title: 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.
authors.affiliation: Department of Clinical Genetics, Erasmus MC, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Cathryn
authors.initials: C
authors.lastname: Poulton
authors.forename: Renske
authors.initials: R
authors.lastname: Oegema
authors.forename: Daphne
authors.initials: D
authors.lastname: Heijsman
authors.forename: Jeannette
authors.initials: J
authors.lastname: Hoogeboom
authors.forename: Rachel
authors.initials: R
authors.lastname: Schot
authors.forename: Hans
authors.initials: H
authors.lastname: Stroink
authors.forename: Michèl A
authors.initials: MA
authors.lastname: Willemsen
authors.forename: Frans W
authors.initials: FW
authors.lastname: Verheijen
authors.forename: Peter
authors.initials: P
authors.lastname: van de Spek
authors.forename: Andreas
authors.initials: A
authors.lastname: Kremer
authors.forename: Grazia M S
authors.initials: GM
authors.lastname: Mancini
mesh_terms: D000293:Adolescent; D002531:Cerebellum / Q000000981:diagnostic imaging; D002648:Child; D003241:Consanguinity; D004252:DNA Mutational Analysis; D045643:DNA Repair Enzymes / Q000235:genetics*; D018450:Disease Progression; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009154:Mutation / Q000502:physiology; D010375:Pedigree; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D011115:Polyneuropathies / Q000000981:diagnostic imaging / Q000209:etiology / Q000235:genetics*; D011859:Radiography; D035781:Siblings; D013132:Spinocerebellar Degenerations / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics*
chemical_list: C530380:PNKP protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor); D045643:DNA Repair Enzymes