Revertant mosaicism: partial correction of a germ-line mutation in COL17A1 by a frame-restoring mutation

Darling, Thomas N.; Yee, Carole; Bauer, Johann; Hintner, Helmut; Yancey, Kim B.

doi:10.1172/jci4338

Cited by 68 publications

(64 citation statements)

References 27 publications

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“…Revertant mosaicism due to a second-site mutation has been reported previously (16)(17)(18). In particular, the occurrence of the same second-site mutation in two brothers with Fanconi anemia has been reported by Waisfisz et al (17), who proposed the presence of the same second-site mutation having resulted from the same specific molecular mechanism in the two subjects.…”

Section: Discussionmentioning

confidence: 77%

Second-site mutation in the Wiskott-Aldrich syndrome (WAS) protein gene causes somatic mosaicism in two WAS siblings

Wada¹,

Konno²,

Schurman³

et al. 2003

J. Clin. Invest.

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Section: Discussionmentioning

confidence: 77%

Second-site mutation in the Wiskott-Aldrich syndrome (WAS) protein gene causes somatic mosaicism in two WAS siblings

Wada¹,

Konno²,

Schurman³

et al. 2003

J. Clin. Invest.

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“…Revertant mosaicism has been reported in various diseases including severe combined immunodeficiency [both X linked and adenosine deaminase (ADA) deficiency; refs. 16, 17, and 27], Duchenne muscular dystrophy (28), tyrosinemia (20), Bloom syndrome (19), and epidermolysis bullosa (18,29) among others. In each of these cases, restoration of a normal allele was demonstrated in cells of a single lineage.…”

Section: Discussionmentioning

confidence: 99%

“…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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“…27 and below). An alternative is to stain an adjacent section (28) and use it as a guide for the microdissection. Fig.…”

Section: X At ϫ132mentioning

confidence: 99%

Genetic mosaic analysis based on Cre recombinase and navigated laser capture microdissection

Wong

Saam

Stappenbeck

et al. 2000

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

115

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Defining molecular interactions that occur at the interface between ''normal'' and ''abnormal'' cell populations represents an important but often underexplored aspect of the pathogenesis of diseases with focal origins. Here, we illustrate an approach for conducting such analyses based on mosaic patterns of Cre recombinase expression in the adult mouse intestinal epithelium. Transgenic mice were generated that express Cre in the stem cell niche of crypts located in specified regions of their intestine. Some of these mice were engineered to allow for doxycycline-inducible Cre expression. Recombination in all pedigrees was mosaic: Cre-expressing crypts that supported recombination in all of their active multipotent stem cells were located adjacent to ''control'' crypts that did not express Cre at detectable levels. Cre-mediated recombination of a floxed LacZ reporter provided direct evidence that adult small-intestinal crypts contain more than one active multipotent stem cell, and that these cells can be retained in both small-intestinal and colonic crypts for at least 80 d. A method was developed to recover epithelial cells from crypts with or without recombination for subsequent gene expression profiling. Stained sections of intestine were used to create electronic image templates to guide laser capture microdissection (LCM) of adjacent frozen sections. This navigated form of LCM overcomes problems with mRNA degradation encountered when cells are marked directly by immunohistochemical methods. Combining Cre-engineered genetic mosaic mice with navigated-LCM will allow biology and pathobiology to be explored at the junction between normal and perturbed cellular cohorts.mouse intestinal stem cells ͉ genetic mosaic analysis

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Revertant mosaicism: partial correction of a germ-line mutation in COL17A1 by a frame-restoring mutation

Cited by 68 publications

References 27 publications

Second-site mutation in the Wiskott-Aldrich syndrome (WAS) protein gene causes somatic mosaicism in two WAS siblings

Second-site mutation in the Wiskott-Aldrich syndrome (WAS) protein gene causes somatic mosaicism in two WAS siblings

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

Genetic mosaic analysis based on Cre recombinase and navigated laser capture microdissection

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