Spontaneous Function Correction of Pathogenic Alleles in Inherited Diseases Resulting in Somatic Mosaicism

Quinten Waisfisz, VU University Medical Center, Amsterdam, The Netherlands
Hans Joenje, VU University Medical Center, Amsterdam, The Netherlands

Published online: January 2006

DOI: 10.1038/npg.els.0006036

Inherited mutations can cause disease, but in monogenic disease correction of just one pathogenic mutation can lead to somatic mosaicism and revert the phenotype, which may ameliorate symptoms. The diseases for which this ‘natural gene therapy’ has been described include Fanconi anemia and Wiskott–Aldrich syndrome, among others.

Keywords: mosaicism; revertant; recombination; mutation; monogenic disorder; gene conversion; Bloom syndrome; Fanconi anemia; epidermolysis bullosa; tyrosinemia type I; adenosine deaminase deficiency; X-linked SCID; Wiskott–Aldrich syndrome; Lesch–Nyhan syndrome

Figure 1. Generation of a wild-type allele in somatic cells through intragenic homologous recombination with crossover, as described in compound heterozygous patients with nonoverlapping mutations. After replication, intragenic recombination involving the homologous chromatids leads to a wild-type allele and a doubly mutated allele. Depending on the segregation of chromatids the genetically corrected daughter cells will (left) or will not (right) exhibit loss of heterozygosity for markers distal to the disease gene.
Figure 2. Mosaicism of the skin in a patient with generalized atrophic benign epidermolysis bullosa (GABEB). The picture shows the characteristic blistering of the skin next to unaffected patches of the skin where somatic recombination with gene conversion has generated a wild-type allele of the disease gene. (Reproduced from Jonkman et al. 1997.)
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 References
    Ellis NA, Ciocci S and German J (2001) Back mutation can produce phenotype reversion in Bloom syndrome somatic cells. Human Genetics 108: 167–173.
    Ellis NA, Lennon DJ, Proytcheva M, et al. (1995) Somatic intragenic recombination within the mutated locus BLM can correct the high sister-chromatid exchange phenotype of Bloom syndrome cells. American Journal of Human Genetics 57: 1019–1027.
    Hirschhorn R, Yang DR, Puck JM, et al. (1996) Spontaneous in vivo reversion to normal of an inherited mutation in a patient with adenosine deaminase deficiency. Nature Genetics 13: 290–295.
    Jonkman MF, Scheffer H, Stulp R, et al. (1997) Revertant mosaicism in epidermolysis bullosa caused by mitotic gene conversion. Cell 21: 543–551.
    Kvittingen EA, Rootwelt H, Berger R and Brandtzaeg P (1994) Self-induced correction of the genetic defect in tyrosinemia type I. Journal of Clinical Investigation 94: 1657–1661.
    Lo Ten Foe JR, Kwee ML, Rooimans MA, et al. (1997) Somatic mosaicism in Fanconi anemia: molecular basis and clinical significance. European Journal of Human Genetics 5: 137–148.
    Stephan V, Wahn V, Le Deist F, et al. (1996) Atypical X-linked severe combined immunodeficiency due to possible spontaneous reversion of the genetic defect in T cells. New England Journal of Medicine 335: 1563–1567.
    Wada T, Schurman SH, Otsu M, et al. (2001) Somatic mosaicism in Wiskott–Aldrich syndrome suggests in vivo reversion by a DNA slippage mechanism. Proceedings of the National Academy of Sciences of the United States of America 98: 8697–8702.
    Waisfisz Q, Morgan NV, Savino M, et al. (1999) Spontaneous functional correction of homozygous Fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism. Nature Genetics 22: 379–383.
    Yang TP, Stout JT, Konecki DS, et al. (1988) Spontaneous reversion of novel Lesch–Nyhan mutation by HPRT gene rearrangement. Somatic Cell and Molecular Genetics 14: 293–303.
 Further Reading
    Ariga T, Kondoh T, Yamaguchi K, et al. (2001) Spontaneous in vivo reversion of an inherited mutation in the Wiskott–Aldrich syndrome. Journal of Immunology 166: 5245–5249.
    Ariga T, Oda N, Yamaguchi K, et al. (2001) T-cell lines from 2 patients with adenosine deaminase (ADA) deficiency showed the restoration of ADA activity resulted from the reversion of an inherited mutation. Blood 97: 2896–2899.
    Gregory Jr JJ, Wagner JE, Verlander PC, et al. (2001) Somatic mosaicism in Fanconi anemia: evidence of genotypic reversion in lymphohematopoietic stem cells. Proceedings of the National Academy of Sciences of the United States of America 98: 2532–2537.
    Jonkman MF (1999) Revertant mosaicism in human genetic disorders. American Journal of Medical Genetics 85: 361–364.
    Stephan V, Wahn V, Le Deist F, et al. (1996) Atypical X-linked severe combined immunodeficiency due to possible spontaneous reversion of the genetic defect in T cells. New England Journal of Medicine 335: 1563–1567.
    Youssoufian H and Pyeritz RE (2002) Mechanisms and consequences of somatic mosaicism in humans. Nature Review Genetics 10: 748–758.
 Web Links
    ePath NCBI Online Mendelian Inheritance in Man (OMIM). An online catalog of human genes and genetic disorders http://www.ncbi.nlm.nih.gov/Omim/
    ePath Collagen, type XVII, alpha 1 (COL17A1); Locus ID: 1308. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=1308
    ePath Hypoxanthine phosphoribosyltransferase 1 (Lesch–Nyhan syndrome) (HPRT1); Locus ID: 3251. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=3251
    ePath Wiskott-Aldrich syndrome (eczema-thrombocytopenia) (WAS); Locus ID: 7454. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=7454
    ePath Collagen, type XVII, alpha 1 (COL17A1); MIM number: 113811. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?113811
    ePath Hypoxanthine phosphoribosyltransferase 1 (Lesch–Nyhan syndrome) (HPRT1); MIM number: 308000. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?308000
    ePath Wiskott–Aldrich syndrome (eczema-thrombocytopenia) (WAS); MIM number: 300392. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?300392

Related Sub-Topics:

Genes, Molecules and Cellular Processes | Cell Differentiation and Stem Cells | Molecular Genetics of Common and Complex Disease | Mutational Mechanisms of Genetic Disease | Genomic Disorders | Evolution of Coding and Functional Modules | DNA Damage and Repair
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Article Title: Spontaneous Function Correction of Pathogenic Alleles in Inherited Diseases Resulting in Somatic Mosaicism
 
How to Cite close
Waisfisz, Quinten, and Joenje, Hans(Jan 2006) Spontaneous Function Correction of Pathogenic Alleles in Inherited Diseases Resulting in Somatic Mosaicism. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0006036]