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PRKDC mutations in a SCID patient with profound neurological abnormalities
Lisa Woodbine, … , E. Graham Davies, Penny A. Jeggo
Lisa Woodbine, … , E. Graham Davies, Penny A. Jeggo
Published June 3, 2013
Citation Information: J Clin Invest. 2013;123(7):2969-2980. https://doi.org/10.1172/JCI67349.
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Research Article Genetics Article has an altmetric score of 10

PRKDC mutations in a SCID patient with profound neurological abnormalities

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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.

Authors

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

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Figure 1

MRI scan images of patient NM720.

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MRI scan images of patient NM720.
Brain MRI in a normal 3-year-old child...
Brain MRI in a normal 3-year-old child (A–E) and in patient NM720 at 3 months (F–J) and 2 years (K–O). In the patient, midline sagittal T1-weighted images (F and K) showed an absent pituitary bright spot (pit), thin and short corpus callosum (cc), and small uprotated cerebellar vermis (cbv). Parasagittal (G and L) and axial T2-weighted (H, I, M, and N) images showed reduced number of gyri, and mildly thick cortex with blurred gray-white border (ctx). Coronal images (J and O) showed the same changes in the cortex, as well as mildly small hippocampi. Striking progressive atrophy was seen involving all brain regions on the second scan (asterisks in L–N).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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