Mitotic recombination in patients with ichthyosis causes reversion of dominant mutations in KRT10

Keith A. Choate, Yin Lu, Jing Zhou, Murim Choi, Peter M. Elias, Anita Farhi, Carol Nelson-Williams, Debra Crumrine, Mary L. Williams, Amy J. Nopper, Alanna Bree, Leonard M. Milstone, Richard P. Lifton

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112 Citations (Scopus)

Abstract

Somatic loss of wild-type alleles can produce disease traits such as neoplasia. Conversely, somatic loss of disease-causing mutations can revert phenotypes; however, these events are infrequently observed. Here we show that ichthyosis with confetti, a severe, sporadic skin disease in humans, is associated with thousands of revertant clones of normal skin that arise from loss of heterozygosity on chromosome 17q via mitotic recombination. This allowed us to map and identify disease-causing mutations in the gene encoding keratin 10 (KRT10); all result in frameshifts into the same alternative reading frame, producing an arginine-rich C-terminal peptide that redirects keratin 10 from the cytokeratin filament network to the nucleolus. The high frequency of somatic reversion in ichthyosis with confetti suggests that revertant stem cell clones are under strong positive selection and/or that the rate of mitotic recombination is elevated in individuals with this disorder.

Original languageEnglish
Pages (from-to)94-97
Number of pages4
JournalScience
Volume330
Issue number6000
DOIs
StatePublished - 1 Oct 2010

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Keratin-10
Ichthyosis
Genetic Recombination
Mutation
Clone Cells
Reading Frames
Loss of Heterozygosity
Keratins
Skin Diseases
Arginine
Stem Cells
Chromosomes
Alleles
Phenotype
Skin
Peptides
Genes
Neoplasms

Cite this

Choate, K. A., Lu, Y., Zhou, J., Choi, M., Elias, P. M., Farhi, A., ... Lifton, R. P. (2010). Mitotic recombination in patients with ichthyosis causes reversion of dominant mutations in KRT10. Science, 330(6000), 94-97. https://doi.org/10.1126/science.1192280
Choate, Keith A. ; Lu, Yin ; Zhou, Jing ; Choi, Murim ; Elias, Peter M. ; Farhi, Anita ; Nelson-Williams, Carol ; Crumrine, Debra ; Williams, Mary L. ; Nopper, Amy J. ; Bree, Alanna ; Milstone, Leonard M. ; Lifton, Richard P. / Mitotic recombination in patients with ichthyosis causes reversion of dominant mutations in KRT10. In: Science. 2010 ; Vol. 330, No. 6000. pp. 94-97.
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abstract = "Somatic loss of wild-type alleles can produce disease traits such as neoplasia. Conversely, somatic loss of disease-causing mutations can revert phenotypes; however, these events are infrequently observed. Here we show that ichthyosis with confetti, a severe, sporadic skin disease in humans, is associated with thousands of revertant clones of normal skin that arise from loss of heterozygosity on chromosome 17q via mitotic recombination. This allowed us to map and identify disease-causing mutations in the gene encoding keratin 10 (KRT10); all result in frameshifts into the same alternative reading frame, producing an arginine-rich C-terminal peptide that redirects keratin 10 from the cytokeratin filament network to the nucleolus. The high frequency of somatic reversion in ichthyosis with confetti suggests that revertant stem cell clones are under strong positive selection and/or that the rate of mitotic recombination is elevated in individuals with this disorder.",
author = "Choate, {Keith A.} and Yin Lu and Jing Zhou and Murim Choi and Elias, {Peter M.} and Anita Farhi and Carol Nelson-Williams and Debra Crumrine and Williams, {Mary L.} and Nopper, {Amy J.} and Alanna Bree and Milstone, {Leonard M.} and Lifton, {Richard P.}",
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Choate, KA, Lu, Y, Zhou, J, Choi, M, Elias, PM, Farhi, A, Nelson-Williams, C, Crumrine, D, Williams, ML, Nopper, AJ, Bree, A, Milstone, LM & Lifton, RP 2010, 'Mitotic recombination in patients with ichthyosis causes reversion of dominant mutations in KRT10', Science, vol. 330, no. 6000, pp. 94-97. https://doi.org/10.1126/science.1192280

Mitotic recombination in patients with ichthyosis causes reversion of dominant mutations in KRT10. / Choate, Keith A.; Lu, Yin; Zhou, Jing; Choi, Murim; Elias, Peter M.; Farhi, Anita; Nelson-Williams, Carol; Crumrine, Debra; Williams, Mary L.; Nopper, Amy J.; Bree, Alanna; Milstone, Leonard M.; Lifton, Richard P.

In: Science, Vol. 330, No. 6000, 01.10.2010, p. 94-97.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Choate, Keith A.

AU - Lu, Yin

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AU - Farhi, Anita

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AU - Crumrine, Debra

AU - Williams, Mary L.

AU - Nopper, Amy J.

AU - Bree, Alanna

AU - Milstone, Leonard M.

AU - Lifton, Richard P.

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