title: STUB1 mutations in autosomal recessive ataxias - evidence for mutation-specific clinical heterogeneity.
abstract: BACKGROUND
  A subset of hereditary cerebellar ataxias is inherited as autosomal recessive traits (ARCAs). Classification of recessive ataxias due to phenotypic differences in the cerebellum and cerebellar structures is constantly evolving due to new identified disease genes. Recently, reports have linked mutations in genes involved in ubiquitination (RNF216, OTUD4, STUB1) to ARCA with hypogonadism.
  
  
  RESULTS
  With a combination of homozygozity mapping and exome sequencing, we identified three mutations in STUB1 in two families with ARCA and cognitive impairment; a homozygous missense variant (c.194A > G, p.Asn65Ser) that segregated in three affected siblings, and a missense change (c.82G > A, p.Glu28Lys) which was inherited in trans with a nonsense mutation (c.430A > T, p.Lys144Ter) in another patient. STUB1 encodes CHIP (C-terminus of Heat shock protein 70 - Interacting Protein), a dual function protein with a role in ubiquitination as a co-chaperone with heat shock proteins, and as an E3 ligase. We show that the p.Asn65Ser substitution impairs CHIP's ability to ubiquitinate HSC70 in vitro, despite being able to self-ubiquitinate. These results are consistent with previous studies highlighting this as a critical residue for the interaction between CHIP and its co-chaperones. Furthermore, we show that the levels of CHIP are strongly reduced in vivo in patients' fibroblasts compared to controls.
  
  
  CONCLUSIONS
  These results suggest that STUB1 mutations might cause disease by impacting not only the E3 ligase function, but also its protein interaction properties and protein amount. Whether the clinical heterogeneity seen in STUB1 ARCA can be related to the location of the mutations remains to be understood, but interestingly, all siblings with the p.Asn65Ser substitution showed a marked appearance of accelerated aging not previously described in STUB1 related ARCA, none display hormonal aberrations/clinical hypogonadism while some affected family members had diabetes, alopecia, uveitis and ulcerative colitis, further refining the spectrum of STUB1 related disease.
authors.forename: Ketil
authors.initials: K
authors.lastname: Heimdal
authors.forename: Monica
authors.initials: M
authors.lastname: Sanchez-Guixé
authors.forename: Ingvild
authors.initials: I
authors.lastname: Aukrust
authors.forename: Jens
authors.initials: J
authors.lastname: Bollerslev
authors.forename: Ove
authors.initials: O
authors.lastname: Bruland
authors.forename: Greg Eigner
authors.initials: GE
authors.lastname: Jablonski
authors.forename: Anne Kjersti
authors.initials: AK
authors.lastname: Erichsen
authors.forename: Einar
authors.initials: E
authors.lastname: Gude
authors.forename: Jeanette A
authors.initials: JA
authors.lastname: Koht
authors.forename: Sigrid
authors.initials: S
authors.lastname: Erdal
authors.forename: Torunn
authors.initials: T
authors.lastname: Fiskerstrand
authors.forename: Bjørn Ivar
authors.initials: BI
authors.lastname: Haukanes
authors.forename: Helge
authors.initials: H
authors.lastname: Boman
authors.forename: Lise
authors.initials: L
authors.lastname: Bjørkhaug
authors.forename: Chantal M E
authors.initials: CM
authors.lastname: Tallaksen
authors.forename: Per M
authors.initials: PM
authors.lastname: Knappskog
authors.forename: Stefan
authors.initials: S
authors.lastname: Johansson
mesh_terms: D000328:Adult; D001259:Ataxia / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D020125:Mutation, Missense; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D055815:Young Adult
chemical_list: C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases