PRKDC mutations in a SCID patient with profound neurological abnormalities

Woodbine, Lisa, Neal, Jessica A, Sasi, Nanda-Kumar, Shimada, Mayuko, Deem, Karen, Coleman, Helen, Dobyns, William B, Ogi, Tomoo, Meek, Katheryn, Davies, E Graham and Jeggo, Penny A (2013) PRKDC mutations in a SCID patient with profound neurological abnormalities. Journal of Clinical Investigation, 123 (7). pp. 2969-2980. ISSN 0021-9738

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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.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects: Q Science
Depositing User: Deeptima Massey
Date Deposited: 19 Sep 2013 13:46
Last Modified: 19 Sep 2013 13:46
URI: http://sro.sussex.ac.uk/id/eprint/46394
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