The many faces of Artemis-deficient combined immunodeficiency - Two patients with DCLRE1C mutations and a systematic literature review of genotype-phenotype correlation.
Defective V(D)J recombination and DNA double-strand break (DSB) repair severely impair the development of T-lymphocytes and B-lymphocytes. Most patients manifest a severe combined immunodeficiency during infancy. We report 2 siblings with combined immunodeficiency (CID) and immunodysregulation caused by compound heterozygous Artemis mutations, including an exon 1-3 deletion generating a null allele, and a missense change (p.T71P). Skin fibroblasts demonstrated normal DSB repair by gamma-H2AX analysis, supporting the predicted hypomorphic nature of the p.T71P allele. In addition to these two patients, 12 patients with Artemis-deficient CID were previously reported. All had significant morbidities including recurrent infections, autoimmunity, EBV-associated lymphoma, and carcinoma despite having hypomorphic mutants with residual Artemis expression, V(D)J recombination or DSB repair capacity. Nine patients underwent stem cell transplant and six survived, while four patients who did not receive transplant died. The progressive nature of immunodeficiency and genomic instability accounts for poor survival, and early HSCT should be considered.
Department of Immunology, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
Pamela P
PP
Lee
Lisa
L
Woodbine
Kimberly C
KC
Gilmour
Shahnaz
S
Bibi
Catherine M
CM
Cale
Persis J
PJ
Amrolia
Paul A
PA
Veys
E Graham
EG
Davies
Penny A
PA
Jeggo
Alison
A
Jones
D000328:Adult; D000595:Amino Acid Sequence; D002675:Child, Preschool; D004268:DNA-Binding Proteins; D004720:Endonucleases; D005260:Female; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D042822:Genomic Instability; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000276:immunology; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D035781:Siblings; D060152:V(D)J Recombination / Q000276:immunology
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C426344:DCLRE1C protein, human; D004720:Endonucleases
Artemis; Combined immunodeficiency; DCLRE1C; Hypomorphic; Radiosensitivity; SCID