STUB1 mutations in autosomal recessive ataxias – evidence for mutation-specific clinical heterogeneity

Abstract

BackgroundA 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 resultsWith 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0146-0) contains supplementary material, which is available to authorized users.

In vitro characterization of six STUB1 variants in spinocerebellar ataxia 16 reveals altered structural properties for the encoded CHIP proteins

“…Future studies should focus on the in cellulo characterization of mutations, using appropriate cell lines and animal models. Since all the mutants were associated with altered stability in vitro , it is likely that this will lead to reduced cellular levels of these variants, as was seen for E28K, N65S, and M211I previously [3,4]. Therefore, further investigations are required in order to find out how misfolding of CHIP itself can lead to the development of SCAR16 in vivo .…”

The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover

“…With regard to the conserved regulation, it is intriguing that mutations in the orthologous human gene STUB1 are linked to accelerated aging (Heimdal et al., 2014). Given the importance of insulin signaling for metabolic regulation, it is also interesting that liver cells of CHIP-null mutant mice develop insulin resistance (Kim et al., 2016).…”

Extending the Phenotypic Spectrum Associated with STUB1 Mutations: A Case of Dystonia

“…To date, there have been 15 families (with 29 members) reported with SCAR16 (ATX‐ STUB1 ; detailed phenotypic data including our patient are presented in Table ) . A total of 20 pathogenic variants in the STUB1 gene causing SCAR16 (ATX‐ STUB1 ) have been described, including truncation, missense, and splice site donor mutation . Dystonia in SCAR16 (ATX‐ STUB1 ) has been described in 1 report of 2 brothers (of 3 affected family members by SCAR16) by Kawarai and colleagues .…”

“…Dystonia is not frequently reported. Associated disease phenotypes are autosomal SCAR16 (ATX‐ STUB1 ), autosomal‐dominant SCA48, and Gordon Holmes syndrome (ATX‐RNF216) . Gordon Holmes syndrome (MIM 212840; ATX‐RNF216) combines autosomal‐recessive ataxia with hypogonadotrophic hypogonadism (low FSH and LH levels).…”

“…It is caused by a homozygous or compound heterozygous mutation in the STUB1 gene on chromosome 16p13 encoding the carboxylate‐terminus of Hsc70 interacting (CHIP) protein (E3 ligase), essential in protein quality control of the ubiquitin proteasome system. Age at onset is variable and ranges from 2 to 57 …”