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.
Data availability
Data will be provided by the corresponding author upon potential requests.
References
Jayadev S, Bird TD (2013) Hereditary ataxias: overview. Genet Med 15(9):673–683. https://doi.org/10.1038/gim.2013.28
Synofzik M, Puccio H, Mochel F, Schols L (2019) Autosomal recessive cerebellar ataxias: paving the way toward targeted molecular therapies. Neuron 101:560–583
Pilotto F, Saxena S (2018) Epidemiology of inherited cerebellar ataxias and challenges in clinical research. Clinical Transl Neurosci 2(2). https://doi.org/10.1177/2514183X18785258.
Krygier M, Mazurkiewicz-Bełdzińska M. (2021) Milestones in genetics of cerebellar ataxias. Neurogenetics. https://doi.org/10.1007/s10048-021-00656-3
Rebelo AP, Eidhof I, Cintra VP et al (2021) Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia. Brain 144(5):1467–1481. https://doi.org/10.1093/brain/awab071
Karpenko IL, Valuev-Elliston VT, Ivanova ON, Smirnova OA, Ivanov AV (2021) Peroxiredoxins-the underrated actors during virus-induced oxidative stress. Antioxidants 10:977. https://doi.org/10.3390/antiox10060977
Hampton MB, O’Connor KM (2016) Peroxiredoxins and the regulation of cell death. Mol Cells 39(1):72–76. https://doi.org/10.14348/molcells.2016.2351
Umair M, Ullah A, Abbas S, Ahmad F, Basit S, Ahmad W (2018) First direct evidence of involvement of a homozygous loss-of-function variant in the EPS15L1 gene underlying split-hand/split-foot malformation. Clin Genet 93(3):699–702. https://doi.org/10.1111/cge.13152
Umair M, Palander O, Bilal M et al (2021) Biallelic variant in DACH1, encoding Dachshund Homolog 1, defines a novel candidate locus for recessive postaxial polydactyly type A. Genomics 113(4):2495–2502. https://doi.org/10.1016/j.ygeno.2021.05.015
Umair M, Khan A, Amin W, Abbas S, Younus M, Alfadhel M, Ahmad F (2019) Biallelic missense mutation in the ECEL1 Underlies Distal Arthrogryposis Type 5 (DA5D). Front in Pedriatics 7:343. https://doi.org/10.3389/fped.2019.00343
Umair M, Seidel H, Ahmed I, Ullah A, Haack TB, Alhaddad B, Jan A, Rafique A, Strom TM, Ahmad F, Meitinger T, Ahmad W (2017) Ellis-van Creveld syndrome and profound deafness resulted by sequence variants in the EVC/EVC2 and TMC1 genes. J Gent 96(6):1005–1014
Martínez-Rubio D, Rodríguez-Prieto Á, Sancho P, Navarro-González C, Gorría-Redondo N, et al. (2022) Protein misfolding and clearance in the pathogenesis of a new infantile onset ataxia caused by mutations in PRDX3. Hum Mol Genet ddac146. https://doi.org/10.1093/hmg/ddac146
Zhang YG, Wang L, Kaifu T, Li J et al (2016) Featured article: accelerated decline of physical strength in peroxiredoxin-3 knockout mice. Exp Biol Med (Maywood) 241:1395–1400
Holzerova E, Danhauser K, Haack TB et al (2016) Human thioredoxin 2 deficiency impairs mitochondrial redox homeostasis and causes early-onset neurodegeneration. Brain 139:346–354
Yun HM, Park KR, Lee HP et al (2014) PRDX6 promotes lung tumor progression via its GPx and iPLA2 activities. Free Radic Biol Med 69:367–376
Wu WB, Menon R, Xu YY et al (2016) Downregulation of peroxiredoxin-3 by hydrophobic bile acid induces mitochondrial dysfunction and cellular senescence in human trophoblasts. Sci Rep 6:38946
Acknowledgements
We are grateful to the patient and his family for their genuine support.
Author information
Authors and Affiliations
Contributions
Rafeeq MM and Umair M drafted the manuscript and performed and analyzed the data. Bilal M and Habib AH performed protein modeling. Waqas A, Sain ZM, and Alam MZ performed clinical analysis. Ali RH and Umair M performed data analysis and reviewed the final manuscript.
Corresponding authors
Ethics declarations
Ethics approval and consent to participate
The study was approved by the Institutional Research Committee. Written informed consent was obtained from the patients.
Consent for publication
The parents of the patients provided written informed consent for publication of the case details and analysis.
Competing interests
The authors declare no competing interests.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Rafeeq, M.M., Umair, M., Bilal, M. et al. A novel biallelic variant further delineates PRDX3-related autosomal recessive cerebellar ataxia. Neurogenetics 24, 55–60 (2023). https://doi.org/10.1007/s10048-022-00701-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10048-022-00701-9