Abstract
Background: Mutations in the gene STUB1, encoding the protein CHIP (C-terminus of HSC70-interacting protein), have recently been suggested as a cause of recessive ataxia based on the findings in few Chinese families. Here we aimed to investigate the phenotypic and genotypic spectrum of STUB1 mutations, and to assess their frequency in different Caucasian disease cohorts. Methods. 300 subjects with degenerative ataxia (n = 167) or spastic paraplegia (n = 133) were screened for STUB1 variants by whole-exome-sequencing (n = 204) or shotgun-fragment-library-sequencing (n = 96). To control for the specificity of STUB1 variants, we screened an additional 1707 exomes from 891 index families with other neurological diseases. Results: We identified 3 ataxia patients (3/167 = 1.8%) with 4 novel missense mutations in STUB1, including 3 mutations in its tetratricopeptide-repeat domain. All patients showed evidence of pyramidal tract damage. Cognitive impairment was present only in one and hypogonadism in none of them. Ataxia did not start before age 48 years in one subject. No recessive STUB1 variants were identified in families with other neurological diseases, demonstrating that STUB1 variants are not simply rare polymorphisms ubiquitous in neurodegenerative disease. Conclusions: STUB1-disease occurs also in Caucasian ataxia populations (1.8%). Our results expand the genotypic spectrum of STUB1-disease, showing that pathogenic mutations affect also the tetratricopeptide-repeat domain, thus providing clinical evidence for the functional importance of this domain. Moreover, they further delineate the phenotypic core features of STUB1-ataxia. Pyramidal tract damage is a common accompanying feature and can include lower limb spasticity, thus adding STUB1-ataxia to the differential diagnosis of "spastic ataxias". However, STUB1 is rare in subjects with predominant spastic paraplegia (0/133). In contrast to previous reports, STUB1-ataxia can start even above age 40 years, and neither hypogonadism nor prominent cognitive impairment are obligatory features.
| Original language | English |
|---|---|
| Article number | 57 |
| Journal | Orphanet Journal of Rare Diseases |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| State | Published - Apr 17 2014 |
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Keywords
- Ataxia
- Cognitive impairment
- Early onset ataxia
- Electrophysiology
- Genetics
- Hereditary spastic paraplegia
- Hypogonadism
- Magnetic resonance imaging
- Recessive ataxia
- Spastic ataxia
ASJC Scopus subject areas
- Medicine(all)
- Genetics(clinical)
- Pharmacology (medical)
Cite this
Phenotype and frequency of STUB1 mutations : Next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts. / Synofzik, Matthis; Schüle, Rebecca; Schulze, Martin; Gburek-Augustat, Janina; Schweizer, Roland; Schirmacher, Anja; Krägeloh-Mann, Ingeborg; Gonzalez, Michael; Young, Peter; Zuchner, Stephan L; Schöls, Ludger; Bauer, Peter.
