Identification of <i>PSMB5</i> as a genetic modifier of fragile X–associated tremor/ataxia syndrome-Reference-Cited by-同舟云学术

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

Published:2022-05-26 Issue:22 Volume:119 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

Kong Ha Eun¹^ORCID,Lim Junghwa¹,Linsalata Alexander²,Kang Yunhee¹,Malik Indranil²,Allen Emily G.¹,Cao Yiqu¹,Shubeck Lisa¹,Johnston Rich¹,Huang Yanting³,Gu Yanghong⁴^ORCID,Guo Xiangxue¹^ORCID,Zwick Michael E.¹,Qin Zhaohui³,Wingo Thomas S.¹⁵^ORCID,Juncos Jorge⁵,Nelson David L.⁴^ORCID,Epstein Michael P.¹,Cutler David J.¹,Todd Peter K.²^ORCID,Sherman Stephanie L.¹,Warren Stephen T.¹⁶⁷,Jin Peng¹^ORCID

Affiliation:

1. Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322

2. Department of Neurology, University of Michigan, Veteran’s Affairs Medical Center, Ann Arbor, MI 48109

3. Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322

4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030

5. Department of Neurology, School of Medicine, Emory University, Atlanta, GA 30322

6. Department of Biochemistry, School of Medicine, Emory University, Atlanta, GA 30322

7. Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322

Abstract

Significance Expansion of 55-200 CGG repeats in the 5′ untranslated region of FMR1 predisposes carriers to fragile X–associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder. FXTAS demonstrates incomplete penetrance, which strongly suggests the presence of genetic modifiers. We performed whole-genome sequencing (WGS) on male premutation carriers (CGG 55–200 ) followed by a functional screen in Drosophila and identified PSMB5 as a strong suppressor of CGG-associated neurodegeneration, thereby presenting a therapeutic strategy for FXTAS.

Funder

HHS | NIH | National Institute of Neurological Disorders and Stroke

HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Link

https://pnas.org/doi/pdf/10.1073/pnas.2118124119

Reference55 articles.

1. Fragile X-associated tremor/ataxia syndrome

2. Penetrance of the Fragile X–Associated Tremor/Ataxia Syndrome in a Premutation Carrier Population