Clinical and pathologic phenotype of a large family with heterozygous
            <i>STUB1</i>
            mutation

Mol, Merel O.; Rooij, Jeroen G.J. van; Brusse, Esther; Verkerk, Annemieke J.M.H.; Melhem, Shamiram; Dunnen, Wilfred F. A. den; Rizzu, Patrizia; Cupidi, Chiara; Swieten, John C. van; Kaat, Laura Donker

doi:10.1212/nxg.0000000000000417

Cited by 24 publications

(21 citation statements)

References 46 publications

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“…Taken together, our findings (1) add an additional qualitative line of evidence for the existence of autosomal-dominant STUB1-disease (hereby corroborating several recent studies [6,9]), (2) provide support for loss-of-function as a mechanism underlying autosomal-dominant STUB1-disease, thus mirroring its autosomal-recessive counterpart and (3) demonstrate that autosomal-dominant STUB1-disease affects the same neurological systems as its autosomal-recessive counterpart. This suggests, in sum, that both modes of inheritance can be associated with a similar STUB1 disease condition and possibly even similar mutational mechanism.…”

Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

“…While variants in STUB1 are well established to cause an autosomal-recessive early-onset multisystemic ataxia (SCAR16) [1][2][3], they have recently received also increasing support to be associated with autosomal-dominant ataxia (SCA48) [4][5][6][7][8][9][10]. Since the initial association of STUB1 with an autosomal-dominant form of spinocerebellar ataxia (SCA48) in 2018, 34 SCA48 patients originating from 17 families have been reported [5][6][7][8][9][10][11][12]. The complex clinical phenotype invariably included ataxia and, in most cases, cognitive and/or psychiatric dysfunction, variably associated with both hyperkinetic and hypokinetic movement disorders, pyramidal tract damage, and urinary symptoms.…”

Section: Introductionmentioning

confidence: 99%

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A de novo STUB1 variant associated with an early adult-onset multisystemic ataxia phenotype

et al. 2021

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Background Biallelic STUB1 variants are a well-established cause of autosomal-recessive early-onset multisystemic ataxia (SCAR16). Evidence for STUB1 variants causing autosomal-dominant ataxia (SCA48) so far largely relies on segregation data in larger families. Presenting the first de novo occurrence of a heterozygous STUB1 variant, we here present additional qualitative evidence for STUB1-disease as an autosomal-dominant disorder. Methods Whole exome sequencing on an index patient with sporadic early-onset ataxia, followed by Sanger sequencing in all family members, was used to identify causative variants as well as to rule out alternative genetic hits and intronic STUB1 variants. STUB1 mRNA and protein levels in PBMCs in all family members were analysed using qRT-PCR and Western Blot. Results A previously unreported start-lost loss-of-function variant c.3G>A in the start codon of STUB1 was identified in the index case, occurring de novo and without evidence for a second (potentially missed) variant (e.g., intronic or copy number) in STUB1. The patient showed an early adult-onset multisystemic ataxia complicated by spastic gait disorder, distal myoclonus and cognitive dysfunction, thus closely mirroring the systems affected in autosomal-recessive STUB1-associated disease. In line with the predicted start-lost effect of the variant, functional investigations demonstrated markedly reduced STUB1 protein expression in PBMCs, whereas mRNA levels were intact. Conclusion De novo occurrence of the loss-of-function STUB1 variant in our case with multisystemic ataxia provides a qualitatively additional line of evidence for STUB1-disease as an autosomal-dominant disorder, in which the same neurological systems are affected as in its autosomal-recessive counterpart. Moreover, this finding adds support for loss-of-function as a mechanism underlying autosomal-dominant STUB1-disease, thus mirroring its autosomal-recessive counterpart also in terms of the underlying mutational mechanism.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A de novo STUB1 variant associated with an early adult-onset multisystemic ataxia phenotype

et al. 2021

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“…35 Fourth, although the age of nonaffected STUB1 heterozygous subjects is not always reported, STUB1 variants in SCA48 families show evidence of reduced penetrance. 24,25,28,36 Fifth, the clinical phenotype and disease course largely overlap between SCA48 and SCA17-DI. Finally, 2 patients with a STUB1 variant were reported to carry an intermediate TBP allele (41 and 46, respectively) as a second hit.…”

