgenet-2019-106335 PMID: 32430360
pubmed: 32430360
pii: jmedgenet-2019-106335
doi: 10.1136/jmedgenet-2019-106335
doi:

Substances chimiques

Axin Protein 0
CTNNB1 protein, human 0
Nuclear Proteins 0
beta Catenin 0
Ubiquitin-Protein Ligases EC 2.3.2.27
seven in absentia proteins EC 2.3.2.27

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

205-212

Informations de copyright

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: TBP is an employee of GeneDx.

Auteurs

Julien Buratti (J)

Département de Génétique, Hôpital Pitié-Salpêtrière, Assistance publique-Hôpitaux de Paris, Paris, France.
ORCID: 0000-0002-0901-0905

Lei Ji (L)

Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.

Boris Keren (B)

Département de Génétique, Hôpital Pitié-Salpêtrière, Assistance publique-Hôpitaux de Paris, Paris, France.

Youngha Lee (Y)

Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.

Stephanie Booke (S)

Department of Pediatrics, Division of Medical Genetics, University of California San Francisco, San Francisco, CA, USA.

Serkan Erdin (S)

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Soo Yeon Kim (SY)

Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea.

Timothy Blake Palculict (TB)

GeneDx, Gaithersburg, MD, USA.

Vardiella Meiner (V)

Department of Genetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Jong Hee Chae (JH)

Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea.

Christopher Geoffrey Woods (CG)

Cambridge Institute for Medical Research, Department of Medical Genetics, Univeristy of Cambridge, Cambridge, UK.
ORCID: 0000-0002-8077-2101

Allison Tam (A)

Department of Pediatrics, Division of Medical Genetics, University of California San Francisco, San Francisco, CA, USA.

Delphine Héron (D)

Département de Génétique et Centre de Référence "déficiences intellectuelles de causes rares", AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France.

Feng Cong (F)

Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.

Tamar Harel (T)

Department of Genetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel tamarhe@hadassah.org.il.
ORCID: 0000-0003-3595-7075

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Complexe de signalisation de l'axine › Axine › De novo variants in
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › De novo variants in
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Enfant d'âge préscolaire › De novo variants in
questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › Incapacités de développement › De novo variants in
questionsmedicales.fr › Régions du corps › Tête › Face › De novo variants in
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › De novo variants in
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HEK293 › De novo variants in
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › De novo variants in
questionsmedicales.fr › Personnes › Tranches d'âge › Nourrisson › De novo variants in
questionsmedicales.fr › États, signes et symptômes pathologiques › Signes et symptômes › Manifestations neurologiques › Manifestations neuromusculaires › Hypotonie musculaire › De novo variants in
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › De novo variants in
questionsmedicales.fr › Métabolisme › Protéolyse › De novo variants in
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Ligases › Ubiquitin-protein ligase complexes › Ubiquitin-protein ligases › De novo variants in
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Voie de signalisation Wnt › De novo variants in
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › bêta-Caténine › De novo variants in