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 - Züchner, Stephan
AU - Schöls, Ludger
AU - Bauer, Peter
N1 - Funding Information:
We are grateful to Jennifer Reichbauer (Hertie-Institute for Clinical Brain Research, Tübingen) and Avencia Sanchez Mejias Garcia (John P. Hussman Institute for Human Genomics, Miami) for performing the Sanger sequencing in some of the subjects. This study was supported by the Interdisciplinary Center for Clinical Research IZKF Tübingen (grant 2191-0-0 to MS, grant 1970-0-0 to RS), the European Union (grant F5-2012-305121 “NEUROMICS” to LS and grant PIOF-GA-2012-326681 “HSP/CMT genetics” to RS), E-RARE grants of the German Ministry for Education and Research (BMBF) to the EUROSCAR project (grant 01GM1206) and the EUROSPA project (grant 01GM0807) (to LS and PB), and the National Institute of Health (NIH) (grants 5R01NS072248 to SZ, 1R01NS075764 to SZ, 5R01NS054132 to SZ). We acknowledge support by the “Deutsche Forschungsgemeinschaft” (DFG) and the Open Access Publishing Fund of Tuebingen University.
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
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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 -