Section: Discussionmentioning

confidence: 99%

Digenic inheritance of STUB1 variants and TBP polyglutamine expansions explains the incomplete penetrance of SCA17 and SCA48

Magri

Nanetti

Gellera

et al. 2022

Genetics in Medicine

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This study aimed to unravel the genetic factors underlying missing heritability in spinocerebellar ataxia type 17 (SCA17) caused by polyglutamine-encoding CAG/CAA repeat expansions in the TBP gene. Alleles with >49 CAG/CAA repeats are fully penetrant. Most patients, however, carry intermediate TBP 41-49 alleles that show incomplete penetrance. Methods: Using next-generation sequencing approaches, we investigated 40 SCA17/TBP 41-54 index patients, their affected (n = 55) and unaffected (n = 51) relatives, and a cohort of patients with ataxia (n = 292). Results: All except 1 (30/31) of the index cases with TBP 41-46 alleles carried a heterozygous pathogenic variant in the STUB1 gene associated with spinocerebellar ataxias SCAR16 (autosomal recessive) and SCA48 (autosomal dominant). No STUB1 variant was found in patients carrying TBP 47-54 alleles. TBP 41-46 expansions and STUB1 variants cosegregate in all affected family members, whereas the presence of either TBP 41-46 expansions or STUB1 variants individually was never associated with the disease. Conclusion: Our data reveal an unexpected genetic interaction between STUB1 and TBP in the pathogenesis of SCA17 and raise questions on the existence of SCA48 as a monogenic disease with crucial implications for diagnosis and counseling. They provide a convincing explanation for the incomplete penetrance of intermediate TBP alleles and demonstrate a dual inheritance pattern for SCA17, which is a monogenic dominant disorder for TBP ≥47 alleles and a digenic TBP/STUB1 disease (SCA17-DI) for intermediate expansions.

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“…The same phenomena also occurred to SPTBN2, causing both SCA5 and SCAR15 due to dominant and recessive mutations, respectively 120,121 . The researchers named this disease SCA48 119,[122][123][124][125][126] (Fig. 2 and Table 2).…”

Section: Neurological Diseases Caused By Chip Mutationsmentioning

confidence: 99%

CHIP as a therapeutic target for neurological diseases

Zhang

Mao

et al. 2020

Cell Death Dis

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Carboxy-terminus of Hsc70-interacting protein (CHIP) functions both as a molecular co-chaperone and ubiquitin E3 ligase playing a critical role in modulating the degradation of numerous chaperone-bound proteins. To date, it has been implicated in the regulation of numerous biological functions, including misfolded-protein refolding, autophagy, immunity, and necroptosis. Moreover, the ubiquitous expression of CHIP in the central nervous system suggests that it may be implicated in a wide range of functions in neurological diseases. Several recent studies of our laboratory and other groups have highlighted the beneficial role of CHIP in the pathogenesis of several neurological diseases. The objective of this review is to discuss the possible molecular mechanisms that contribute to the pathogenesis of neurological diseases in which CHIP has a pivotal role, such as stroke, intracerebral hemorrhage, Alzheimer’s disease, Parkinson’s disease, and polyglutamine diseases; furthermore, CHIP mutations could also cause neurodegenerative diseases. Based on the available literature, CHIP overexpression could serve as a promising therapeutic target for several neurological diseases.

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Clinical and pathologic phenotype of a large family with heterozygous STUB1 mutation

Cited by 24 publications

References 46 publications

A de novo STUB1 variant associated with an early adult-onset multisystemic ataxia phenotype

A de novo STUB1 variant associated with an early adult-onset multisystemic ataxia phenotype

Digenic inheritance of STUB1 variants and TBP polyglutamine expansions explains the incomplete penetrance of SCA17 and SCA48

CHIP as a therapeutic target for neurological diseases

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