Background Primary immunodeficiencies are a rare group of inborn diseases characterized by a broad clinical and genetic heterogeneity. Substantial advances in the identification of the underlying ...molecular mechanisms can be achieved through the study of patients with increased susceptibility to specific infections and immune dysregulation. We evaluated 3 siblings from a consanguineous family presenting with EBV-associated B-cell lymphoproliferation at an early age (12, 7½, and 14 months, respectively) and profound naive T-cell lymphopenia. Objective On the basis of the hypothesis of a rare inborn immunodeficiency of autosomal recessive inheritance, we sought to characterize the underlying genetic defect. Methods We performed genome-wide homozygosity mapping, followed by whole-exome sequencing. Results We identified a homozygous inherited missense mutation in the gene encoding Coronin-1A (CORO1A) in the 3 siblings. This mutation, p. V134M, results in the substitution of an evolutionarily conserved amino acid within the β-propeller domain, which abrogates almost completely the protein expression in the patients' cells. In addition to a significant diminution of naive T-cell numbers, we found impaired development of a diverse T-cell repertoire, near-to-absent invariant natural killer T cells, and severely diminished mucosal-associated invariant T cell numbers. Conclusions Our findings define a new clinical entity of a primary immunodeficiency with increased susceptibility to EBV-induced lymphoproliferation in patients associated with hypomorphic Coronin-1A mutation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Myb-Like, SWIRM, and MPN domains 1 (MYSM1) is a metalloprotease that deubiquitinates the K119-monoubiquitinated form of histone 2A (H2A), a chromatin marker associated with gene ...transcription silencing. Likewise, it has been reported that murine Mysm1 participates in transcription derepression of genes, among which are transcription factors involved in hematopoietic stem cell homeostasis, hematopoiesis, and lymphocyte differentiation. However, whether MYSM1 has a similar function in human subjects remains unclear. Here we describe a patient presenting with a complete lack of B lymphocytes, T-cell lymphopenia, defective hematopoiesis, and developmental abnormalities. Objectives We sought to characterize the underlying genetic cause of this syndrome. Methods We performed genome-wide homozygosity mapping, followed by whole-exome sequencing. Results Genetic analysis revealed that this novel disorder is caused by a homozygous MYSM1 missense mutation affecting the catalytic site within the deubiquitinase JAB1/MPN/Mov34 (JAMM)/MPN domain. Remarkably, during the course of our study, the patient recovered a normal immunohematologic phenotype. Genetic analysis indicated that this improvement originated from a spontaneous genetic reversion of the MYSM1 mutation in a hematopoietic stem cell. Conclusions We here define a novel human immunodeficiency and provide evidence that MYSM1 is essential for proper immunohematopoietic development in human subjects. In addition, we describe one of the few examples of spontaneous in vivo genetic cure of a human immunodeficiency.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background The endonuclease ARTEMIS, which is encoded by the DCLRE1C gene, is a component of the nonhomologous end-joining pathway and participates in hairpin opening during the V(D)J recombination ...process and repair of a subset of DNA double-strand breaks. Patients with ARTEMIS deficiency usually present with severe combined immunodeficiency (SCID) and cellular radiosensitivity, but hypomorphic mutations can cause milder phenotypes (leaky SCID). Objective We sought to correlate the functional effect of human DCLRE1C mutations on phenotypic presentation in patients with ARTEMIS deficiency. Methods We studied the recombination and DNA repair activity of 41 human DCLRE1C mutations in Dclre1c −/− v-abl kinase–transformed pro-B cells retrovirally engineered with a construct that allows quantification of recombination activity by means of flow cytometry. For assessment of DNA repair efficacy, resolution of γH2AX accumulation was studied after ionizing radiation. Results Low or absent activity was detected for mutations causing a typical SCID phenotype. Most of the patients with leaky SCID were compound heterozygous for 1 loss-of-function and 1 hypomorphic allele, with significant residual levels of recombination and DNA repair activity. Deletions disrupting the C-terminus result in truncated but partially functional proteins and are often associated with leaky SCID. Overexpression of hypomorphic mutants might improve the functional defect. Conclusions Correlation between the nature and location of DCLRE1C mutations, functional activity, and the clinical phenotype has been observed. Hypomorphic variants that have been reported in the general population can be disease causing if combined in trans with a loss-of-function allele. Therapeutic strategies aimed at inducing overexpression of hypomorphic alleles might be beneficial.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Telomeres represent the tips of linear chromosomes. In human subjects telomere maintenance deficiency leads to dyskeratosis congenita (DC), a rare genetic disorder characterized by ...progressive bone marrow failure, accelerated aging, and cancer predisposition. Hoyeraal-Hreidarsson syndrome (HH) is a severe variant of DC in which an early onset of bone marrow failure leading to combined immunodeficiency is associated with microcephaly, cerebellar hypoplasia, and growth retardation. Objectives Limited information is available on the cellular and molecular phenotypes of cells from patients with HH. We analyzed fibroblasts and whole blood cells from 5 patients with HH, 3 of them of unknown molecular origin. Methods Telomere length, cellular senescence rate, telomerase activity, telomeric aberration, and DNA repair pathways were investigated. Results Although patients’ cells exhibit dysfunctional telomeres, sharp differences in the telomeric aberrations and telomere lengths were noted among these patients. In some patients the dysfunctional telomere phenotype was unprecedented and associated with either normal telomere length or with telomeric aberrations akin to fragile telomeres. This result is of particular importance because the molecular diagnosis of these patients is primarily based on telomere length, which therefore misses a subset of patients with telomere dysfunction. Conclusion These observations provide the notions that (1) various telomere defects can lead to similar clinical features, (2) telomere dysfunction in cells from patients with DC/HH is not always associated with short telomeres, and (3) additional factors, likely involved in telomere protection rather than in length regulation, are responsible for a subset of DC/HH.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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