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dc.contributor.authorHeimdal, Ketil
dc.contributor.authorSanchez-Guixé, Monica
dc.contributor.authorAukrust, Ingvild
dc.contributor.authorBollerslev, Jens
dc.contributor.authorBruland, Ove
dc.contributor.authorJablonski, Greg E
dc.contributor.authorErichsen, Anne K
dc.contributor.authorGude, Einar
dc.contributor.authorKoht, Jeanette A
dc.contributor.authorErdal, Sigrid
dc.contributor.authorFiskerstrand, Torunn
dc.contributor.authorHaukanes, Bjørn I
dc.contributor.authorBoman, Helge
dc.contributor.authorBjørkhaug, Lise
dc.contributor.authorTallaksen, Chantal M
dc.contributor.authorKnappskog, Per M
dc.contributor.authorJohansson, Stefan
dc.date.accessioned2015-10-20T12:45:34Z
dc.date.available2015-10-20T12:45:34Z
dc.date.issued2014
dc.identifier.citationOrphanet Journal of Rare Diseases. 2014 Sep 26;9(1):146
dc.identifier.urihttp://hdl.handle.net/10852/47296
dc.description.abstractBackground 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. Methods and 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.
dc.language.isoeng
dc.rightsHeimdal et al.; licensee BioMed Central Ltd.
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.titleSTUB1 mutations in autosomal recessive ataxias – evidence for mutation-specific clinical heterogeneity
dc.typeJournal article
dc.date.updated2015-10-20T12:45:34Z
dc.creator.authorHeimdal, Ketil
dc.creator.authorSanchez-Guixé, Monica
dc.creator.authorAukrust, Ingvild
dc.creator.authorBollerslev, Jens
dc.creator.authorBruland, Ove
dc.creator.authorJablonski, Greg E
dc.creator.authorErichsen, Anne K
dc.creator.authorGude, Einar
dc.creator.authorKoht, Jeanette A
dc.creator.authorErdal, Sigrid
dc.creator.authorFiskerstrand, Torunn
dc.creator.authorHaukanes, Bjørn I
dc.creator.authorBoman, Helge
dc.creator.authorBjørkhaug, Lise
dc.creator.authorTallaksen, Chantal M
dc.creator.authorKnappskog, Per M
dc.creator.authorJohansson, Stefan
dc.identifier.doihttp://dx.doi.org/10.1186/s13023-014-0146-0
dc.identifier.urnURN:NBN:no-51394
dc.type.documentTidsskriftartikkel
dc.type.peerreviewedPeer reviewed
dc.identifier.fulltextFulltext https://www.duo.uio.no/bitstream/handle/10852/47296/1/13023_2014_Article_146.pdf
dc.type.versionPublishedVersion
cristin.articleid146


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