A novel biallelic variant further delineates PRDX3-related autosomal recessive cerebellar ataxia.

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Abstract

Cerebellar ataxias (CAs) comprise a rare group of neurological disorders characterized by extensive phenotypic and genetic heterogeneity. In the last several years, our understanding of the CA etiology has increased significantly and resulted in the discoveries of numerous ataxia-associated genes. Herein, we describe a single affected individual from a consanguineous family segregating a recessive neurodevelopmental disorder. The proband showed features such as global developmental delay, cerebellar atrophy, hypotonia, speech issues, dystonia, and profound hearing impairment. Whole-exome sequencing and Sanger sequencing revealed a biallelic nonsense variant (c.496A > T; p.Lys166*) in the exon 5 of the PRDX3 gene that segregated perfectly within the family. This is the third report that associates the PRDX3 gene variant with cerebellar ataxia. In addition, associated hearing impairment further delineates the PRDX3 associated gene phenotypes.

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Hereditary ataxias: overview.

Chethan S Jayadev, T. Bird (2013)

The hereditary ataxias are a highly heterogeneous group of disorders phenotypically characterized by gait ataxia, incoordination of eye movements, speech, and hand movements, and usually associated with atrophy of the cerebellum. There are more than 35 autosomal dominant types frequently termed spinocerebellar ataxia and typically having adult onset. The most common subtypes are spinocerebellar ataxia 1, 2, 3, 6, and 7, all of which are nucleotide repeat expansion disorders. Autosomal recessive ataxias usually have onset in childhood; the most common subtypes are -Friedreich, ataxia-telangiectasia, ataxia with oculomotor apraxia type 1, and ataxia with oculomotor apraxia type 2. Four autosomal recessive types have dietary or biochemical treatment modalities (ataxia with vitamin E deficiency, cerebrotendinous xanthomatosis, Refsum, and coenzyme Q10 deficiency), whereas there are no specific treatments for other ataxias. Diagnostic genetic testing is complicated because of the large number of relatively uncommon subtypes with extensive phenotypic overlap. However, the best testing strategy is based on assessing relative frequencies, ethnic predilections, and recognition of associated phenotypic features such as seizures, visual loss, or associated movement abnormalities.

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Human thioredoxin 2 deficiency impairs mitochondrial redox homeostasis and causes early-onset neurodegeneration.

Eliška Holzerová, Katharina Danhauser, Tobias Haack … (2016)

Thioredoxin 2 (TXN2; also known as Trx2) is a small mitochondrial redox protein essential for the control of mitochondrial reactive oxygen species homeostasis, apoptosis regulation and cell viability. Exome sequencing in a 16-year-old adolescent suffering from an infantile-onset neurodegenerative disorder with severe cerebellar atrophy, epilepsy, dystonia, optic atrophy, and peripheral neuropathy, uncovered a homozygous stop mutation in TXN2. Analysis of patient-derived fibroblasts demonstrated absence of TXN2 protein, increased reactive oxygen species levels, impaired oxidative stress defence and oxidative phosphorylation dysfunction. Reconstitution of TXN2 expression restored all these parameters, indicating the causal role of TXN2 mutation in disease development. Supplementation with antioxidants effectively suppressed cellular reactive oxygen species production, improved cell viability and mitigated clinical symptoms during short-term follow-up. In conclusion, our report on a patient with TXN2 deficiency suggests an important role of reactive oxygen species homeostasis for human neuronal maintenance and energy metabolism.

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PRDX6 promotes lung tumor progression via its GPx and iPLA2 activities.

Hyung-Mun Yun, Kyung-Ran Park, Hee Lee … (2014)

PRDX6 is a bifunctional protein with both glutathione peroxidase (GPx) and calcium-independent phospholipase A2 (iPLA2) activities, which are concomitantly increased with the expression of PRDX6. PRDX6 promoted lung tumor growth in an in vivo allograft model. Herein, we further studied the vital roles in tumor progression of PRDX6 in lung cancer using nude mice bearing PRDX6-overexpressing lung cancer cells. Nude mice xenografted with PRDX6 showed increases in tumor size and weight compared to control mice. Histopathological and Western blotting examination demonstrated that expression of proliferating cell nuclear antigen, vascular endothelial growth factor, metalloproteinases 2 and 9, and cyclin-dependent kinases accompanied by increased iPLA2 and GPx activities were increased in the tumor tissues of PRDX6-overexpressing nude mice. In tumor tissues of PRDX6-overexpressing mice, the activation of mitogen-activated protein kinases and AP-1 DNA binding were also increased. The growth of lung cancer cell lines (A549 and NCI-H460) was enhanced by the increase in iPLA2 and GPx activities of PRDX6. In addition, mutant PRDX6 (C47S) attenuated PRDX6-mediated p38, ERK1/2, and AP-1 activities as well as its enzyme activities in the A549 and NCI-H460 lines. Furthermore, tumor growth and p38, ERK1/2, and AP-1 activities were also inhibited in nude mice bearing mutant PRDX6 (C47S) compared to PRDX6. Therefore, our findings indicate that PRDX6 promotes lung tumor growth via increased glutathione peroxidase and iPLA2 activities.

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Author and article information

Journal

Journal ID (iso-abbrev): Neurogenetics

Title: Neurogenetics

Publisher: Springer Science and Business Media LLC

ISSN (Electronic): 1364-6753

ISSN (Print): 1364-6745

Publication date (Electronic): Jan 2023

Volume: 24

Issue: 1

Affiliations

[1 ] Department of Pharmacology, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, 21589, Kingdom of Saudi Arabia.

[2 ] Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, P.O. Box 3660, Riyadh, 11481, Kingdom of Saudi Arabia, (KSA). khugoo4u@yahoo.com.

[3 ] Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, Pakistan. khugoo4u@yahoo.com.

[4 ] Department of Biochemistry, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, Pakistan.

[5 ] Department Zoology, Division of Science and Technology, University of Education Lahore, Punjab, Pakistan.

[6 ] Department of Microbiology, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, 21589, Kingdom of Saudi Arabia.

[7 ] Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.

[8 ] Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.

[9 ] Department of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Teaching Hospital, Boston, MA, USA. khugoo4u@yahoo.com.

Article

Publisher Item ID: 10.1007/s10048-022-00701-9

DOI: 10.1007/s10048-022-00701-9

PubMed ID: 36190665

SO-VID: 21cb7420-36d2-4ea0-b74e-58211fff6987

History

Keywords: Novel variant,PRDX3,Profound deafness,Whole-exome sequencing,Cerebellar ataxia,Nonsense variant

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Keywords: Novel variant, PRDX3, Profound deafness, Whole-exome sequencing, Cerebellar ataxia, Nonsense variant

A novel biallelic variant further delineates PRDX3-related autosomal recessive cerebellar ataxia.

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Most cited references 16

Hereditary ataxias: overview.

Human thioredoxin 2 deficiency impairs mitochondrial redox homeostasis and causes early-onset neurodegeneration.

PRDX6 promotes lung tumor progression via its GPx and iPLA2 activities.

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