title: PRKDC mutations in a SCID patient with profound neurological abnormalities.
abstract: The DNA-dependent protein kinase catalytic subunit (DNA-PKcs; encoded by PRKDC) functions in DNA non-homologous end-joining (NHEJ), the major DNA double strand break (DSB) rejoining pathway. NHEJ also functions during lymphocyte development, joining V(D)J recombination intermediates during antigen receptor gene assembly. Here, we describe a patient with compound heterozygous mutations in PRKDC, low DNA-PKcs expression, barely detectable DNA-PK kinase activity, and impaired DSB repair. In a heterologous expression system, we found that one of the PRKDC mutations inactivated DNA-PKcs, while the other resulted in dramatically diminished but detectable residual function. The patient suffered SCID with reduced or absent T and B cells, as predicted from PRKDC-deficient animal models. Unexpectedly, the patient was also dysmorphic; showed severe growth failure, microcephaly, and seizures; and had profound, globally impaired neurological function. MRI scans revealed microcephaly-associated cortical and hippocampal dysplasia and progressive atrophy over 2 years of life. These neurological features were markedly more severe than those observed in patients with deficiencies in other NHEJ proteins. Although loss of DNA-PKcs in mice, dogs, and horses was previously shown not to impair neuronal development, our findings demonstrate a stringent requirement for DNA-PKcs during human neuronal development and suggest that high DNA-PK protein expression is required to sustain efficient pre- and postnatal neurogenesis.
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
authors.forename: Lisa
authors.initials: L
authors.lastname: Woodbine
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Neal
authors.forename: Nanda-Kumar
authors.initials: NK
authors.lastname: Sasi
authors.forename: Mayuko
authors.initials: M
authors.lastname: Shimada
authors.forename: Karen
authors.initials: K
authors.lastname: Deem
authors.forename: Helen
authors.initials: H
authors.lastname: Coleman
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: Tomoo
authors.initials: T
authors.lastname: Ogi
authors.forename: Katheryn
authors.initials: K
authors.lastname: Meek
authors.forename: E Graham
authors.initials: EG
authors.lastname: Davies
authors.forename: Penny A
authors.initials: PA
authors.lastname: Jeggo
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics; D000595:Amino Acid Sequence; D001483:Base Sequence; D001921:Brain / Q000002:abnormalities*; D002460:Cell Line; D002675:Child, Preschool; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase / Q000235:genetics*; D017809:Fatal Outcome; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008831:Microcephaly / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics; D025202:Molecular Diagnostic Techniques; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*; D017354:Point Mutation; D016511:Severe Combined Immunodeficiency / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics
chemical_list: D009687:Nuclear Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human