Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Roux, Thomas Le; Barbier, Mathieu; Papin, Mélanie; Davoine, Claire-Sophie; Sayah, Sabrina; Coarelli, Giulia; Charles, Perrine; Parodi, Livia; Tranchant, Christine; Klebe, Stephan; Lohmann, Ebba; Maldergem, Lionel Van; Broeckhoven, Christine Van; Coutelier, Marie; Tesson, Christelle; Stevanin, Giovanni; Duyckaerts, Charles; Brice, Alexis; Dürr, Alexandra; Darios, Frédéric; Forlani, Sylvie; Site, Pitié-Salpêtrière; Banneau, Guillaume; Cazeneuve, Cécile; Fontaine, Bertrand; Azulay, Jean‐Philippe; Boesfplug-Tanguy, Odile; Goizet, Cyril; Hannequin, Didier; Hazan, Jamilé; Burgo, Andrea; Verny, Christophe; Kœnig, M.; Labauge, Pierre; Marelli, Cécilia; Nguyen, Karine; Rodriguez, Diana; Belarbi, Soreya; Hamri, Abdelmadjid; Tazir, Mériem; Boesch, Sylvia; Pandolfo, Massimo; Jardim, Laura; Guergueltcheva, Velina; Tournev, Ivalo; Linares, Olga Lucía Pedraza; Nielsen, Jørgen E.; Svenstrup, Kirsten; Zaki, Maha S.; Bauer, Péter; Schöls, Lüdger; Schüle, Rebecca; Lossos, Alexander; Bassi, Maria-Teresa; Basso, Manuela; Bertini, Enrico; Brusco, Alfredo; Casali, Carlo; Casari, Giorgio; Criscuolo, Chiara; Filla, Alessandro; Orsi, Laura; Santorelli, Filippo M.; Valente, Enza Maria; Vavla, Marinela; Vazza, Giovanni; Mégarbané, André; Benomar, Ali; Kremer, Berry; Roon-Mom, Willeke van; Roxburgh, Richard; Erichsen, Anne Kjersti; Tallaksen, Chantal; Alonso, Isabel; Coutinho, Paula; Loureiro, José; Sequeiros, Jorge; Salih, Mustapha; Kostić, Vladimir; Axpe, I. Rouco; Elsayed, Liena; Paucar, Martin; Roumani, Samir; Soong, Bing‐Wen; Reid, Evan; Nethisinghe, Suran; Warner, Thomas T.; Wood, Nicholas W.

doi:10.1038/s41436-020-0899-x

Cited by 31 publications

(51 citation statements)

References 27 publications

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“…Seven patients from three families were investigated. Clinically, all patients had a phenotype compatible with that described in SCA48 [ 4 , 5 , 16 , 17 ], and the majority of them had an early-onset dysarthria and progressive cerebellar ataxia with cognitive impairment developing later. Parkinsonism was seen in one patient.…”

Section: Discussionmentioning

confidence: 81%

“…Despite a small sample size, we observed a tendency for females to develop a more severe phenotype, with earlier onset, than men. A sex-dependent penetrance has been suggested earlier [ 17 ], but also been questioned [ 18 ], and larger cohorts are probably needed to resolve this question.…”

Section: Discussionmentioning

confidence: 99%

“…The SCAR16 variant p.Asn65Ser (N65S) was originally described as a cause of SCAR16 in three siblings born from healthy parents [ 22 ]. This variant was, however, was recently reported as a cause for an autosomal dominant disorder in three families, with later onset and different clinical picture compared to the original SCAR16 families [ 17 ]. Based on this, we suggest that a close follow up of STUB1 carriers in SCAR16 families is warranted.…”