In: Orphanet Journal of Rare Diseases, Vol. 9, No. 1, 57, 17.04.2014.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Phenotype and frequency of STUB1 mutations
T2 - Next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts
AU - Synofzik, Matthis
AU - Schüle, Rebecca
AU - Schulze, Martin
AU - Gburek-Augustat, Janina
AU - Schweizer, Roland
AU - Schirmacher, Anja
AU - Krägeloh-Mann, Ingeborg
AU - Gonzalez, Michael
AU - Young, Peter
AU - Zuchner, Stephan L
AU - Schöls, Ludger
AU - Bauer, Peter
PY - 2014/4/17
Y1 - 2014/4/17
N2 - Background: Mutations in the gene STUB1, encoding the protein CHIP (C-terminus of HSC70-interacting protein), have recently been suggested as a cause of recessive ataxia based on the findings in few Chinese families. Here we aimed to investigate the phenotypic and genotypic spectrum of STUB1 mutations, and to assess their frequency in different Caucasian disease cohorts. Methods. 300 subjects with degenerative ataxia (n = 167) or spastic paraplegia (n = 133) were screened for STUB1 variants by whole-exome-sequencing (n = 204) or shotgun-fragment-library-sequencing (n = 96). To control for the specificity of STUB1 variants, we screened an additional 1707 exomes from 891 index families with other neurological diseases. Results: We identified 3 ataxia patients (3/167 = 1.8%) with 4 novel missense mutations in STUB1, including 3 mutations in its tetratricopeptide-repeat domain. All patients showed evidence of pyramidal tract damage. Cognitive impairment was present only in one and hypogonadism in none of them. Ataxia did not start before age 48 years in one subject. No recessive STUB1 variants were identified in families with other neurological diseases, demonstrating that STUB1 variants are not simply rare polymorphisms ubiquitous in neurodegenerative disease. Conclusions: STUB1-disease occurs also in Caucasian ataxia populations (1.8%). Our results expand the genotypic spectrum of STUB1-disease, showing that pathogenic mutations affect also the tetratricopeptide-repeat domain, thus providing clinical evidence for the functional importance of this domain. Moreover, they further delineate the phenotypic core features of STUB1-ataxia. Pyramidal tract damage is a common accompanying feature and can include lower limb spasticity, thus adding STUB1-ataxia to the differential diagnosis of "spastic ataxias". However, STUB1 is rare in subjects with predominant spastic paraplegia (0/133). In contrast to previous reports, STUB1-ataxia can start even above age 40 years, and neither hypogonadism nor prominent cognitive impairment are obligatory features.
AB - Background: Mutations in the gene STUB1, encoding the protein CHIP (C-terminus of HSC70-interacting protein), have recently been suggested as a cause of recessive ataxia based on the findings in few Chinese families. Here we aimed to investigate the phenotypic and genotypic spectrum of STUB1 mutations, and to assess their frequency in different Caucasian disease cohorts. Methods. 300 subjects with degenerative ataxia (n = 167) or spastic paraplegia (n = 133) were screened for STUB1 variants by whole-exome-sequencing (n = 204) or shotgun-fragment-library-sequencing (n = 96). To control for the specificity of STUB1 variants, we screened an additional 1707 exomes from 891 index families with other neurological diseases. Results: We identified 3 ataxia patients (3/167 = 1.8%) with 4 novel missense mutations in STUB1, including 3 mutations in its tetratricopeptide-repeat domain. All patients showed evidence of pyramidal tract damage. Cognitive impairment was present only in one and hypogonadism in none of them. Ataxia did not start before age 48 years in one subject. No recessive STUB1 variants were identified in families with other neurological diseases, demonstrating that STUB1 variants are not simply rare polymorphisms ubiquitous in neurodegenerative disease. Conclusions: STUB1-disease occurs also in Caucasian ataxia populations (1.8%). Our results expand the genotypic spectrum of STUB1-disease, showing that pathogenic mutations affect also the tetratricopeptide-repeat domain, thus providing clinical evidence for the functional importance of this domain. Moreover, they further delineate the phenotypic core features of STUB1-ataxia. Pyramidal tract damage is a common accompanying feature and can include lower limb spasticity, thus adding STUB1-ataxia to the differential diagnosis of "spastic ataxias". However, STUB1 is rare in subjects with predominant spastic paraplegia (0/133). In contrast to previous reports, STUB1-ataxia can start even above age 40 years, and neither hypogonadism nor prominent cognitive impairment are obligatory features.
KW - Ataxia
KW - Cognitive impairment
KW - Early onset ataxia
KW - Electrophysiology
KW - Genetics
KW - Hereditary spastic paraplegia
KW - Hypogonadism
KW - Magnetic resonance imaging
KW - Recessive ataxia
KW - Spastic ataxia
UR - http://www.scopus.com/inward/record.url?scp=84899569375&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84899569375&partnerID=8YFLogxK
U2 - 10.1186/1750-1172-9-57
DO - 10.1186/1750-1172-9-57
M3 - Article
C2 - 24742043
AN - SCOPUS:84899569375
VL - 9
JO - Orphanet Journal of Rare Diseases
JF - Orphanet Journal of Rare Diseases
SN - 1750-1172
IS - 1
M1 - 57
ER -