Role of Gα(olf) in Familial and Sporadic Adult-Onset Primary Dystonia.
Vemula, Satya R ; Puschmann, Andreas LU
; Xiao, Jianfeng
; Rudzinska, Monika
; Frei, Karen P
; Truong, Daniel D
; Wszolek, Zbigniew K
and LeDoux, Mark S
(2013)
In Human Molecular Genetics
22(12).
p.2510-2519
- Abstract
- The vast majority of patients with primary dystonia are adults with focal or segmental distribution of involuntary movements. Although approximately 10% of probands have at least one first- or second-degree relative with dystonia, large families suited for linkage analysis are exceptional. After excluding mutations in known primary dystonia genes (TOR1A, THAP1, and CIZ1), whole-exome sequencing identified a GNAL missense mutation (c.682G>T, p.V228F) in an African-American pedigree with clinical phenotypes that include cervical, laryngeal and hand-forearm dystonia. Screening of 760 subjects with familial and sporadic primary dystonia identified 3 Caucasian pedigrees with GNAL mutations (c.591dupA [p.R198Tfs*13]; c.733C>T [p.R245*];... (More)
- The vast majority of patients with primary dystonia are adults with focal or segmental distribution of involuntary movements. Although approximately 10% of probands have at least one first- or second-degree relative with dystonia, large families suited for linkage analysis are exceptional. After excluding mutations in known primary dystonia genes (TOR1A, THAP1, and CIZ1), whole-exome sequencing identified a GNAL missense mutation (c.682G>T, p.V228F) in an African-American pedigree with clinical phenotypes that include cervical, laryngeal and hand-forearm dystonia. Screening of 760 subjects with familial and sporadic primary dystonia identified 3 Caucasian pedigrees with GNAL mutations (c.591dupA [p.R198Tfs*13]; c.733C>T [p.R245*]; and c.3G>A [p.M1?]). These mutations show incomplete penetrance. Our findings corroborate those of a recent study which used whole exome sequencing to identify missense and nonsense GNAL mutations in Caucasian pedigrees of mixed European ancestry with mainly adult-onset cervical and segmental dystonia. GNAL encodes guanine nucleotide-binding protein G(olf), subunit alpha [Gα(olf)]. Gα(olf) plays a role in olfaction, coupling D1 and A2a receptors to adenylyl cyclase, and histone H3 phosphorylation. African-American subjects harboring the p.V228F mutation exhibited microsmia. Lymphoblastoid cell lines from subjects with the p.V228F mutation showed up-regulation of genes involved in cell cycle control and development. Consistent with known sites of network pathology in dystonia, immunohistochemical studies indicated that Gα(olf) is highly expressed in the striatum and cerebellar Purkinje cells, and co-localized with corticotropin-releasing hormone receptors in the latter. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3561081
- author
- Vemula, Satya R
; Puschmann, Andreas
LU
; Xiao, Jianfeng
; Rudzinska, Monika
; Frei, Karen P
; Truong, Daniel D
; Wszolek, Zbigniew K
and LeDoux, Mark S
- organization
- publishing date
- 2013
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- dystonia, genetics, neurogenetics, movement disorders, GNAL, olfaction, Purkinje cell
- in
- Human Molecular Genetics
- volume
- 22
- issue
- 12
- pages
- 2510 - 2519
- publisher
- Oxford University Press
- external identifiers
-
- wos:000319432800016
- scopus:84878508579
- pmid:23449625
- ISSN
- 0964-6906
- DOI
- 10.1093/hmg/ddt102
- language
- English
- LU publication?
- yes
- id
- 41ea8421-7a71-430c-a7e5-dffc6bb1bea2 (old id 3561081)
- alternative location
- http://hmg.oxfordjournals.org/content/early/2013/02/27/hmg.ddt102.abstract
- date added to LUP
- 2016-04-01 11:16:09
- date last changed
- 2023-11-10 15:53:14
@article{41ea8421-7a71-430c-a7e5-dffc6bb1bea2,
abstract = {{The vast majority of patients with primary dystonia are adults with focal or segmental distribution of involuntary movements. Although approximately 10% of probands have at least one first- or second-degree relative with dystonia, large families suited for linkage analysis are exceptional. After excluding mutations in known primary dystonia genes (TOR1A, THAP1, and CIZ1), whole-exome sequencing identified a GNAL missense mutation (c.682G>T, p.V228F) in an African-American pedigree with clinical phenotypes that include cervical, laryngeal and hand-forearm dystonia. Screening of 760 subjects with familial and sporadic primary dystonia identified 3 Caucasian pedigrees with GNAL mutations (c.591dupA [p.R198Tfs*13]; c.733C>T [p.R245*]; and c.3G>A [p.M1?]). These mutations show incomplete penetrance. Our findings corroborate those of a recent study which used whole exome sequencing to identify missense and nonsense GNAL mutations in Caucasian pedigrees of mixed European ancestry with mainly adult-onset cervical and segmental dystonia. GNAL encodes guanine nucleotide-binding protein G(olf), subunit alpha [Gα(olf)]. Gα(olf) plays a role in olfaction, coupling D1 and A2a receptors to adenylyl cyclase, and histone H3 phosphorylation. African-American subjects harboring the p.V228F mutation exhibited microsmia. Lymphoblastoid cell lines from subjects with the p.V228F mutation showed up-regulation of genes involved in cell cycle control and development. Consistent with known sites of network pathology in dystonia, immunohistochemical studies indicated that Gα(olf) is highly expressed in the striatum and cerebellar Purkinje cells, and co-localized with corticotropin-releasing hormone receptors in the latter.}},
author = {{Vemula, Satya R and Puschmann, Andreas and Xiao, Jianfeng and Rudzinska, Monika and Frei, Karen P and Truong, Daniel D and Wszolek, Zbigniew K and LeDoux, Mark S}},
issn = {{0964-6906}},
keywords = {{dystonia; genetics; neurogenetics; movement disorders; GNAL; olfaction; Purkinje cell}},
language = {{eng}},
number = {{12}},
pages = {{2510--2519}},
publisher = {{Oxford University Press}},
series = {{Human Molecular Genetics}},
title = {{Role of Gα(olf) in Familial and Sporadic Adult-Onset Primary Dystonia.}},
url = {{https://lup.lub.lu.se/search/files/2522149/3694096.pdf}},
doi = {{10.1093/hmg/ddt102}},
volume = {{22}},
year = {{2013}},
}