Genetic Dominant Variants in STUB1, Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16.

Pakdaman, Y; Berland, S; Bustad, HJ; Erdal, S; Thompson, BA; James, PA; Power, KN; Ellingsen, S; Krooni, M; Berge, LI; Sexton, A; Bindoff, LA; Knappskog, PM; Johansson, S; Aukrust, I

Genetic Dominant Variants in STUB1, Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16.

Pakdaman, Y Berland, S Bustad, HJ Erdal, S Thompson, BA James, PA Power, KN Ellingsen, S Krooni, M Berge, LI Sexton, A

Bindoff, LA Knappskog, PM Johansson, S Aukrust, I

Permalink

Publisher:: MDPI
Publication Type:: Journal Article
Citation:: Int J Mol Sci, 2021, 22, (11)
Issue Date:: 2021-05-30

Open Access

Copyright Clearance Process

Recently Added
In Progress
Open Access

This item is open access.

Adobe PDF

Download Published versionAdobe PDF (1.41 MB)

View on publisher's site

View statistics

Full metadata record

Field	Value	Language
dc.contributor.author	Pakdaman, Y
dc.contributor.author	Berland, S
dc.contributor.author	Bustad, HJ
dc.contributor.author	Erdal, S
dc.contributor.author	Thompson, BA
dc.contributor.author	James, PA
dc.contributor.author	Power, KN
dc.contributor.author	Ellingsen, S
dc.contributor.author	Krooni, M
dc.contributor.author	Berge, LI
dc.contributor.author	Sexton, A https://orcid.org/0000-0001-8749-1639
dc.contributor.author	Bindoff, LA
dc.contributor.author	Knappskog, PM
dc.contributor.author	Johansson, S
dc.contributor.author	Aukrust, I
dc.date.accessioned	2022-03-04T07:25:07Z
dc.date.available	2021-05-26
dc.date.available	2022-03-04T07:25:07Z
dc.date.issued	2021-05-30
dc.identifier.citation	Int J Mol Sci, 2021, 22, (11)
dc.identifier.issn	1422-0067
dc.identifier.issn	1422-0067
dc.identifier.uri	http://hdl.handle.net/10453/154986
dc.description.abstract	Variants in STUB1 cause both autosomal recessive (SCAR16) and dominant (SCA48) spinocerebellar ataxia. Reports from 18 STUB1 variants causing SCA48 show that the clinical picture includes later-onset ataxia with a cerebellar cognitive affective syndrome and varying clinical overlap with SCAR16. However, little is known about the molecular properties of dominant STUB1 variants. Here, we describe three SCA48 families with novel, dominantly inherited STUB1 variants (p.Arg51_Ile53delinsProAla, p.Lys143_Trp147del, and p.Gly249Val). All the patients developed symptoms from 30 years of age or later, all had cerebellar atrophy, and 4 had cognitive/psychiatric phenotypes. Investigation of the structural and functional consequences of the recombinant C-terminus of HSC70-interacting protein (CHIP) variants was performed in vitro using ubiquitin ligase activity assay, circular dichroism assay and native polyacrylamide gel electrophoresis. These studies revealed that dominantly and recessively inherited STUB1 variants showed similar biochemical defects, including impaired ubiquitin ligase activity and altered oligomerization properties of the CHIP. Our findings expand the molecular understanding of SCA48 but also mean that assumptions concerning unaffected carriers of recessive STUB1 variants in SCAR16 families must be re-evaluated. More investigations are needed to verify the disease status of SCAR16 heterozygotes and elucidate the molecular relationship between SCA48 and SCAR16 diseases.
dc.format	Electronic
dc.language	eng
dc.publisher	MDPI
dc.relation.ispartof	Int J Mol Sci
dc.relation.isbasedon	10.3390/ijms22115870
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	0399 Other Chemical Sciences, 0604 Genetics, 0699 Other Biological Sciences
dc.subject.classification	Chemical Physics
dc.subject.mesh	Adult
dc.subject.mesh	Age of Onset
dc.subject.mesh	Aged
dc.subject.mesh	Family
dc.subject.mesh	Female
dc.subject.mesh	Frontotemporal Dementia
dc.subject.mesh	Gene Expression
dc.subject.mesh	Genes, Dominant
dc.subject.mesh	Genes, Recessive
dc.subject.mesh	Heterozygote
dc.subject.mesh	Humans
dc.subject.mesh	Male
dc.subject.mesh	Middle Aged
dc.subject.mesh	Mutation
dc.subject.mesh	Pedigree
dc.subject.mesh	Protein Folding
dc.subject.mesh	Spinocerebellar Ataxias
dc.subject.mesh	Ubiquitin-Protein Ligases
dc.subject.mesh	Humans
dc.subject.mesh	Spinocerebellar Ataxias
dc.subject.mesh	Ubiquitin-Protein Ligases
dc.subject.mesh	Pedigree
dc.subject.mesh	Family
dc.subject.mesh	Age of Onset
dc.subject.mesh	Gene Expression
dc.subject.mesh	Protein Folding
dc.subject.mesh	Heterozygote
dc.subject.mesh	Genes, Dominant
dc.subject.mesh	Genes, Recessive
dc.subject.mesh	Mutation
dc.subject.mesh	Adult
dc.subject.mesh	Aged
dc.subject.mesh	Middle Aged
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Frontotemporal Dementia
dc.title	Genetic Dominant Variants in STUB1, Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16.
dc.type	Journal Article
utslib.citation.volume	22
utslib.location.activity	Switzerland
utslib.for	0399 Other Chemical Sciences
utslib.for	0604 Genetics
utslib.for	0699 Other Biological Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/Graduate School of Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/Graduate School of Health/GSH.Genetic Counselling
utslib.copyright.status	open_access	*
dc.date.updated	2022-03-04T07:25:03Z
pubs.issue	11
pubs.publication-status	Published online
pubs.volume	22
utslib.citation.issue	11

Abstract:

Variants in STUB1 cause both autosomal recessive (SCAR16) and dominant (SCA48) spinocerebellar ataxia. Reports from 18 STUB1 variants causing SCA48 show that the clinical picture includes later-onset ataxia with a cerebellar cognitive affective syndrome and varying clinical overlap with SCAR16. However, little is known about the molecular properties of dominant STUB1 variants. Here, we describe three SCA48 families with novel, dominantly inherited STUB1 variants (p.Arg51_Ile53delinsProAla, p.Lys143_Trp147del, and p.Gly249Val). All the patients developed symptoms from 30 years of age or later, all had cerebellar atrophy, and 4 had cognitive/psychiatric phenotypes. Investigation of the structural and functional consequences of the recombinant C-terminus of HSC70-interacting protein (CHIP) variants was performed in vitro using ubiquitin ligase activity assay, circular dichroism assay and native polyacrylamide gel electrophoresis. These studies revealed that dominantly and recessively inherited STUB1 variants showed similar biochemical defects, including impaired ubiquitin ligase activity and altered oligomerization properties of the CHIP. Our findings expand the molecular understanding of SCA48 but also mean that assumptions concerning unaffected carriers of recessive STUB1 variants in SCAR16 families must be re-evaluated. More investigations are needed to verify the disease status of SCAR16 heterozygotes and elucidate the molecular relationship between SCA48 and SCAR16 diseases.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/154986