Spinocerebellar ataxia type 15 caused by missense variants in the ITPR1 gene

Background and purpose: Spinocerebellar ataxia type 15 (SCA15) is a degenerative, adult onset autosomal dominant cerebellar ataxia, caused almost exclusively by deletions in the inositol 1,4,5 triphosphate receptor type 1 (ITPR1) gene (ITPR1). ITPR1 mediates cal-cium release from the endoplasmic ret...

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Autores: Gazulla, José, Bellosta-Diago, Elena, Izquierdo-Alvarez, Silvia, Berciano, José Ángel|||0000-0001-9261-9748
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universidad de Cantabria (UC)
Repositorio:UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:inglés
OAI Identifier:oai:repositorio.unican.es:10902/29764
Acceso en línea:https://hdl.handle.net/10902/29764
Access Level:acceso abierto
Palabra clave:Cerebellar ataxia
Chorea
ITPR1 gene
Missense
Spinocerebellar ataxia type 15
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spelling Spinocerebellar ataxia type 15 caused by missense variants in the ITPR1 geneGazulla, JoséBellosta-Diago, ElenaIzquierdo-Alvarez, SilviaBerciano, José Ángel|||0000-0001-9261-9748Cerebellar ataxiaChoreaITPR1 geneMissenseSpinocerebellar ataxia type 15Background and purpose: Spinocerebellar ataxia type 15 (SCA15) is a degenerative, adult onset autosomal dominant cerebellar ataxia, caused almost exclusively by deletions in the inositol 1,4,5 triphosphate receptor type 1 (ITPR1) gene (ITPR1). ITPR1 mediates cal-cium release from the endoplasmic reticulum, and particularly abounds in Purkinje cells. It plays a pivotal role in excitatory and inhibitory actions on Purkinje cells, and alterations in their balance cause cerebellar dysfunction in ITPR1 knockout mice. To date, only two single missense mutations have been reported to cause SCA15. They were considered pathogenic because cosegregation occurred with disease, and haploinsufficiency was hy-pothesized as their pathogenic mechanism.Methods: In this study, three Caucasian kindreds with different heterozygous missense variants in ITPR1 are reported. The main clinical manifestation was a slowly progressive gait ataxia with onset after 40 years of age, with chorea in two patients and hand tremor in another one, concordant with manifestations found in SCA15.Results: The three missense variants identified in ITPR1 were c.1594G>A; p.(Ala532Thr) in Kindred A, c.56C>T; p.(Ala19Val) in Kindred B, and c.256G>A; p.(Ala86Thr) in Kindred C. Every variant was labelled as of unknown significance; however, each one cosegre-gated with disease and was predicted to be pathogenic by in silico tests.Conclusions: The three ITPR1 missense variants found in this study exhibited cosegrega-tion with disease, a result that sustains their pathogenicity. Further studies are needed to confirm the role of missense mutations in SCA15.WileyUniversidad de Cantabria20232023-05-08journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articlehttps://hdl.handle.net/10902/29764European Journal of Neurology, 2023, 30(8), 2539-2543reponame:UCrea Repositorio Abierto de la Universidad de Cantabriainstname:Universidad de Cantabria (UC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repositorio.unican.es:10902/297642026-06-02T12:39:31Z
dc.title.none.fl_str_mv Spinocerebellar ataxia type 15 caused by missense variants in the ITPR1 gene
title Spinocerebellar ataxia type 15 caused by missense variants in the ITPR1 gene
spellingShingle Spinocerebellar ataxia type 15 caused by missense variants in the ITPR1 gene
Gazulla, José
Cerebellar ataxia
Chorea
ITPR1 gene
Missense
Spinocerebellar ataxia type 15
title_short Spinocerebellar ataxia type 15 caused by missense variants in the ITPR1 gene
title_full Spinocerebellar ataxia type 15 caused by missense variants in the ITPR1 gene
title_fullStr Spinocerebellar ataxia type 15 caused by missense variants in the ITPR1 gene
title_full_unstemmed Spinocerebellar ataxia type 15 caused by missense variants in the ITPR1 gene
title_sort Spinocerebellar ataxia type 15 caused by missense variants in the ITPR1 gene
dc.creator.none.fl_str_mv Gazulla, José
Bellosta-Diago, Elena
Izquierdo-Alvarez, Silvia
Berciano, José Ángel|||0000-0001-9261-9748
author Gazulla, José
author_facet Gazulla, José
Bellosta-Diago, Elena
Izquierdo-Alvarez, Silvia
Berciano, José Ángel|||0000-0001-9261-9748
author_role author
author2 Bellosta-Diago, Elena
Izquierdo-Alvarez, Silvia
Berciano, José Ángel|||0000-0001-9261-9748
author2_role author
author
author
dc.contributor.none.fl_str_mv Universidad de Cantabria
dc.subject.none.fl_str_mv Cerebellar ataxia
Chorea
ITPR1 gene
Missense
Spinocerebellar ataxia type 15
topic Cerebellar ataxia
Chorea
ITPR1 gene
Missense
Spinocerebellar ataxia type 15
description Background and purpose: Spinocerebellar ataxia type 15 (SCA15) is a degenerative, adult onset autosomal dominant cerebellar ataxia, caused almost exclusively by deletions in the inositol 1,4,5 triphosphate receptor type 1 (ITPR1) gene (ITPR1). ITPR1 mediates cal-cium release from the endoplasmic reticulum, and particularly abounds in Purkinje cells. It plays a pivotal role in excitatory and inhibitory actions on Purkinje cells, and alterations in their balance cause cerebellar dysfunction in ITPR1 knockout mice. To date, only two single missense mutations have been reported to cause SCA15. They were considered pathogenic because cosegregation occurred with disease, and haploinsufficiency was hy-pothesized as their pathogenic mechanism.Methods: In this study, three Caucasian kindreds with different heterozygous missense variants in ITPR1 are reported. The main clinical manifestation was a slowly progressive gait ataxia with onset after 40 years of age, with chorea in two patients and hand tremor in another one, concordant with manifestations found in SCA15.Results: The three missense variants identified in ITPR1 were c.1594G>A; p.(Ala532Thr) in Kindred A, c.56C>T; p.(Ala19Val) in Kindred B, and c.256G>A; p.(Ala86Thr) in Kindred C. Every variant was labelled as of unknown significance; however, each one cosegre-gated with disease and was predicted to be pathogenic by in silico tests.Conclusions: The three ITPR1 missense variants found in this study exhibited cosegrega-tion with disease, a result that sustains their pathogenicity. Further studies are needed to confirm the role of missense mutations in SCA15.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023-05-08
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/10902/29764
url https://hdl.handle.net/10902/29764
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
dc.source.none.fl_str_mv European Journal of Neurology, 2023, 30(8), 2539-2543
reponame:UCrea Repositorio Abierto de la Universidad de Cantabria
instname:Universidad de Cantabria (UC)
instname_str Universidad de Cantabria (UC)
reponame_str UCrea Repositorio Abierto de la Universidad de Cantabria
collection UCrea Repositorio Abierto de la Universidad de Cantabria
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.198674

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