In vivo reversion to normal of inherited mutations in humans

Hirschhorn, Rochelle

doi:10.1136/jmg.40.10.721

Cited by 171 publications

(169 citation statements)

References 45 publications

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“…We also considered the additional possibility of the in vivo reversion (at the DNA level) of the inherited mutations [Hirschhorn, 2003] to wild-type in a proportion of the somatic cells of the three patients under study. This could, however, be effectively excluded on account of the fact that no wild-type IDS DNA sequence was ever detectable in PCR-based analyses of samples of patient genomic DNA.…”

Section: Discussionmentioning

confidence: 99%

Enigmatic In Vivo iduronate-2-sulfatase (IDS) mutant transcript correction to wild-type in Hunter syndrome

et al. 2010

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Sequence analysis of the X-linked iduronate-2-sulfatase (IDS) gene in two Hunter syndrome patients revealed a lack of concordance between IDS genomic DNA and cDNA. These individuals were found to be hemizygous respectively for a nonsense mutation [c.22C>T;p.R8X] and a frameshift micro-insertion [c.10insT;p.P4Sfs] in their genomic DNA. However, both wildtype and mutant IDS sequences were evident upon cDNA analysis. Similar discrepant results were also obtained in a third unrelated patient carrying the same p.R8X mutation. Since both p.R8X mutations were inherited from carrier mothers, somatic mosaicism could be excluded. Although the presence of wild-type IDS mRNA-transcripts was confirmed in all three patients by restriction enzyme digestion, clone sequencing, pyrosequencing and single nucleotide primer extension (SNuPE), no wild-type IDS genomic sequence was detectable. The relative abundance of wild-type and mutation-bearing IDS-transcripts in different tissues was quantified by SNuPE. Although IDS transcript levels, as measured by real-time PCR, were reduced (51-71% normal) in these patients, some wild-type IDS protein was detectable by western blotting. Various possible explanations for these unprecedented findings (e.g. accidental contamination, artefactual in vitro nucleotide misincorporation, malsegregation of an extra maternal X-chromosome) were explored and experimentally excluded. PCR-based discriminant assay and segregation analysis of a linked IDS polymorphism (rs1141608) also served to exclude the presence of IDS cDNA derived from the maternal wild-type chromosome. Although it remains to be formally demonstrated by direct experimentation, the intriguing possibility arises that we have observed the in vivo correction of heritable gene lesions at the RNA level operating via a correction mechanism akin to RNA-editing.

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Section: Discussionmentioning

confidence: 99%

Enigmatic In Vivo iduronate-2-sulfatase (IDS) mutant transcript correction to wild-type in Hunter syndrome

et al. 2010

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“…Most spontaneous reversions have been found to occur in severe skin disease and hematologic or immunological diseases. [2][3][4][5][6] The growth advantage of revertant cells has been the central dogma for the success of gene therapy in severe combined immunodeficiency (SCID). 7,8 SCID is a collection of various gene defects that result in the absence of T lymphocytes with or without the involvement of B cells and/or NK cells.…”

Section: Introductionmentioning

confidence: 99%

“…Like somatic mosaicism due to de novo mutations during embryogenesis, mosaicism due to reversions to normal of an inherited mutation have been discovered because of milder than expected clinical courses and/or the presence of both phenotypically normal and abnormal cells in vivo and in vitro. 2 In the case of spontaneous reversion, the mutation that has reverted to normal in some cells has been inherited from a parent.…”

