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- Title
PRKDC mutations in a SCID patient with profound neurological abnormalities.
- Authors
Woodbine, Lisa; Neal, Jessica A; Sasi, Nanda-Kumar; Shimada, Mayuko; Deem, Karen; Coleman, Helen; Dobyns, William B; Ogi, Tomoo; Meek, Katheryn; Davies, E Graham; Jeggo, Penny A
- 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.
- Publication
The Journal of clinical investigation, 2013, Vol 123, Issue 7, p2969
- ISSN
1558-8238
- Publication type
Journal Article
- DOI
10.1172/JCI67349