Progressive cerebellar atrophy and polyneuropathy: expanding the spectrum of PNKP mutations

Abstract

We present a neurodegenerative disorder starting in early childhood of two brothers consisting of severe progressive polyneuropathy, severe progressive cerebellar atrophy, microcephaly, mild epilepsy, and intellectual disability. The cause of this rare syndrome was found to be a homozygous mutation (c.1250_1266dup, resulting in a frameshift p.Thr424GlyfsX48) in PNKP, identified by applying homozygosity mapping and whole-genome sequencing. Mutations in PNKP have previously been associated with a syndrome of microcephaly, seizures and developmental delay (MIM 613402), but not with a neurodegenerative disorder. PNKP is a dual-function enzyme with a key role in different pathways of DNA damage repair. DNA repair disorders can result in accelerated cell death, leading to underdevelopment and neurodegeneration. In skin fibroblasts from both affected individuals, we show increased susceptibility to apoptosis under stress conditions and reduced PNKP expression. PNKP is known to interact with DNA repair proteins involved in the onset of polyneuropathy and cerebellar degeneration; therefore, our findings explain this novel phenotype.

Copy number variants associated with epilepsy from gene expression microarrays

“…Mutations in another gene, polynucleotide kinase 3 0 -phosphatase (PNKP), could universally cause defects in DNA repair and lead to severe seizures [20]. In DNA repair disorders, PNKP mutations could result in accelerated cell death, leading to underdevelopment and neurodegeneration [21]. Our results indicated that genes were significantly enriched in the nervous system development, supporting that this region might be associated with the occurrence of epilepsy.…”

Polynucleotide kinase-phosphatase (PNKP) mutations and neurologic disease

“…In a subsequent report (Poulton et al, 2013), the same homozygous PNKP mutation in MCSZ, T424GfsX48, was identified in two affected Dutch siblings with microcephaly, but as distinct to MCSZ, these individuals also developed ataxia and progressive cerebellar degeneration (Figure 1 and Table 2). Why identical PNKP mutations give rise to two different phenotypes isn’t clear, although the most likely explanation points to genetic modifiers.…”

“…Human inherited disorders that disrupt SSBR lead to pathology that is mostly restricted to the nervous system (Fig.1). Examples include; ataxia with oculomotor apraxia-1 (AOA1) caused by mutations in APTX, spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) caused by mutated TDP1 and recently, progressive cerebellar atrophy and AOA4, caused by specific mutations in PNKP (see later for details) (Bras et al, 2015; Date et al, 2001; Poulton et al, 2013; Shen et al, 2010; Takashima et al, 2002). These syndromes underscore the importance of SSBR for normal neural function.…”

“…These include, microcephaly with seizures (MCSZ), which is characterized by microcephaly, early-onset, intractable seizures and developmental delay (Shen et al, 2010), progressive cerebellar atrophy and polyneuropathy (Poulton et al, 2013), and ataxia with oculomotor apraxia type 4 (AOA4), characterized by neurodegeneration (Bras et al, 2015). PNKP is a multifunctional DNA repair enzyme important for both the SSBR/BER and NHEJ pathways (Weinfeld et al, 2011).…”

Genome integrity and disease prevention in the nervous system

“…Mutations in PNKP can result in different neurologic disease characterized by either microcephaly or neurodegeneration. parents developed both microcephaly and ataxia but had mutations identical to those of individuals with MCSZ who did not develop ataxia; thus, it is likely that genetic modifiers influence the outcome of PNKP mutations (Poulton et al 2013;Dumitrache and McKinnon 2017).…”