The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25

Journal article


Publication Details

Author(s): Leal A, Bogantes-Ledezma S, Ekici AB, Uebe S, Thiel CT, Sticht H, Berghoff M, Berghoff M, Berghoff C, Morera B, Meisterernst M, Meisterernst M, Reis A
Journal: Neurogenetics
Publication year: 2018
Volume: 19
Journal issue: 4
Pages range: 215-225
ISSN: 1364-6745


Abstract

Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of hereditary peripheral neuropathies. We previously reported a CMT locus on chromosome 19q13.3 segregating with the disease in a large Costa Rican family with axonal neuropathy and autosomal recessive pattern of inheritance (CMT2B2). We proposed a homozygous missense variant in the Mediator complex 25 (MED25) gene as causative of the disease. Nevertheless, the fact that no other CMT individuals with MED25 variants were reported to date led us to reevaluate the original family. Using exome sequencing, we now identified a homozygous nonsense variant (p.Gln517ter) in the last exon of an adjacent gene, the polynucleotide kinase 3'-phosphatase (PNKP) gene. It encodes a DNA repair protein recently associated with recessive ataxia with oculomotor apraxia type 4 (AOA4) and microcephaly, seizures, and developmental delay (MCSZ). Subsequently, five unrelated Costa Rican CMT2 subjects initially identified as being heterozygous for the same MED25 variant were found to be also compound heterozygote for PNKP. All were heterozygous for the same variant found homozygous in the large family and a second one previously associated with ataxia (p.Thr408del). Detailed clinical reassessment of the initial family and the new individuals revealed in all an adult-onset slowly progressive CMT2 associated with signs of cerebellar dysfunction such as slurred speech and oculomotor involvement, but neither microcephaly, seizures, nor developmental delay. We propose that PKNP variants are the major causative variant for the CMT2 phenotype in these individuals and that the milder clinical manifestation is due to an allelic effect.


FAU Authors / FAU Editors

Sticht, Heinrich Prof. Dr.
Professur für Bioinformatik
Thiel, Christian Thomas Dr.
Medizinische Fakultät
Uebe, Steffen Dr. rer. nat.
Humangenetisches Institut


External institutions
Hospital Sant Joan de Déu Barcelona
Universidad de Costa Rica
Universidad Nacional de Costa Rica (UNA)
Universitätsklinikum Gießen und Marburg (UKGM)
Westfälische Wilhelms-Universität (WWU) Münster


How to cite

APA:
Leal, A., Bogantes-Ledezma, S., Ekici, A.B., Uebe, S., Thiel, C.T., Sticht, H.,... Reis, A. (2018). The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25. Neurogenetics, 19(4), 215-225. https://dx.doi.org/10.1007/s10048-018-0555-7

MLA:
Leal, Alejandro, et al. "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25." Neurogenetics 19.4 (2018): 215-225.

BibTeX: 

Last updated on 2019-11-01 at 23:08