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

Abstract

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..)

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References

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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.

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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.

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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.

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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

NCBI Online Mendelian Inheritance in Man (OMIM). An online catalog of human genes and genetic disorders http://www.ncbi.nlm.nih.gov/Omim/

Collagen, type XVII, alpha 1 (COL17A1); Locus ID: 1308. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=1308

Hypoxanthine phosphoribosyltransferase 1 (Lesch–Nyhan syndrome) (HPRT1); Locus ID: 3251. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=3251

Wiskott‐Aldrich syndrome (eczema‐thrombocytopenia) (WAS); Locus ID: 7454. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=7454

Collagen, type XVII, alpha 1 (COL17A1); MIM number: 113811. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?113811

Hypoxanthine phosphoribosyltransferase 1 (Lesch–Nyhan syndrome) (HPRT1); MIM number: 308000. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?308000

Wiskott–Aldrich syndrome (eczema‐thrombocytopenia) (WAS); MIM number: 300392. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?300392

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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]