Section: Discussionmentioning

confidence: 99%

“…Penetrance may possibly vary to a greater degree in dominant forms, and it is probable that genetic variation elsewhere in the genome impacts the penetrance or expression of certain variants. For example, an additional variant of unknown significance in PRKCG , the gene coding for protein kinase C Gamma associated with SCA14, was seen in heterozygous carriers of N65S, suggesting a possible synergy of the two variants in the early development of disease [ 17 ]. In our Family B, both the proband and her father were heterozygous for a 41-repeat expansion in TBP .…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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“…Furthermore, we investigated the biological functions of these DEGs by using online website, and GO and pathway enrichment analysis. Husemoen et al [ [94], Tang et al [95], Goodier et al [96], Petyuk et al [97], Roux et al [98], Castrogiovanni et al [99], Suleiman et al [100] [111], Ma et al [112], Chabbert et al [113], Abramsson et al [114], Aeby et al [115] and Roll et al [116] found that the expression of DCC (DCC netrin 1 receptor), PLP1, SNX19, SH3RF1, TNFRSF1A, NCSTN (nicastrin), DGCR2, NPAS2, CDNF (cerebral dopamine neurotrophic factor), SMCR8, HSPA2, STUB1, CHID1, ATP13A2, SQSTM1, LIG3, SP4, ACSL6, ERN1, ATF6B, LRFN2, NRG3, LRRTM3, GABRA2, ADAM30, GABRR2, TSHZ3, LOXL1, SCN1B and SRPX2 are associated with the prognosis of patients with cognitive impairment, but these genes might be novel target for T1DM. Recent studies found that KCP (kielin cysteine rich BMP regulator) [117], NOG (noggin) [118], COL6A3 [119], BTG2 [120], RPS6 [121], KLF15 [122], KLF3 [123], ZFP36 [124], ETV5 [125], TLE3 [126], NNMT (nicotinamide Nmethyltransferase) [127], WDTC1 [128], ZFHX3 [129], SIAH2 [130], MBOAT7 [131], RUNX1T1 [132], MAPK4 [133], KLF9 [134], SELENBP1 [135], HELZ2 [136], ELK1 [137], SERTAD2 [138], CRTC3 [139], ABCB11 [140], TACR1 [141], SLC22A11 [142], PER3…”

Section: Discussionmentioning

confidence: 99%

Identification of candidate biomarkers and pathways associated with type 1 diabetes mellitus using bioinformatics analysis

Bm¹,

Cm²

2021

Preprint

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Type 1 diabetes mellitus (T1DM) is a metabolic disorder for which the underlying molecular mechanisms remain largely unclear. This investigation aimed to elucidate essential candidate genes and pathways in T1DM by integrated bioinformatics analysis. In this study, differentially expressed genes (DEGs) were analyzed using DESeq2 of R package from GSE162689 of the Gene Expression Omnibus (GEO). Gene ontology (GO) enrichment analysis, REACTOME pathway enrichment analysis, and construction and analysis of protein-protein interaction (PPI) network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network, and validation of hub genes were then performed. A total of 952 DEGs (477 up regulated and 475 down regulated genes) were identified in T1DM. GO and REACTOME enrichment result results showed that DEGs mainly enriched in multicellular organism development, detection of stimulus, diseases of signal transduction by growth factor receptors and second messengers, and olfactory signaling pathway. The top hub genes such as MYC, EGFR, LNX1, YBX1, HSP90AA1, ESR1, FN1, TK1, ANLN and SMAD9 were screened out as the critical genes among the DEGs from the PPI network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network. Receiver operating characteristic curve (ROC) analysis and RT-PCR confirmed that these genes were significantly associated with T1DM. In conclusion, the identified DEGs, particularly the hub genes, strengthen the understanding of the advancement and progression of T1DM, and certain genes might be used as candidate target molecules to diagnose, monitor and treat T1DM.

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Nomenclature of Genetic Movement Disorders: Recommendations of the International Parkinson and Movement Disorder Society Task Force – An Update

et al. 2022

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In 2016, the Movement Disorder Society Task Force for the Nomenclature of Genetic Movement Disorders presented a new system for naming genetically determined movement disorders and provided a criterion‐based list of confirmed monogenic movement disorders. Since then, a substantial number of novel disease‐causing genes have been described, which warrant classification using this system. In addition, with this update, we further refined the system and propose dissolving the imaging‐based categories of Primary Familial Brain Calcification and Neurodegeneration with Brain Iron Accumulation and reclassifying these genetic conditions according to their predominant phenotype. We also introduce the novel category of Mixed Movement Disorders (MxMD), which includes conditions linked to multiple equally prominent movement disorder phenotypes. In this article, we present updated lists of newly confirmed monogenic causes of movement disorders. We found a total of 89 different newly identified genes that warrant a prefix based on our criteria; 6 genes for parkinsonism, 21 for dystonia, 38 for dominant and recessive ataxia, 5 for chorea, 7 for myoclonus, 13 for spastic paraplegia, 3 for paroxysmal movement disorders, and 6 for mixed movement disorder phenotypes; 10 genes were linked to combined phenotypes and have been assigned two new prefixes. The updated lists represent a resource for clinicians and researchers alike and they have also been published on the website of the Task Force for the Nomenclature of Genetic Movement Disorders on the homepage of the International Parkinson and Movement Disorder Society (https://www.movementdisorders.org/MDS/About/Committees--Other-Groups/MDS-Task-Forces/Task-Force-on-Nomenclature-in-Movement-Disorders.htm). © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

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Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Cited by 31 publications

References 27 publications

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

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

Identification of candidate biomarkers and pathways associated with type 1 diabetes mellitus using bioinformatics analysis

Nomenclature of Genetic Movement Disorders: Recommendations of the International Parkinson and Movement Disorder Society Task Force – An Update

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