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Novel PANK2 Mutations in Patients With Pantothenate Kinase-Associated Neurodegeneration and the Genotype–Phenotype Correlation

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare genetic disorder caused by mutations in the mitochondrial pantothenate kinase 2 (PANK2) gene and displays an inherited autosomal recessive pattern. In this study, we identified eight PANK2 mutations, including three novel mutations (c...

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Autores principales: Li, Wen-Bin, Shen, Nan-Xiang, Zhang, Chao, Xie, Huan-Cheng, Li, Zong-Yan, Cao, Li, Chen, Li-Zhi, Zeng, Yuan-jin, Fan, Cui-Xia, Chen, Qian, Shi, Yi-Wu, Song, Xing-Wang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9019683/
https://www.ncbi.nlm.nih.gov/pubmed/35462688
http://dx.doi.org/10.3389/fnagi.2022.848919
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author Li, Wen-Bin
Shen, Nan-Xiang
Zhang, Chao
Xie, Huan-Cheng
Li, Zong-Yan
Cao, Li
Chen, Li-Zhi
Zeng, Yuan-jin
Fan, Cui-Xia
Chen, Qian
Shi, Yi-Wu
Song, Xing-Wang
author_facet Li, Wen-Bin
Shen, Nan-Xiang
Zhang, Chao
Xie, Huan-Cheng
Li, Zong-Yan
Cao, Li
Chen, Li-Zhi
Zeng, Yuan-jin
Fan, Cui-Xia
Chen, Qian
Shi, Yi-Wu
Song, Xing-Wang
author_sort Li, Wen-Bin
collection PubMed
description Pantothenate kinase-associated neurodegeneration (PKAN) is a rare genetic disorder caused by mutations in the mitochondrial pantothenate kinase 2 (PANK2) gene and displays an inherited autosomal recessive pattern. In this study, we identified eight PANK2 mutations, including three novel mutations (c.1103A > G/p.D368G, c.1696C > G/p.L566V, and c.1470delC/p.R490fs494X), in seven unrelated families with PKAN. All the patients showed an eye-of-the-tiger sign on the MRI, six of seven patients had dystonia, and two of seven patients had Parkinsonism. Biallelic mutations of PANK2 decreased PANK2 protein expression and reduced mitochondrial membrane potential in human embryonic kidney (HEK) 293T cells. The biallelic mutations from patients with early-onset PKAN, a severity phenotype, showed decreased mitochondrial membrane potential more than that from late-onset patients. We systematically reviewed all the reported patients with PKAN with PANK2 mutations. The results indicated that the early-onset patients carried a significantly higher frequency of biallelic loss-of-function (LoF) mutations compared to late-onset patients. In general, patients with LoF mutations showed more severe phenotypes, including earlier onset age and loss of gait. Although there was no significant difference in the frequency of biallelic missense mutations between the early-onset and late-onset patients, we found that patients with missense mutations in the mitochondrial trafficking domain (transit peptide/mitochondrial domain) of PANK2 exhibited the earliest onset age when compared to patients with mutations in the other two domains. Taken together, this study reports three novel mutations and indicates a correlation between the phenotype and mitochondrial dysfunction. This provides new insight for evaluating the clinical severity of patients based on the degree of mitochondrial dysfunction and suggests genetic counseling not just generalized identification of mutated PANK2 in clinics.
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spelling pubmed-90196832022-04-21 Novel PANK2 Mutations in Patients With Pantothenate Kinase-Associated Neurodegeneration and the Genotype–Phenotype Correlation Li, Wen-Bin Shen, Nan-Xiang Zhang, Chao Xie, Huan-Cheng Li, Zong-Yan Cao, Li Chen, Li-Zhi Zeng, Yuan-jin Fan, Cui-Xia Chen, Qian Shi, Yi-Wu Song, Xing-Wang Front Aging Neurosci Neuroscience Pantothenate kinase-associated neurodegeneration (PKAN) is a rare genetic disorder caused by mutations in the mitochondrial pantothenate kinase 2 (PANK2) gene and displays an inherited autosomal recessive pattern. In this study, we identified eight PANK2 mutations, including three novel mutations (c.1103A > G/p.D368G, c.1696C > G/p.L566V, and c.1470delC/p.R490fs494X), in seven unrelated families with PKAN. All the patients showed an eye-of-the-tiger sign on the MRI, six of seven patients had dystonia, and two of seven patients had Parkinsonism. Biallelic mutations of PANK2 decreased PANK2 protein expression and reduced mitochondrial membrane potential in human embryonic kidney (HEK) 293T cells. The biallelic mutations from patients with early-onset PKAN, a severity phenotype, showed decreased mitochondrial membrane potential more than that from late-onset patients. We systematically reviewed all the reported patients with PKAN with PANK2 mutations. The results indicated that the early-onset patients carried a significantly higher frequency of biallelic loss-of-function (LoF) mutations compared to late-onset patients. In general, patients with LoF mutations showed more severe phenotypes, including earlier onset age and loss of gait. Although there was no significant difference in the frequency of biallelic missense mutations between the early-onset and late-onset patients, we found that patients with missense mutations in the mitochondrial trafficking domain (transit peptide/mitochondrial domain) of PANK2 exhibited the earliest onset age when compared to patients with mutations in the other two domains. Taken together, this study reports three novel mutations and indicates a correlation between the phenotype and mitochondrial dysfunction. This provides new insight for evaluating the clinical severity of patients based on the degree of mitochondrial dysfunction and suggests genetic counseling not just generalized identification of mutated PANK2 in clinics. Frontiers Media S.A. 2022-04-06 /pmc/articles/PMC9019683/ /pubmed/35462688 http://dx.doi.org/10.3389/fnagi.2022.848919 Text en Copyright © 2022 Li, Shen, Zhang, Xie, Li, Cao, Chen, Zeng, Fan, Chen, Shi and Song. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Li, Wen-Bin
Shen, Nan-Xiang
Zhang, Chao
Xie, Huan-Cheng
Li, Zong-Yan
Cao, Li
Chen, Li-Zhi
Zeng, Yuan-jin
Fan, Cui-Xia
Chen, Qian
Shi, Yi-Wu
Song, Xing-Wang
Novel PANK2 Mutations in Patients With Pantothenate Kinase-Associated Neurodegeneration and the Genotype–Phenotype Correlation
title Novel PANK2 Mutations in Patients With Pantothenate Kinase-Associated Neurodegeneration and the Genotype–Phenotype Correlation
title_full Novel PANK2 Mutations in Patients With Pantothenate Kinase-Associated Neurodegeneration and the Genotype–Phenotype Correlation
title_fullStr Novel PANK2 Mutations in Patients With Pantothenate Kinase-Associated Neurodegeneration and the Genotype–Phenotype Correlation
title_full_unstemmed Novel PANK2 Mutations in Patients With Pantothenate Kinase-Associated Neurodegeneration and the Genotype–Phenotype Correlation
title_short Novel PANK2 Mutations in Patients With Pantothenate Kinase-Associated Neurodegeneration and the Genotype–Phenotype Correlation
title_sort novel pank2 mutations in patients with pantothenate kinase-associated neurodegeneration and the genotype–phenotype correlation
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9019683/
https://www.ncbi.nlm.nih.gov/pubmed/35462688
http://dx.doi.org/10.3389/fnagi.2022.848919
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