| Abstract: | The DNA-dependent protein kinase catalytic subunit (DNA-PKcs; encoded byPRKDC) functions in DNA non-homologous end-joining (NHEJ), themajor DNA double strand break (DSB) rejoining pathway. NHEJ also functions duringlymphocyte development, joining V(D)J recombination intermediates during antigenreceptor gene assembly. Here, we describe a patient with compound heterozygousmutations in PRKDC, low DNA-PKcs expression, barely detectableDNA-PK kinase activity, and impaired DSB repair. In a heterologous expression system,we found that one of the PRKDC mutations inactivated DNA-PKcs, whilethe other resulted in dramatically diminished but detectable residual function. Thepatient suffered SCID with reduced or absent T and B cells, as predicted fromPRKDC-deficient animal models. Unexpectedly, the patient was alsodysmorphic; showed severe growth failure, microcephaly, and seizures; and hadprofound, globally impaired neurological function. MRI scans revealedmicrocephaly-associated cortical and hippocampal dysplasia and progressive atrophyover 2 years of life. These neurological features were markedly more severe thanthose observed in patients with deficiencies in other NHEJ proteins. Although loss ofDNA-PKcs in mice, dogs, and horses was previously shown not to impair neuronaldevelopment, our findings demonstrate a stringent requirement for DNA-PKcs duringhuman neuronal development and suggest that high DNA-PK protein expression isrequired to sustain efficient pre- and postnatal neurogenesis. |
