Homozygote of spinocerebellar Ataxia type 3 correlating with severe phenotype based on analyses of clinical features

Shang, Xianjin; Xu, Hao-Ling; Yang, Jiajun; Chen, Pingping; Lin, Min; Qian, Mei-Zhen; Lin, Hui‐Xia; Chen, Xiaoping; Chen, Yuchao; Jiang, Bin; Chen, Yijun; Chen, Wan‐Jin; Wang, Ning; Zhou, Zhiming; Gan, Shi‐Rui

doi:10.1016/j.jns.2018.04.026

Cited by 7 publications

(8 citation statements)

References 24 publications

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“…SCAR16 is a recessive disorder caused by either a homozygous mutation (the same mutation on each allele) or a compound heterozygous mutation (different mutation on each allele). In other recessive forms of spinocerebellar ataxia, homozygous mutations associate with earlier AOO and higher degrees of ataxia (21, 22). The AOO of SCAR16 patients with homozygous mutations was 12 years earlier than patients with compound heterozygous mutations (Fig.…”

Section: Resultsmentioning

confidence: 99%

Changes in protein function underlie the disease spectrum in patients with CHIP mutations

Madrigal

McNeil

Sanchez‐Hodge

et al. 2019

Journal of Biological Chemistry

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Monogenetic disorders that cause cerebellar ataxia are characterized by defects in gait and atrophy of the cerebellum; however, patients often suffer from a spectrum of disease, complicating treatment options. Spinocerebellar ataxia autosomal recessive 16 (SCAR16) is caused by coding mutations in STUB1, a gene that encodes the multifunctional enzyme CHIP (C terminus of HSC70-interacting protein). The disease spectrum of SCAR16 includes a varying age of disease onset, cognitive dysfunction, increased tendon reflex, and hypogonadism. Although SCAR16 mutations span the multiple functional domains of CHIP, it is unclear whether the location of the mutation and the change in the biochemical properties of CHIP contributes to the clinical spectrum of SCAR16. In this study, we examined relationships between the clinical phenotypes of SCAR16 patients and the changes in biophysical, biochemical, and functional properties of the corresponding mutated protein. We found that the severity of ataxia did not correlate with age of onset; however, cognitive dysfunction, increased tendon reflex, and ancestry were able to predict 54% of the variation in ataxia severity. We further identified domain-specific relationships between biochemical changes in CHIP and clinical phenotypes and specific biochemical activities that associate selectively with either increased tendon reflex or cognitive dysfunction, suggesting that specific changes to CHIP–HSC70 dynamics contribute to the clinical spectrum of SCAR16. Finally, linear models of SCAR16 as a function of the biochemical properties of CHIP support the concept that further inhibiting mutant CHIP activity lessens disease severity and may be useful in the design of patient-specific targeted approaches to treat SCAR16.

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Section: Resultsmentioning

confidence: 99%

Changes in protein function underlie the disease spectrum in patients with CHIP mutations

Madrigal

McNeil

Sanchez‐Hodge

et al. 2019

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…SCAR16 is a recessive disorder caused by either a homozygous mutation (the same mutation on each allele) or a compound heterozygous mutation (different mutation on each allele). In other recessive forms of spinocerebellar ataxia, homozygous mutations associate with earlier AOO and higher degrees of ataxia (26,27). The AOO of SCAR16 patients with homozygous mutations was 12 years earlier than patients with compound heterozygous mutations (Figure 1C).…”

Section: Relationships Within the Clinical Spectrum Of Scar16mentioning

confidence: 93%

Changes in protein function underlies the disease spectrum in patients with CHIP mutations

Madrigal

McNeil

Shi

et al. 2019

Preprint

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Monogenetic disorders that cause cerebellar ataxia are characterized by defects in gait and atrophy of the cerebellum; however, patients often suffer from a spectrum of disease, complicating treatment options. Spinocerebellar ataxia autosomal recessive 16 (SCAR16) is caused by coding mutations in STUB1, a gene that encodes the multi-functional enzyme CHIP (C-terminus of HSC70-interacting protein). The spectrum of disease found in SCAR16 patients includes a wide range in the age of disease onset, cognitive dysfunction, increased tendon reflex, and hypogonadism. Although SCAR16 mutations span the multiple functional domains of CHIP, it is unclear if the location of the mutation contributes to the clinical spectrum of SCAR16 or with changes in the biochemical properties of CHIP. In this study, we examined the associations and relationships between the clinical phenotypes of SCAR16 patients and how they relate to changes in the biophysical, biochemical, and functional properties of the corresponding mutated protein. We found that the severity of ataxia did not correlate with age of onset; however, cognitive dysfunction, increased tendon reflex, and ancestry were able to predict 54% of the variation in ataxia severity. We further identified domain-specific relationships between biochemical changes in CHIP and clinical phenotypes, and specific biochemical activities that associate selectively to either increased tendon reflex or cognitive dysfunction, suggesting that specific changes to CHIP-HSC70 dynamics contributes to the clinical spectrum of SCAR16. Finally, linear models of SCAR16 as a function of the biochemical properties of CHIP support the concept that further inhibiting mutant CHIP activity lessens disease severity and may be useful in the design of patient-specific targeted approaches to treat SCAR16. ataxia | aging | ubiquitin | protein quality control | modeling disease 1 These authors contributed equally to this work 2

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“…An inverse relationship between the age at onset (AAO) and the number of CAG repeats in the pathogenic allele has been widely reported. 3 , 4 …”

Section: Introductionmentioning

confidence: 99%

“…An inverse relationship between the age at onset (AAO) and the number of CAG repeats in the pathogenic allele has been widely reported. 3,4 To date, few studies have recorded homozygous cases among patients with SCA3. [3][4][5][6][7][8][9][10] Homozygous individuals carrying both expanded ATXN3 alleles present with an earlier AAO and more severe clinical symptoms than heterozygotes, which may result from an effect of gene dosage.…”

Section: Introductionmentioning

confidence: 99%

Homozygous spinocerebellar ataxia type 3 in China: a case report

Chen

Wei

et al. 2021

J Int Med Res

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Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease caused by a heterozygous CAG repeat expansion in the ataxin 3 gene ( ATXN3). However, patients with homozygous SCA3 carrying expanded CAG repeats in both alleles of ATXN3 are extremely rare. Herein, we present a case of a 50-year-old female who had homozygous SCA3 with expansion of 62/62 repeats. Segregation analysis of the patient’s family showed both a contraction pattern of CAG repeat length and stable transmission. The present case demonstrated an earlier onset and more severe clinical phenotype than that seen in heterozygous individuals, suggesting that the gene dosage enhances disease severity.

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Homozygote of spinocerebellar Ataxia type 3 correlating with severe phenotype based on analyses of clinical features

Cited by 7 publications

References 24 publications

Changes in protein function underlie the disease spectrum in patients with CHIP mutations

Changes in protein function underlie the disease spectrum in patients with CHIP mutations

Changes in protein function underlies the disease spectrum in patients with CHIP mutations

Homozygous spinocerebellar ataxia type 3 in China: a case report

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