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Spontaneous functional correction of homozygous Fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism
Abstract
Somatic mosaicism due to reversion of a pathogenic allele to wild type has been described in several autosomal recessive disorders. The best known mechanism involves intragenic mitotic recombination or gene conversion in compound heterozygous patients, whereby one allele serves to restore the wild-type sequence in the other. Here we document for the first time functional correction of a pathogenic microdeletion, microinsertion and missense mutation in homozygous Fanconi anaemia (FA) patients resulting from compensatory secondary sequence alterations in cis. The frameshift mutation 1615delG in FANCA was compensated by two additional single base-pair deletions (1637delA and 1641delT); another FANCA frameshift mutation, 3559insG, was compensated by 3580insCGCTG; and a missense mutation in FANCC(1749T-->G, Leu496Arg) was altered by 1748C-->T, creating a cysteine codon. Although in all three cases the predicted proteins were different from wild type, their cDNAs complemented the characteristic hypersensitivity of FA cells to crosslinking agents, thus establishing a functional correction to wild type.
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“In FA, the high incidence of somatic mosaics in up to 10% of patients may point towards a selective advantage of genetically fit wt HSC[56–59].”
From Finding the needle in the hay stack: Hematopoietic stem cells in Fanconi anemia (2009) · cites this paper as [59]
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Xia, B., Dorsman, J. C., Ameziane, N., de Vries, Y., Rooimans, M. A., Sheng, Q., Pals, G., Errami, A., Gluckman, E., Llera, J., et al. (2007) · Nature Genetics · doi:10.1038/ng1942 · Cited by 465
Self-citationde Lange, I. M., Koudijs, M. J., van 't Slot, R., Gunning, B., Sonsma, A. C. M., van Gemert, L. J. J. M., Mulder, F., Carbo, E. C., van Kempen, M. J. A., Verbeek, N. E., et al. (2018) · Epilepsia · doi:10.1111/epi.14021 · Cited by 64
Finding the needle in the hay stack: Hematopoietic stem cells in Fanconi anemia
Müller, L. U. W., & Williams, D. A. (2009) · Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis · doi:10.1016/j.mrfmmm.2009.03.010 · Cited by 31
Metadata
- Authors
- Waisfisz, Q., Morgan, N. V., Savino, M., de Winter, J. P., van Berkel, C. G. M., Hoatlin, M. E., Ianzano, L., Gibson, R. A., Arwert, F., Savoia, A., Mathew, C. G., Pronk, J. C., & Joenje, H.
- Venue
- Nature Genetics
- Published
- 1999-08
- Volume
- 22
- Issue
- 4
- Pages
- 379-383
- ISSN
- 1061-4036
- 1546-1718
- Cited by
- 173
- References
- 1
- Language
- en
- Licence
- www.springer.com/tdm (tdm)
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- Waisfisz, Q., Morgan, N. V., Savino, M., de Winter, J. P., van Berkel, C. G. M., Hoatlin, M. E., Ianzano, L., Gibson, R. A., Arwert, F., Savoia, A., Mathew, C. G., Pronk, J. C., & Joenje, H. (1999). Spontaneous functional correction of homozygous Fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism. Nature Genetics. https://doi.org/10.1038/11956
