Expanding the clinical spectrum of STIP1 homology and U-box containing protein 1-associated ataxia

Ravel, Jean‐Marie; Benkirane, Mehdi; Calmels, Nadège; Marelli, Cécilia; Ory‐Magne, Fabienne; Ewenczyk, Claire; Halleb, Yosra; Tison, François; Lecocq, Claire; Pisché, Guillaume; Casenave, Philippe; Chaussenot, Annabelle; Frismand, Solène; Tyvaert, Louise; Larrieu, Lise; Pointaux, Morgane; Drouot, Nathalie; Bossenmeyer‐Pourié, Carine; Oussalah, Abderrahim; Guéant, Jean‐Louis; Leheup, Bruno; Bonnet, Céline; Anheim, Mathieu; Tranchant, Christine; Lambert, Laëtitia; Chelly, Jamel; Kœnig, M.; Renaud, Mathilde

doi:10.1007/s00415-020-10348-x

Cited by 18 publications

(23 citation statements)

References 38 publications

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“…In our cohort, STUB1, a gene originally described in SCAR16 and recently also associated with SCA48 [64], was found to be the most frequent disease-causing gene in HA [61,63], as also confirmed by others [95,96]. We cannot, however, exclude that the relative novelty of this gene might be a source of bias explaining its high rate in our study.…”

Section: Discussionsupporting

confidence: 61%

NGS in Hereditary Ataxia: When Rare Becomes Frequent

Galatolo

Michele

Silvestri

et al. 2021

IJMS

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The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests. We obtained a positive result (genetic diagnosis) in 33.2% of the patients, a rate significantly higher than those reported in similar studies employing TRP (average 19.4%), and in line with those performed using exome sequencing (ES, average 34.6%). Moreover, 15.6% of the patients had an uncertain molecular diagnosis. STUB1, PRKCG, and SPG7 were the most common causative genes. A comparison with published literature data showed that our panel would have identified 97% of the positive cases reported in previous TRP-based studies and 92% of those diagnosed by ES. Proper use of multigene panels, when combined with detailed phenotypic data, seems to be even more efficient than ES in clinical practice.

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Section: Discussionsupporting

confidence: 61%

NGS in Hereditary Ataxia: When Rare Becomes Frequent

Galatolo

Michele

Silvestri

et al. 2021

IJMS

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“…In 2019, heterozygous STUB1 mutations identified in patients with ataxia uncovered a new classification of autosomal dominant spinocerebellar ataxia, SCA48 [94]. To date 19 different CHIP mutations have been identified in SCA48 patients [91,95,96]. SCA48-associated disease mutations are limited to the TPR and U-box domain in CHIP with one exception; a nonsense mutation (p.R225*) at the end of the coiled-coil domain that results in the deletion of the entire U-box domain [91].…”

Section: Spinocerebellar Ataxiasmentioning

confidence: 99%

With or Without You: Co-chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

Altınok¹,

Sanchez‐Hodge²,

Stewart³

et al. 2021

Preprint

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Heat shock proteins (HSPs) are a family of molecular chaperones that regulate essential protein refolding and triage decisions to maintaining protein homeostasis. Numerous co-chaperone proteins directly interact and modify the function of HSPs, and these interactions impact the outcome of protein triage, impacting everything from structural proteins to cell signaling mediators. The chaperone/co-chaperone machinery protects against various stressors to ensuring cellular function in the face of stress. However, coding mutations, expression changes, and post-translational modifications of the chaperone/co-chaperone machinery can alter the cellular stress response. Importantly, these dysfunctions appear to contribute to numerous human diseases. Therapeutic targeting of chaperones is an attractive but challenging approach due to the vast functions of HSPs, likely contributing to the off-target effects of these therapies. Current efforts focus on targeting co-chaperones to develop precise treatments for numerous diseases caused by defects in protein quality control. This review focuses on the recent developments regarding selected HSP70/HSP90 co-chaperones, focusing on cardioprotection, neuroprotection, and cancer. We also discuss therapeutic approaches that highlight both the utility and challenges of targeting co-chaperones.

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“…To date, 18 heterozygous pathogenic STUB1 variants have been reported to be associated with a SCA48 phenotype; however, how these mutations affect protein structure and the function remains unclear. Functional data are essential to elucidate mechanisms underlying the dominant inheritance of this disease [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic Dominant Variants in STUB1, Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16

Pakdaman

Berland

Bustad

et al. 2021

IJMS

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Variants in STUB1 cause both autosomal recessive (SCAR16) and dominant (SCA48) spinocerebellar ataxia. Reports from 18 STUB1 variants causing SCA48 show that the clinical picture includes later-onset ataxia with a cerebellar cognitive affective syndrome and varying clinical overlap with SCAR16. However, little is known about the molecular properties of dominant STUB1 variants. Here, we describe three SCA48 families with novel, dominantly inherited STUB1 variants (p.Arg51_Ile53delinsProAla, p.Lys143_Trp147del, and p.Gly249Val). All the patients developed symptoms from 30 years of age or later, all had cerebellar atrophy, and 4 had cognitive/psychiatric phenotypes. Investigation of the structural and functional consequences of the recombinant C-terminus of HSC70-interacting protein (CHIP) variants was performed in vitro using ubiquitin ligase activity assay, circular dichroism assay and native polyacrylamide gel electrophoresis. These studies revealed that dominantly and recessively inherited STUB1 variants showed similar biochemical defects, including impaired ubiquitin ligase activity and altered oligomerization properties of the CHIP. Our findings expand the molecular understanding of SCA48 but also mean that assumptions concerning unaffected carriers of recessive STUB1 variants in SCAR16 families must be re-evaluated. More investigations are needed to verify the disease status of SCAR16 heterozygotes and elucidate the molecular relationship between SCA48 and SCAR16 diseases.

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Expanding the clinical spectrum of STIP1 homology and U-box containing protein 1-associated ataxia

Cited by 18 publications

References 38 publications

NGS in Hereditary Ataxia: When Rare Becomes Frequent

NGS in Hereditary Ataxia: When Rare Becomes Frequent

With or Without You: Co-chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

Genetic Dominant Variants in STUB1, Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16

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