Phenotype and frequency of STUB1 mutations: Next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts

Matthis Synofzik, Rebecca Schüle, Martin Schulze, Janina Gburek-Augustat, Roland Schweizer, Anja Schirmacher, Ingeborg Krägeloh-Mann, Michael Gonzalez, Peter Young, Stephan Züchner, Ludger Schöls, Peter Bauer

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44 Scopus citations


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 languageEnglish (US)
Article number57
JournalOrphanet journal of rare diseases
Issue number1
StatePublished - Apr 17 2014


  • 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)


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