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Journal of Immunology (Baltimore, Md. :... Jan 2016Hypomorphic mutations in the nonhomologous end-joining (NHEJ) DNA repair protein DNA ligase IV (LIG4) lead to immunodeficiency with varying severity. In this study,...
Hypomorphic mutations in the nonhomologous end-joining (NHEJ) DNA repair protein DNA ligase IV (LIG4) lead to immunodeficiency with varying severity. In this study, using a murine knock-in model, we investigated the mechanisms underlying abnormalities in class switch recombination (CSR) associated with the human homozygous Lig4 R278H mutation. Previously, we found that despite the near absence of Lig4 end-ligation activity and severely reduced mature B cell numbers, Lig4(R278H/R278H) (Lig4(R/R)) mice exhibit only a partial CSR block, producing near normal IgG1 and IgE but substantially reduced IgG3, IgG2b, and IgA serum levels. In this study, to address the cause of these abnormalities, we assayed CSR in Lig4(R/R) B cells generated via preassembled IgH and IgK V region exons (HL). This revealed that Lig4(R278H) protein levels while intact exhibited a higher turnover rate during activation of switching to IgG3 and IgG2b, as well as delays in CSR kinetics associated with defective proliferation during activation of switching to IgG1 and IgE. Activated Lig4(R/R)HL B cells consistently accumulated high frequencies of activation-induced cytidine deaminase-dependent IgH locus chromosomal breaks and translocations and were more prone to apoptosis, effects that appeared to be p53-independent, as p53 deficiency did not markedly influence these events. Importantly, NHEJ instead of alternative end-joining (A-EJ) was revealed as the predominant mechanism catalyzing robust CSR. Defective CSR was linked to failed NHEJ and residual A-EJ access to unrepaired double-strand breaks. These data firmly demonstrate that Lig4(R278H) activity renders NHEJ to be more error-prone, and they predict increased error-prone NHEJ activity and A-EJ suppression as the cause of the defective B lymphopoiesis in Lig4 patients.
Topics: Animals; Apoptosis; B-Lymphocytes; Base Sequence; Cell Proliferation; Cells, Cultured; Cytidine Deaminase; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Ligase ATP; DNA Ligases; Disease Models, Animal; Eczema; Facies; Gene Knock-In Techniques; Growth Disorders; Humans; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin E; Immunoglobulin G; Immunoglobulin Variable Region; Immunoglobulins; Intellectual Disability; Lymphopoiesis; Mice; Mice, Knockout; Microcephaly; Molecular Sequence Data; Severe Combined Immunodeficiency; Tumor Suppressor Protein p53
PubMed: 26608917
DOI: 10.4049/jimmunol.1403099 -
Journal of Human Genetics Dec 2015Dubowitz syndrome is a presumed autosomal recessive disorder characterized by multiple congenital abnormalities: microcephaly, learning and developmental delay, growth...
Dubowitz syndrome is a presumed autosomal recessive disorder characterized by multiple congenital abnormalities: microcephaly, learning and developmental delay, growth failure, and a predisposition to allergies and eczema. There have been more than 150 individuals reported to have this diagnosis, but no unifying genetic alteration has been identified indicating genetic heterogeneity. We report on a pair of monozygotic twins diagnosed clinically with Dubowitz syndrome by Professor Dubowitz over 30 years ago and identified to have a de novo heterozygous 3.2-Mb deletion at 19q13.11q13.12. Exome sequencing did not identify either a putative pathogenic variant on the trans allele supporting recessive inheritance or any other causative sequence variants. Comparison of the phenotype in our cases shows considerable overlap with the 19q13.11 microdeletion syndrome, suggesting that a subset of individuals diagnosed with Dubowitz syndrome may be due to deletions at 19q13. Our finding further reinforces the genetic and phenotypic heterogeneity of Dubowitz syndrome.
Topics: Adult; Alleles; Base Sequence; Chromosomes, Human, Pair 19; Eczema; Facies; Growth Disorders; Humans; Intellectual Disability; Male; Microcephaly; Sequence Deletion; Twins, Monozygotic
PubMed: 26377242
DOI: 10.1038/jhg.2015.111 -
Pediatric Allergy and Immunology :... Dec 2015
Topics: Eczema; Growth Disorders; Humans; Intellectual Disability; Male; Microcephaly; T-Lymphocytes
PubMed: 26009798
DOI: 10.1111/pai.12411 -
The Journal of Clinical Endocrinology... Jan 2015
Topics: Bloom Syndrome; Contraindications; Female; Human Growth Hormone; Humans; Male; Silver-Russell Syndrome
PubMed: 25559542
DOI: 10.1210/jc.2014-3931 -
European Journal of Pediatrics Sep 2014To date, the genetic basis of Dubowitz syndrome (short stature, microcephaly, facial abnormalities, eczema) is unknown and vascular complications are not known to be...
UNLABELLED
To date, the genetic basis of Dubowitz syndrome (short stature, microcephaly, facial abnormalities, eczema) is unknown and vascular complications are not known to be associated with this syndrome. In microcephalic osteodysplastic primordial dwarfism type II (MOPD II; disproportionate short statue, microcephaly, facial abnormalities), however, cerebral aneurysms and other vascular abnormalities are frequent complications. MOPD II is a genetic disorder caused by mutations in the pericentrin (PCNT) gene (21q22). We report on a patient who came to our attention as a 22-year-old with subarachnoid bleeding due to a ruptured cranial aneurysm. Until then, the patient was thought and published to have Dubowitz syndrome; previously, he was treated with coronary bypass surgery for extensive coronary angiopathy. Consecutive genetic testing revealed MOPD II. After clinical stabilization, the patient was discharged to a specialized rehabilitation center where he died due to re-rupture of a cranial aneurysm.
CONCLUSION
In patients with short stature-especially when clinical features are accompanied by vascular complications-MOPD II should be considered as a differential diagnosis leading to consecutive genetic testing. After detection of mutations in the PCNT gene, a full vascular status including cerebral imaging and cardiac evaluation needs to be determined in order to analyze vascular abnormalities and initiate prophylactic treatment.
Topics: Adult; Antigens; Biomarkers; Diagnosis, Differential; Diagnostic Errors; Dwarfism; Eczema; Facies; Fatal Outcome; Fetal Growth Retardation; Growth Disorders; Humans; Intellectual Disability; Intracranial Aneurysm; Male; Microcephaly; Mutation; Osteochondrodysplasias; Patient Transfer; Recurrence
PubMed: 24973050
DOI: 10.1007/s00431-014-2368-5 -
Pediatric Allergy and Immunology :... Aug 2014
Topics: Child; Eczema; Facies; Growth Disorders; Humans; Intellectual Disability; Male; Microcephaly; T-Lymphocytes
PubMed: 24899539
DOI: 10.1111/pai.12238