Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design.
Humans
Cerebellar Ataxia
/ genetics
Mutation, Missense
/ genetics
Movement Disorders
/ complications
Atrophy
Inositol 1,4,5-Trisphosphate Receptors
/ chemistry
Carbonic Anhydrases
/ genetics
Intracellular Signaling Peptides and Proteins
/ genetics
Intellectual Disability
Spinocerebellar Degenerations
Aniridia
Gillespie syndrome
IP3R1
ITPR1
cerebellum
next-generation sequencing
spinocerebellar ataxia type 29
Journal
Movement disorders : official journal of the Movement Disorder Society
ISSN: 1531-8257
Titre abrégé: Mov Disord
Pays: United States
ID NLM: 8610688
Informations de publication
Date de publication:
Jan 2024
Jan 2024
Historique:
revised:
16
09
2023
received:
30
07
2023
accepted:
16
10
2023
medline:
1
2
2024
pubmed:
15
11
2023
entrez:
15
11
2023
Statut:
ppublish
Résumé
The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Sections du résumé
BACKGROUND
BACKGROUND
The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP
OBJECTIVES
OBJECTIVE
We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy.
METHODS
METHODS
Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction.
RESULTS
RESULTS
We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP
CONCLUSIONS
CONCLUSIONS
This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Substances chimiques
Inositol 1,4,5-Trisphosphate Receptors
0
ITPR1 protein, human
0
CA8 protein, human
EC 4.2.1.1
Carbonic Anhydrases
EC 4.2.1.1
Intracellular Signaling Peptides and Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
141-151Subventions
Organisme : Medical Research Council
ID : MR/V007068/1
Pays : United Kingdom
Informations de copyright
© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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