Investigating <i>TBP</i> CAG/CAA trinucleotide repeat expansions in a Taiwanese cohort with ALS

Jih, Kang-Yang; Lin, Kon‐Ping; Tsai, Pei‐Chien; Soong, Bing‐Wen; Liao, Yi‐Chu; Lee, Yi‐Chung

doi:10.1080/21678421.2020.1867182

Cited by 4 publications

(2 citation statements)

References 31 publications

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“…In our Family B, both the proband and her father were heterozygous for a 41-repeat expansion in TBP . Repeat expansions of 41–45 in TBP have been described as intermediate penetrant alleles associated with SCA17 [ 23 , 24 ]; however, the pathogenicity of the 41-repeat expansion allele has been questioned since it is present at a minor allele frequency of 0.5–0.7% in control populations [ 25 , 26 ] and has been found in many asymptomatic individuals [ 27 ]. Since no SCA17 families with a heterozygous 41-repeat allele and dominant inheritance have been published, it is highly unlikely that this alone can cause the severe phenotype in patient II-1, and milder effects on I-2 in family B.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…2 In addition, the CAG trinucleotide repeats in ATXN1 and ATXN2 as well as the CAG/CAA trinucleotide repeats in TBP have also been implicated in ALS. [3][4][5] The CAG repeat expansion of HTT, another pathogenic tandem repeat expansion, was once thought to be unassociated with ALS. 6,7 However, a recent large-scale study based on two ALS and frontotemporal dementia (FTD) cohorts has provided new evidence supporting that pathogenic HTT repeat expansions are a rare cause of FTD and ALS spectrum diseases.…”

Section: Introductionmentioning

confidence: 99%

Reduced-penetrance Huntington’s disease-causing alleles with 39 CAG trinucleotide repeats could be a genetic factor of amyotrophic lateral sclerosis

Jih

Lai

Lin

et al. 2022

Journal of the Chinese Medical Association

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Background: Expanded HTT alleles with 40 or more CAG repeats were recently found to be a rare cause of frontotemporal dementia and amyotrophic lateral sclerosis (ALS) spectrum diseases. The aim of this study was to investigate the role of HTT repeat expansions in a Taiwanese cohort with ALS. Methods: We analyzed the numbers of CAG repeats in exon 1 of HTT in a cohort of 410 Taiwanese patients with ALS and 1514 control individuals by utilizing polymerase chain reaction and amplicon fragment length analysis. Results: Only one of the 410 ALS patients carried a reduced-penetrance HD-causing allele with 39 CAG repeats, and none had an expanded HTT CAG repeats ≥40. The patient presented with rapidly progressive bulbar-onset ALS with disease onset at the age of 64 years. He had neither chorea nor cognitive impairment. He had a family history of chorea, but no other family member manifested with ALS. None of the 1514 control individuals carried an HTT expanded allele with CAG repeats larger than 37 repeats. Conclusion: The HTT allele with 39 CAG repeats could be a genetic factor linked to ALS susceptibility.

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Autosomal dominant cerebellar ataxias: new genes and progress towards treatments

Coarelli

Coutelier

Dürr

2023

The Lancet Neurology

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Investigating TBP CAG/CAA trinucleotide repeat expansions in a Taiwanese cohort with ALS

Cited by 4 publications

References 31 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

Reduced-penetrance Huntington’s disease-causing alleles with 39 CAG trinucleotide repeats could be a genetic factor of amyotrophic lateral sclerosis

Autosomal dominant cerebellar ataxias: new genes and progress towards treatments

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