PRKDC mutations in a SCID patient with profound neurological abnormalities

Lisa Woodbine, Jessica A. Neal, Nanda Kumar Sasi, Mayuko Shimada, Karen Deem, Helen Coleman, William B. Dobyns, Tomoo Ogi, Katheryn Meek, E. Graham Davies, Penny A. Jeggo

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2969-2980
Number of pages12
JournalJournal of Clinical Investigation
Volume123
Issue number7
DOIs
StatePublished - Jul 1 2013
Externally publishedYes

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