Regulatory rare variants of the dopaminergic gene ANKK1 as potential risk factors for Parkinson’s disease

Abstract Parkinson’s disease (PD) is characterized by cerebral dopamine depletion that causes motor and cognitive deficits. The dopamine-related gene ANKK1 has been associated with neuropsychiatric disorders with a dopaminergic deficiency in the striatum. This study aims to define the contribution o...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Estela Pérez-Santamarina, Pedro García-Ruiz, Dolores Martínez-Rubio, Mario Ezquerra, Irene Pla-Navarro, Jorge Puente, María José Martí, Francesc Palau, Janet Hoenicka
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b94e1e211a1843e58d9c48db44c76a82
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:b94e1e211a1843e58d9c48db44c76a82
record_format	dspace
spelling	oai:doaj.org-article:b94e1e211a1843e58d9c48db44c76a822021-12-02T17:02:21ZRegulatory rare variants of the dopaminergic gene ANKK1 as potential risk factors for Parkinson’s disease10.1038/s41598-021-89300-62045-2322https://doaj.org/article/b94e1e211a1843e58d9c48db44c76a822021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89300-6https://doaj.org/toc/2045-2322Abstract Parkinson’s disease (PD) is characterized by cerebral dopamine depletion that causes motor and cognitive deficits. The dopamine-related gene ANKK1 has been associated with neuropsychiatric disorders with a dopaminergic deficiency in the striatum. This study aims to define the contribution of ANKK1 rare variants in PD. We found in 10 out of 535 PD patients 6 ANKK1 heterozygous rare alleles located at the 5′UTR, the first exon, intron 1, and the nearby enhancer located 2.6 kb upstream. All 6 ANKK1 single nucleotide variants were located in conserved regulatory regions and showed significant allele-dependent effects on gene regulation in vitro. ANKK1 variant carriers did not show other PD-causing Mendelian mutations. Nevertheless, four patients were heterozygous carriers of rare variants of ATP7B gene, which is related to catecholamines. We also found an association between the polymorphic rs7107223 of the ANKK1 enhancer and PD in two independent clinical series (P = 0.007 and 0.021). rs7107223 functional analysis showed significant allele-dependent effects on both gene regulation and dopaminergic response. In conclusion, we have identified in PD patients functional variants at the ANKK1 locus highlighting the possible relevance of rare variants and non-coding regulatory regions in both the genetics of PD and the dopaminergic vulnerability of this disease.Estela Pérez-SantamarinaPedro García-RuizDolores Martínez-RubioMario EzquerraIrene Pla-NavarroJorge PuenteMaría José MartíFrancesc PalauJanet HoenickaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Estela Pérez-Santamarina Pedro García-Ruiz Dolores Martínez-Rubio Mario Ezquerra Irene Pla-Navarro Jorge Puente María José Martí Francesc Palau Janet Hoenicka Regulatory rare variants of the dopaminergic gene ANKK1 as potential risk factors for Parkinson’s disease
description	Abstract Parkinson’s disease (PD) is characterized by cerebral dopamine depletion that causes motor and cognitive deficits. The dopamine-related gene ANKK1 has been associated with neuropsychiatric disorders with a dopaminergic deficiency in the striatum. This study aims to define the contribution of ANKK1 rare variants in PD. We found in 10 out of 535 PD patients 6 ANKK1 heterozygous rare alleles located at the 5′UTR, the first exon, intron 1, and the nearby enhancer located 2.6 kb upstream. All 6 ANKK1 single nucleotide variants were located in conserved regulatory regions and showed significant allele-dependent effects on gene regulation in vitro. ANKK1 variant carriers did not show other PD-causing Mendelian mutations. Nevertheless, four patients were heterozygous carriers of rare variants of ATP7B gene, which is related to catecholamines. We also found an association between the polymorphic rs7107223 of the ANKK1 enhancer and PD in two independent clinical series (P = 0.007 and 0.021). rs7107223 functional analysis showed significant allele-dependent effects on both gene regulation and dopaminergic response. In conclusion, we have identified in PD patients functional variants at the ANKK1 locus highlighting the possible relevance of rare variants and non-coding regulatory regions in both the genetics of PD and the dopaminergic vulnerability of this disease.
format	article
author	Estela Pérez-Santamarina Pedro García-Ruiz Dolores Martínez-Rubio Mario Ezquerra Irene Pla-Navarro Jorge Puente María José Martí Francesc Palau Janet Hoenicka
author_facet	Estela Pérez-Santamarina Pedro García-Ruiz Dolores Martínez-Rubio Mario Ezquerra Irene Pla-Navarro Jorge Puente María José Martí Francesc Palau Janet Hoenicka
author_sort	Estela Pérez-Santamarina
title	Regulatory rare variants of the dopaminergic gene ANKK1 as potential risk factors for Parkinson’s disease
title_short	Regulatory rare variants of the dopaminergic gene ANKK1 as potential risk factors for Parkinson’s disease
title_full	Regulatory rare variants of the dopaminergic gene ANKK1 as potential risk factors for Parkinson’s disease
title_fullStr	Regulatory rare variants of the dopaminergic gene ANKK1 as potential risk factors for Parkinson’s disease
title_full_unstemmed	Regulatory rare variants of the dopaminergic gene ANKK1 as potential risk factors for Parkinson’s disease
title_sort	regulatory rare variants of the dopaminergic gene ankk1 as potential risk factors for parkinson’s disease
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/b94e1e211a1843e58d9c48db44c76a82
work_keys_str_mv	AT estelaperezsantamarina regulatoryrarevariantsofthedopaminergicgeneankk1aspotentialriskfactorsforparkinsonsdisease AT pedrogarciaruiz regulatoryrarevariantsofthedopaminergicgeneankk1aspotentialriskfactorsforparkinsonsdisease AT doloresmartinezrubio regulatoryrarevariantsofthedopaminergicgeneankk1aspotentialriskfactorsforparkinsonsdisease AT marioezquerra regulatoryrarevariantsofthedopaminergicgeneankk1aspotentialriskfactorsforparkinsonsdisease AT ireneplanavarro regulatoryrarevariantsofthedopaminergicgeneankk1aspotentialriskfactorsforparkinsonsdisease AT jorgepuente regulatoryrarevariantsofthedopaminergicgeneankk1aspotentialriskfactorsforparkinsonsdisease AT mariajosemarti regulatoryrarevariantsofthedopaminergicgeneankk1aspotentialriskfactorsforparkinsonsdisease AT francescpalau regulatoryrarevariantsofthedopaminergicgeneankk1aspotentialriskfactorsforparkinsonsdisease AT janethoenicka regulatoryrarevariantsofthedopaminergicgeneankk1aspotentialriskfactorsforparkinsonsdisease
_version_	1718381929669066752

Regulatory rare variants of the dopaminergic gene ANKK1 as potential risk factors for Parkinson’s disease

Ejemplares similares