Spontaneous in vivo reversion to normal of an inherited mutation in a patient with adenosine deaminase deficiency

Hirschhorn, Rochelle; Yang, Dongliang; Puck, Jennifer M.; Huie, Maryann L.; Jiang, C K; Kurlandsky, Lawrence E.

doi:10.1038/ng0796-290

Cited by 216 publications

(107 citation statements)

References 16 publications

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“…Unlike X-SCID and ADA-deficient SCID where there is an in vivo selective advantage for corrected cells, 57,58 there is no evidence of in vivo selection in disorders like the hemoglobinopathies or chronic granulomatous disease. Gene therapy for these disorders will require a higher level of transduction than is currently available with vectors pseudotyped with GaLV or amphotropic envelopes.…”

Section: Discussionmentioning

confidence: 99%

Improved transduction of human sheep repopulating cells by retrovirus vectors pseudotyped with feline leukemia virus type C or RD114 envelopes

Lucas

Seidel

Porada

et al. 2005

Blood

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Section: Discussionmentioning

confidence: 99%

Improved transduction of human sheep repopulating cells by retrovirus vectors pseudotyped with feline leukemia virus type C or RD114 envelopes

Lucas

Seidel

Porada

et al. 2005

Blood

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“…In each of these cases, restoration of a normal allele was demonstrated in cells of a single lineage. In some of these reports, evidence suggesting a mechanism for the reversion was presented, including mitotic gene conversion (18), back mutation (20,27), intragenic mitotic recombination (19), and the introduction of compensatory mutations (28,29). Each of these mechanisms can result in the restoration of one allele coding for a functional product.…”

Section: Discussionmentioning

confidence: 99%

Somatic mosaicism in Fanconi anemia: Evidence of genotypic reversion in lymphohematopoietic stem cells

Gregory

Wagner

Verlander

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

207

137

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Somatic mosaicism has been observed previously in the lymphocyte population of patients with Fanconi anemia (FA). To identify the cellular origin of the genotypic reversion, we examined each lymphohematopoietic and stromal cell lineage in an FA patient with a 2815-2816ins19 mutation in FANCA and known lymphocyte somatic mosaicism. DNA extracted from individually plucked peripheral blood T cell colonies and marrow colony-forming unit granulocyte-macrophage and burst-forming unit erythroid cells revealed absence of the maternal FANCA exon 29 mutation in 74.0%, 80.3%, and 86.2% of colonies, respectively. These data, together with the absence of the FANCA exon 29 mutation in Epstein-Barr virus-transformed B cells and its presence in fibroblasts, indicate that genotypic reversion, most likely because of back mutation, originated in a lymphohematopoietic stem cell and not solely in a lymphocyte population. Contrary to a predicted increase in marrow cellularity resulting from reversion in a hematopoietic stem cell, pancytopenia was progressive. Additional evaluations revealed a partial deletion of 11q in 3 of 20 bone marrow metaphase cells. By using interphase fluorescence in situ hybridization with an MLL gene probe mapped to band 11q23 to identify colonyforming unit granulocyte-macrophage and burst-forming unit erythroid cells with the 11q deletion, the abnormal clone was exclusive to colonies with the FANCA exon 29 mutation. Thus, we demonstrate the spontaneous genotypic reversion in a lymphohematopoietic stem cell. The subsequent development of a clonal cytogenetic abnormality in nonrevertant cells suggests that ex vivo correction of hematopoietic stem cells by gene transfer may not be sufficient for providing life-long stable hematopoiesis in patients with FA. F anconi anemia (FA) is an autosomal recessive disorder characterized by congenital abnormalities, bone marrow failure, and a predisposition to malignancies, including myelodysplastic syndrome and acute myelogenous leukemia (1). Seven FA complementation groups (FA-A through FA-G) have been reported (2), with FA-A (Online Mendelian Inheritance in Man, OMIM no. 227650) constituting approximately two-thirds of the patients. The FANCA, FANCC, FANCE, FANCF, and FANCG genes have been cloned and mapped to chromosomes 16q24. 3, 9q22.3, 6p21.2-21.3, 11p15, and 9p13, respectively (3-8). However, the specific function of these genes remains unclear.FA cells are uniquely hypersensitive to DNA cross-linking agents such as diepoxybutane (DEB) and mitomycin C (MMC) (9). This cellular phenotype can be demonstrated in cultured T cells, B cells, fibroblasts, and fetal cells cultured from amniotic fluid or chorionic villi (10). Hypersensitivity of phytohemagglutinin (PHA)-stimulated peripheral blood lymphocytes (PBLs) to DEB is used routinely as a diagnostic test for the syndrome (11). At a DEB concentration that has a minimal effect on normal PBLs (0.1 g͞ml), 80-100% of PBLs analyzed will have chromatid breaks and exchanges in the typical FA patient. However, in a small grou...

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“…Genetic milestones included the discoveries of an autosomal dominant immunodeficiency in 1963 (115), spontaneous cure by somatic reversion in 1996 (116), and a gainof-function mutation in 2001 (117). Other spectacular achievements have been made in the domain of therapy, including the first successful cases of hematopoietic stem cell transplantation in 1968 (118) and gene therapy in 2000 (119).…”

Section: Primary Immunodeficiencies: a Success Storymentioning

confidence: 99%

Human genetic basis of interindividual variability in the course of infection

Casanova

2015

Proc. Natl. Acad. Sci. U.S.A.

161

111

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The key problem in human infectious diseases was posed at the turn of the 20th century: their pathogenesis. For almost any given virus, bacterium, fungus, or parasite, life-threatening clinical disease develops in only a small minority of infected individuals. Solving this infection enigma is important clinically, for diagnosis, prognosis, prevention, and treatment. Some microbes will inevitably remain refractory to, or escape vaccination, or chemotherapy, or both. The solution also is important biologically, because the emergence and evolution of eukaryotes alongside more rapidly evolving prokaryotes, archaea, and viruses posed immunological challenges of an ecological and evolutionary nature. We need to study these challenges in natural, as opposed to experimental, conditions, and also at the molecular and cellular levels. According to the human genetic theory of infectious diseases, inborn variants underlie life-threatening infectious diseases. Here I review the history of the field of human genetics of infectious diseases from the turn of the 19th century to the second half of the 20th century. This paper thus sets the scene, providing the background information required to understand and appreciate the more recently described monogenic forms of resistance or predisposition to specific infections discussed in a second paper in this issue.

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Spontaneous in vivo reversion to normal of an inherited mutation in a patient with adenosine deaminase deficiency

Cited by 216 publications

References 16 publications

Improved transduction of human sheep repopulating cells by retrovirus vectors pseudotyped with feline leukemia virus type C or RD114 envelopes

Improved transduction of human sheep repopulating cells by retrovirus vectors pseudotyped with feline leukemia virus type C or RD114 envelopes

Somatic mosaicism in Fanconi anemia: Evidence of genotypic reversion in lymphohematopoietic stem cells

Human genetic basis of interindividual variability in the course of infection

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