SCID mice, which are homozygous for the severe combined immune deficiency (SCID) spontaneous mutation Prkdcscid, were shown to exhibit social deficits and hyper-connectivity between mutiple brain regions that could be rescued by repopulation of the adaptive immune system (Filiano et al., 2016). Three novel de novo predicted damaging missense variants in PRKDC were observed in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014). A SCID patient with compound heterozygous variants in PRKDC was also found to exhibit dysmorphic features, severe growth failure, microcephaly, seizures, and developmental delay (Woodbine et al., 2013). Two non-synonymous postzygotic mosaic mutations (PZMs) in the PRKDC gene were identified in ASD probands (one previously identified variant from Iossifov et al., 2014, and a novel variant in Lim et al., 2017); comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected genome-wide based on background rates (2/571 observed vs. 30/84,448 expected; hypergeometric P-value 0.018).
Molecular Function
This gene encodes the catalytic subunit of the DNA-dependent protein kinase (DNA-PK) and functions with the Ku70/Ku80 heterodimer protein in DNA double strand break repair and recombination. Homozygous or compound heterozygous mutations in the PRKDC gene are responsible for immunodeficiency 26, with or without neurologic abnormalities (IMD26; OMIM 615966)
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Unexpected role of interferon- in regulating neuronal connectivity and social behaviour.
Prkdc null mice display severe combined immunodeficiency (SCID) and have no functional B or T cells as the DNA repair and non homologous end joining (NHEJ) function of the PRKDC protein is needed for reaarangement of genes that encode antigen- specific immune receptors.
References
Type
Title
Author, Year
Primary
Unexpected role of interferon- in regulating neuronal connectivity and social behaviour.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Prkdc-scid mice are homozygous for the spontaneous mutation involving a T-to-A transversion point mutation in codon 4095 that creates a premature stop codon and lack adaptive immune cells. Scid leakiness is high in C57Bl/6 background as more than 1 microgram / ml of immunoglobulin levels are detectable.
Allele Type: Spontaneous
Strain of Origin: CB-17 BALB/C-Igh
Genetic Background: C57Bl/6
ES Cell Line: Mutant ES Cell Line: Model Source: JAX
Model Type:
RESCUE-Transplantation
Model Genotype:
Homozygous
Mutation:
Four week old Prkdc scid mice were repopulated with wild type lymphocytes from the spleen and lymph nodes (axillary, brachial, cervical, inguinal and lumbar). Lymphocytes were injected i.v. at 5 X 10 ^6 cells in 250 microliter of saline into the tail vein.
Allele Type: Spontaneous
Strain of Origin: CB-17 BALB/C-Igh
Genetic Background: C57Bl/6
ES Cell Line: Mutant ES Cell Line: Model Source: JAX
Neuronal activation following behavioral stimulation: c-fos levels1
Increased
Description: C-fos positive cells are increased in the prefrontal and orbital cortices, indicating hyper-responsiveness, in prkdc scid mice exposed to a social stimulus, compared to wt controls
Exp Paradigm: NA
Functional magnetic resonance imaging: connectivity1
Increased
Description: Prkdc scid mice have hyperconnectivity between prelimbic cortex and frontal cortex, frontal association area and orbital cortex, insula and orbital cortex, insula and prelimbic cortex
Exp Paradigm: NA
Functional magnetic resonance imaging (fmri)-resting state
Description: Prkdc scid mice have no preference for stimulus mouse over object in the three chamber social approach test unlike wt controls
Exp Paradigm: NA
Functional magnetic resonance imaging: connectivity1
Restored
Description: Introduction of wt lymphocytes normalizes connectivity between prelimbic cortex and frontal cortex, frontal association area and orbital cortex, insula and orbital cortex, insula and prelimbic cortex in prkdc scid mice
Exp Paradigm: NA
Functional magnetic resonance imaging (fmri)-resting state
