Analysis of the recovery of CD247 expression in a PID patient: insights into the spontaneous repair of defective genes

Abstract

Mutations in T-cell antigen receptor (TCR) subunit genes cause rare immunodeficiency diseases characterized by impaired expression of the TCR at the cell surface and selective T lymphopenia. Here, detailed analyses of spontaneously arising somatic mutations that recover CD247, and thus TCR expression, in a newly identified CD247-deficient patient are described. The recovery of CD247 expression in some patient T cells was associated with both reversion of the inactivating mutation and a variant with a compensating mutation that could reconstitute TCR expression, but not as efficiently as wild-type CD247. Multiple mutations were found in CD247 complementary DNAs (cDNAs) cloned from the patient as well as in cDNA and genomic DNA from other individuals, suggesting that genetic variation in this gene is frequent. Analyses of other genes mutated in primary immunodeficiency diseases (PIDs) where reversions have been described also revealed a higher rate of mutation than that observed for genes mutated in PIDs where revertants have not been identified or control genes. These data support the hypothesis that the occurrence of somatic mutations that may reconstitute genetic defects in PID is related to an increased propensity of those genes to mutate.

Reversion Mosaicism in Primary Immunodeficiency Diseases

“…Loss-of-function mutations in genes that are involved in genomic stability such as BLM, LIG4, FANCA, FANCC, FANCD2, and presumably WAS may be associated with a high incidence of reversion mutations (3,(51)(52)(53). Gene variation analysis, used to evaluate the mutation frequency of PID genes in which reversion events have or have not been described, has revealed that genetic variation is significantly greater for revertant genes than for nonrevertant or control genes, especially in coding sequences (18). The study also demonstrated that the presence of CpG islands was more frequent in revertant PID genes than in nonrevertant genes; however, other factors such as local chromatin structure and accessibility for DNA repair may influence mutation frequency (18).…”

“…Three patients with CD3z deficiency were previously found to have somatic reversion mutations in CD3Z gene (16)(17)(18)(19). The first patient, who carried a germline mutation within the intracellular first immunoreceptor tyrosine-based activation motif domain and presented with the SCID phenotype, harbored three second-site mutations that partially rescued membranous TCR expression but functioned poorly (16).…”

“…The first case of reversion mosaicism in PIDs was recognized because of a milder than expected clinical phenotype in a patient with adenosine deaminase (ADA) deficiency (6). Reversion mosaicism has subsequently been found in some PIDs such as X-linked severe combined immunodeficiency (X-SCID) (5,(7)(8)(9)(10)(11)(12)(13), recombination activating gene 1 (RAG1) deficiency (14,15), CD3z deficiency (16)(17)(18)(19), and Wiskott-Aldrich syndrome (WAS) (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). The establishment of reversion mosaicism has modified the clinical phenotype of these disorders in which revertant cells have a selective advantage in vivo (5).…”

Prediction for Intravenous Immunoglobulin Resistance Combining Genetic Risk Loci Identified From Next Generation Sequencing and Laboratory Data in Kawasaki Disease

“…CD3ζ chain can alter TCR signaling and participate in T cell activation (18). Previous studies found that CD247 were associated with Systemic lupus erythematosus (SLE) and other autoimmune disorders by T cell-mediated mechanism (19,20). Interleukin-2 receptor subunit alpha encoded by IL2RA gene is a hallmark antigen of regulatory T cells, and functions in the suppression of immune responses and maintenance of immune homeostasis (21,22).…”

Protein functionality as a potential bottleneck for somatic revertant variants

“…Most somatic variants retained such a characteristic distribution of amino acids despite a difference in the primary structure and several variants were found recurrently (Fig 2 Somatic mosaicism caused by revertant variants has been observed in many cases of severe combined immunodeficiencyincluding several reports on CD247 deficiency-but never to this extreme extent, which may be explained by the lack of a deepsequencing-based approach. 3,8,9 We believe that the unique location of the disease-causing mutation in the signal peptide sequence is integral to understanding the pathogenicity of this case. Disease-causing germline mutations are mostly located in regions that are integral to protein function.…”