Identification of
            <i>PSMB5</i>
            as a genetic modifier of fragile X–associated tremor/ataxia syndrome

Kong, Ha Eun; Linsalata, Alexander E.; Kang, Yunhee; Malik, Indranil; Allen, Emily G.; Cao, Yiqu; Shubeck, Lisa; Johnston, Rich; Huang, Yanting; Gu, Yanghong; Guo, Xiangxue; Zwick, Michael E.; Qin, Zhaohui; Wingo, Thomas S.; Juncos, Jorge L.; Nelson, David L.; Epstein, Michael P.; Cutler, David J.; Todd, Peter K.; Sherman, Stephanie L.; Warren, Stephen T.; Jin, Peng

doi:10.1073/pnas.2118124119

Cited by 8 publications

(9 citation statements)

References 54 publications

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“…Furthermore, modifier genes can also impact the phenotypic expression of neurodevelopmental disorders. For example, in fragile X-associated tremor/ataxia syndrome (FXTAS), caused by expanded CGG repeat mutations in the FMR1 gene, PSMB5 (proteasome subunit, beta-type 5) acting as a strong suppressor of CGG-associated neurodegeneration, has been associated with a delayed onset of FXTAS in human premutation carriers [22].…”

Section: Phenotypic Variability and Modifiers In Presumed Monogenic D...mentioning

confidence: 99%

Digenic or oligogenic mutations in presumed monogenic disorders: A review

et al. 2023

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Monogenic disorders are traditionally attributed to the presence of mutations in a single gene. However, recent advancements in genomics have revealed instances where the phenotypic expression of apparently monogenic disorders cannot be fully explained by mutations in a single gene alone. This review article aims to explore the emerging concept of digenic or oligogenic inheritance in seemingly monogenic disorders. We discuss the underlying mechanisms, clinical implications, and the challenges associated with deciphering the contribution of multiple genes in the development and manifestation of such disorders. We present relevant studies and highlight the importance of adopting a broader genetic approach in understanding the complex genetic architecture of these conditions.

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Section: Phenotypic Variability and Modifiers In Presumed Monogenic D...mentioning

confidence: 99%

Digenic or oligogenic mutations in presumed monogenic disorders: A review

et al. 2023

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“…Table 1 summarizes general demographics of the participants. FXTAS subjects were screened for eligibility as described in Kong et al (2022). Briefly, case subjects were male or female premutation carriers with symptoms of tremor or ataxia before age 65, as reviewed by a neurologist.…”

Section: Study Populationmentioning

confidence: 99%

“…Whole genome sequencing was performed on samples using Illumina platforms at Hudson Alpha or Novogene as described in Kong et al (2022). All samples were mapped using PEMapper and called using PECaller (Johnston et al, 2017).…”

Section: Genotyping Of Aqp4 Snpsmentioning

confidence: 99%

Evaluation of AQP4 functional variants and its association with fragile X-associated tremor/ataxia syndrome

Elias-Mas

Potrony²,

Bague³

et al. 2023

Front. Aging Neurosci.

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IntroductionFragile X-associated tremor/ataxia syndrome (FXTAS, OMIM# 300623) is a late-onset neurodegenerative disorder with reduced penetrance that appears in adult FMR1 premutation carriers (55–200 CGGs). Clinical symptoms in FXTAS patients usually begin with an action tremor. After that, different findings including ataxia, and more variably, loss of sensation in the distal lower extremities and autonomic dysfunction, may occur, and gradually progress. Cognitive deficits are also observed, and include memory problems and executive function deficits, with a gradual progression to dementia in some individuals. Aquaporin 4 (AQP4) is a commonly distributed water channel in astrocytes of the central nervous system. Changes in AQP4 activity and expression have been implicated in several central nervous system disorders. Previous studies have suggested the associations of AQP4 single nucleotide polymorphisms (SNPs) with brain-water homeostasis, and neurodegeneration disease. To date, this association has not been studied in FXTAS.MethodsTo investigate the association of AQP4 SNPs with the risk of presenting FXTAS, a total of seven common AQP4 SNPs were selected and genotyped in 95 FMR1 premutation carriers with FXTAS and in 65 FMR1 premutation carriers without FXTAS.ResultsThe frequency of AQP4-haplotype was compared between groups, denoting 26 heterozygous individuals and 5 homozygotes as carriers of the minor allele in the FXTAS group and 25 heterozygous and 2 homozygotes in the no-FXTAS group. Statistical analyses showed no significant associations between AQP4 SNPs/haplotypes and development of FXTAS.DiscussionAlthough AQP4 has been implicated in a wide range of brain disorders, its involvement in FXTAS remains unclear. The identification of novel genetic markers predisposing to FXTAS or modulating disease progression is critical for future research involving predictors and treatments.

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“…[73][74][75][76] This phenomenon may be attributed to differences in the expression levels of translational regulators such as 5MP, 57) repeat interruptions that stabilize RNA secondary structures, 77) or protein-degrading factors such as PSBM5. 78) Many laboratories around the world are currently searching for such diseasemodifying targets.…”

Section: Ran Translation Serves a Physiologi-cal Role In Regulating F...mentioning

confidence: 99%

Between Order and Chaos: Understanding the Mechanism and Pathology of RAN Translation

Reyes

Asano

2023

Biological & Pharmaceutical Bulletin

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Repeat-associated non-AUG (RAN) translation is a pathogenic mechanism in which repetitive sequences are translated into aggregation-prone proteins from multiple reading frames, even without a canonical AUG start codon. Since its discovery in spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1), RAN translation is now known to occur in the context of 12 disease-linked repeat expansions. This review discusses recent advances in understanding the regulatory mechanisms controlling RAN translation and its contribution to the pathophysiology of repeat expansion diseases. We discuss the key findings in the context of Fragile X Tremor Ataxia Syndrome (FXTAS), a neurodegenerative disorder caused by a CGG repeat expansion in the 5′ untranslated region of FMR1.

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Identification of PSMB5 as a genetic modifier of fragile X–associated tremor/ataxia syndrome

Cited by 8 publications

References 54 publications

Digenic or oligogenic mutations in presumed monogenic disorders: A review

Digenic or oligogenic mutations in presumed monogenic disorders: A review

Evaluation of AQP4 functional variants and its association with fragile X-associated tremor/ataxia syndrome

Between Order and Chaos: Understanding the Mechanism and Pathology of RAN Translation

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