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

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.

From congenital microcephaly to adult onset cerebellar ataxia: Distinct and overlapping phenotypes in patients with PNKP gene mutations

“…She was initially diagnosed as having a CMT‐like polyneuropathy, while cerebellar signs occurred 10 years later. Her phenotype and disease progression were consistent to those described in the other four patients with adult‐onset disease (Leal et al, ). Interestingly, this patient did not carry the nonsense variant affecting the C‐terminal tail of PNKP protein common to all adult‐onset cases, but was a compound heterozygous for a missense and a splicing variant, both affecting the kinase domain of the protein.…”

“…In recent years, the availability of next‐generation sequencing or whole exome sequencing in the diagnostic procedure allowed the identification of several patients worldwide with MCSZ (Entezam, Razipour, Talebi, Beiraghi Toosi, & Keramatipour, ; Nair et al, ; Nakashima et al, ) or AOA4 phenotype (Paucar et al, ; Schiess, Zee, Siddiqui, Szolics, & El‐Hattab, ; Scholz et al, ; Tzoulis et al, ) or with symptoms encompassing both conditions (Taniguchi‐Ikeda et al, ). In other cases, the presenting clinical phenotype was characterized by the presence of a motor and sensory axonal polyneuropathy, resembling a form of Charcot–Marie–Tooth disease (Leal et al, ; Pedroso et al, ). In these patients, slurred speech and cerebellar atrophy at brain MRI were also described (Leal et al, ).…”

“…In other cases, the presenting clinical phenotype was characterized by the presence of a motor and sensory axonal polyneuropathy, resembling a form of Charcot–Marie–Tooth disease (Leal et al, ; Pedroso et al, ). In these patients, slurred speech and cerebellar atrophy at brain MRI were also described (Leal et al, ). Very recently, a phenotype mimicking a benign hereditary chorea was observed in a 2‐year‐old child with PNKP variants, further increasing the variability in clinical presentation.…”

The Phenotypic Spectrum of PNKP-Associated Disease and the Absence of Immunodeficiency and Cancer Predisposition in a Dutch Cohort

“…Patients with clinical syndromes that are dominated by chorea, peripheral neuropathy and dystonia have been reported. [19][20]3] The diverse role of PNKP in both SSBR and DSBR, neurogenesis and genome maintenance might explain the presence of both microcephaly and neurodegeneration. [21] This does not, however, explain the difference in phenotype between patients harbouring identical PNKP mutations.…”

Mutational Survivorship Bias: The case of PNKP

“…The most severe phenotype is Microcephaly with early-onset Seizures (MCSZ) [20]. In the middle, Ataxia with Oculomotor Apraxia 4 (AOA4) [21] and in the other end the milder Charcot-Marie-Tooth disease type 2B2 (CMT2B2) [22][23][24]. The vast majority of mutations in PNKP are confined to the kinase domain, both in homozygous and compound heterozygous conditions.…”