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

Rafeeq, Misbahuddin M; Umair, Muhammad; Bilal, Muhammad; Habib, Alaa Hamed; Waqas, Ahmed; Sain, Ziaullah M; Alam, Mohammad Zubair; Ali, Raheel

doi:10.1007/s10048-022-00701-9

Cited by 5 publications

(7 citation statements)

References 16 publications

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“…After WES, data analysis and variant filtration were performed using standard methods (Younus et al, 2019). Variants in genes already known to cause syndromic or nonsyndromic ID were shortlisted for downstream cosegregation analysis with Sanger sequencing standard protocols as described earlier (Rafeeq et al, 2022; Umair, Khan, et al, 2021; Umair, Palander, et al, 2021; Figure 1a). A homozygous nonsense variant (c.466C > T; p.Gln156*) in the Exon 6 of the PPFIBP1 gene (NM_003622.4; NP_003613.3) was identified that co‐segregated with the disease phenotype in the family (Figure 2a,b).…”

Section: Resultsmentioning

confidence: 99%

A novel homozygous truncating variant in PPFIBP1 further delineates PPFIBP1‐associated neurodevelopmental disorder

Waqas

Liaqat

Shaheen

et al. 2022

Intl J of Devlp Neuroscience

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Neurodevelopmental disorders (NDDs) are classified as a group of disorders affecting function and development of the brain and having wide clinical variability. Herein, we describe two affected individuals segregating a recessive NDD. The affected individuals exhibited phenotypes such as global developmental delay (GDD), intellectual disability (ID), microcephaly and speech delay. Wholeexome sequencing (WES) followed by bidirectional Sanger sequencing techniques identified a homozygous nonsense variant (c.466C > T; p.Gln156*) in the PPFIBP1 gene (NM_003622.4) that segregated with the disease phenotype.Further, to elucidate the effect of the variant on protein structure, 3D protein Abbreviations: GDD, global developmental delay; ID, intellectual disability; NIPT, noninvasive prenatal testing; PGTA, preimplantation genetic testing for aneuploidies; PPFIBP1, protein-tyrosine phosphatase receptor-type F polypeptide-interacting protein-binding protein 1; SAM, sterile alpha motif; WES, whole-exome sequencing.Ahmed Waqas and Romana Liaqat contributed equally.

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Section: Resultsmentioning

confidence: 99%

A novel homozygous truncating variant in PPFIBP1 further delineates PPFIBP1‐associated neurodevelopmental disorder

Waqas

Liaqat

Shaheen

et al. 2022

Intl J of Devlp Neuroscience

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“…In addition, there was a third report that associates a PRDX3 non-sense variant p.Lys166* with cerebellar ataxia and profound hearing impairment. 7 Herein, we present a further simplex case carrying a reported homozygous variant in PRDX3 as well as two additional cases with novel bi-allelic variants. The variants were identified by screening of exome data from a large cohort of patients with cerebellar ataxia (>1,200 cases) of multi-ethnic background.…”

Section: Introductionmentioning

confidence: 96%

“…One case had infantile‐onset cerebellar ataxia, but the other first developed ataxic gait at age 35, indicating that PRDX3 ‐associated disease may have a broader age of onset range than previously thought. In addition, there was a third report that associates a PRDX3 non‐sense variant p.Lys166* with cerebellar ataxia and profound hearing impairment 7 …”

Section: Introductionmentioning

confidence: 99%

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Pure cerebellar ataxia due to bi‐allelic PRDX3 variants including recurring p.Asp202Asn

Efthymiou,

Novis,

Koutsis

et al. 2023

Ann Clin Transl Neurol

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Bi‐allelic variants in peroxiredoxin 3 (PRDX3) have only recently been associated with autosomal recessive spinocerebellar ataxia characterized by early onset slowly progressive cerebellar ataxia, variably associated with hyperkinetic and hypokinetic features, accompanied by cerebellar atrophy and occasional olivary and brainstem involvement. Herein, we describe a further simplex case carrying a reported PRDX3 variant as well as two additional cases with novel variants. We report the first Brazilian patient with SCAR32, replicating the pathogenic status of a known variant. All presented cases from the Brazilian and Indian populations expand the phenotypic spectrum of the disease by displaying prominent neuroradiological findings. SCAR32, although rare, should be included in the differential diagnosis of sporadic or recessive childhood and adolescent‐onset pure and complex cerebellar ataxia.

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“… 10 Recently, mutations in PRDX3 have been linked to autosomal recessive spinocerebellar ataxia type 32 [SCAR32; MIM #619862]. 11 , 12 , 13 , 14 Since the first description of the PRDX3‐ associated phenotype, 12 15 individuals harboring pathogenic variants have been described with onset ages ranging from infancy to adulthood. 12 , 13 , 14 , 15 , 16 In vitro knockdown of PRDX3 results in reduced levels of glutathione peroxidase activity and increased susceptibility to apoptosis triggered by ROS.…”

Section: Introductionmentioning

confidence: 99%

SCAR32: Functional characterization and expansion of the clinical‐genetic spectrum

Naef,

Lieto,

Satolli

et al. 2024

Ann Clin Transl Neurol

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ObjectiveBiallelic mutations in PRDX3 have been linked to autosomal recessive spinocerebellar ataxia type 32. In this study, which aims to contribute to the growing body of knowledge on this rare disease, we identified two unrelated patients with mutations in PRDX3. We explored the impact of PRDX3 mutation in patient skin fibroblasts and the role of the gene in neurodevelopment.MethodsWe performed trio exome sequencing that identified mutations in PRDX3 in two unrelated patients. We also performed functional studies in patient skin fibroblasts and generated a “crispant” zebrafish (Danio rerio) model to investigate the role of the gene during nervous system development.ResultsOur study reports two additional patients. Patient 1 is a 19‐year‐old male who showed a novel homozygous c.525_535delGTTAGAAGGTT (p. Leu176TrpfsTer11) mutation as the genetic cause of cerebellar ataxia. Patient 2 is a 20‐year‐old male who was found to present the known c.425C>G/p. Ala142Gly variant in compound heterozygosity with the p. Leu176TrpfsTer11 one. While the fibroblast model failed to recapitulate the pathological features associated with PRDX3 loss of function, our functional characterization of the prdx3 zebrafish model revealed motor defects, increased susceptibility to reactive oxygen species‐triggered apoptosis, and an impaired oxygen consumption rate.ConclusionsWe identified a new variant, thereby expanding the genetic spectrum of PRDX3‐related disease. We developed a novel zebrafish model to investigate the consequences of prdx3 depletion on neurodevelopment and thus offered a potential new tool for identifying new treatment opportunities.

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

Cited by 5 publications

References 16 publications

A novel homozygous truncating variant in PPFIBP1 further delineates PPFIBP1‐associated neurodevelopmental disorder

A novel homozygous truncating variant in PPFIBP1 further delineates PPFIBP1‐associated neurodevelopmental disorder

Pure cerebellar ataxia due to bi‐allelic PRDX3 variants including recurring p.Asp202Asn

SCAR32: Functional characterization and expansion of the clinical‐genetic spectrum

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