Section: Introductionmentioning

confidence: 99%

A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells

Kuijpers

Leeuwen²,

Barendregt

et al. 2013

Haematologica

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Mutations in the common gamma chain (γ c , CD132, encoded by the IL2RG gene) can lead to B + T − NK − X-linked severe combined immunodeficiency, as a consequence of unresponsiveness to γc-cytokines such as interleukins-2, -7 and -15. Hypomorphic mutations in CD132 may cause combined immunodeficiencies with a variety of clinical presentations. We analyzed peripheral blood mononuclear cells of a 6-year-old boy with normal lymphocyte counts, who suffered from recurrent pneumonia and disseminated mollusca contagiosa. Since proliferative responses of T cells and NK cells to γc -cytokines were severely impaired, we performed IL2RG gene analysis, showing a heterozygous mutation in the presence of a single X-chromosome. Interestingly, an IL2RG reversion to normal predominated in both naïve and antigen-primed CD8 + T cells and increased over time. Only the revertant CD8 + T cells showed normal expression of CD132 and the various CD8 + T cell populations had a different T-cell receptor repertoire. Finally, a fraction of γδ + T cells and differentiated CD4 + CD27 − effector-memory T cells carried the reversion, whereas NK or B cells were repeatedly negative. In conclusion, in a patient with a novel IL2RG mutation, gene-reverted CD8 + T cells accumulated over time. Our data indicate that selective outgrowth of particular T-cell subsets may occur following reversion at the level of committed T progenitor cells. A reversion of an IL2RG mutation in combined immunodeficiency

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“…Another explanation for DEB+ patients with both FANCD2 isoforms is the presence of mosaicism, i.e., the co-existence of genetically distinct hematopoietic populations probably due to reversion of inherited deleterious mutations to wild type (34)(35)(36)(37)(38)(39)40). Clinical significance of somatic mosaicism is not well understood.…”

Section: Chromosome Breakage Test -Diepoxybutanementioning

confidence: 99%

“…Somatic mosaicism in hematopoietic FA cells comes from reversion of inherited deleterious mutations to the normal wild-type allele and it results in the presence of both normal and mutant hematopoietic cells in a single individual (34).…”

Section: Introductionmentioning

confidence: 99%

FANCD2 Western blot as a diagnostic tool for Brazilian patients with Fanconi anemia

Pilonetto

Pereira

Bitencourt

et al. 2009

Braz J Med Biol Res

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Fanconi anemia is a rare hereditary disease showing genetic heterogeneity due to a variety of mutations in genes involved in DNA repair pathways, which may lead to different clinical manifestations. Phenotypic variability makes diagnosis difficult based only on clinical manifestations, therefore laboratory tests are necessary. New advances in molecular pathogenesis of this disease led researchers to develop a diagnostic test based on Western blot for FANCD2. The objective of the present study was to determine the efficacy of this method for the diagnosis of 84 Brazilian patients with Fanconi anemia, all of whom tested positive for the diepoxybutane test, and 98 healthy controls. The FANCD2 monoubiquitinated isoform (FANCDS+/FANCD2L-) was not detected in 77 patients (91.7%). In 2 patients (2.4%), there was an absence of both the monoubiquitinated and the non-ubiquitinated proteins (FANCD2S-/FANCD2L-) and 5 patients (5.9%) had both isoforms (FANCD2S+/FANCD2L+). This last phenotype suggests downstream subtypes or mosaicism. All controls were diepoxybutane negative and were also negative on the FANCD2 Western blot. The Western blot for FANCD2 presented a sensitivity of 94% (79/84) and specificity of 100% (98/98). This method was confirmed as an efficient approach to screen Brazilian patients with deleterious mutations on FANCD2 (FANCD2S-/FANCD2L-) or other upstream genes of the FA/BRCA pathway (FANCDS+/FANCD2L-), to confirm the chromosome breakage test and to classify patients according to the level of FA/BRCA pathway defects. However, patients showing both FANCD2 isoforms (FANCD2S+/FANCD2L+) require additional studies to confirm mutations on downstream Fanconi anemia genes or the presence of mosaicism.

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In vivo reversion to normal of inherited mutations in humans

Cited by 171 publications

References 45 publications

Enigmatic In Vivo iduronate-2-sulfatase (IDS) mutant transcript correction to wild-type in Hunter syndrome

Enigmatic In Vivo iduronate-2-sulfatase (IDS) mutant transcript correction to wild-type in Hunter syndrome

A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells

FANCD2 Western blot as a diagnostic tool for Brazilian patients with Fanconi anemia

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