A novel somatic mutation achieves partial rescue in a child with Hutchinson-Gilford progeria syndrome
| Autor: | Bar, Daniel Z, Arlt, Martin F, Brazier, Joan F, Norris, Wendy E, Campbell, Susan E, Chines, Peter, Larrieu, Delphine, Jackson, Stephen P, Collins, Francis S, Glover, Thomas W, Gordon, Leslie B |
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| Přispěvatelé: | Larrieu, Delphine [0000-0002-2335-9361], Jackson, Stephen [0000-0001-9317-7937], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Cell Nucleus
Male congenital hereditary and neonatal diseases and abnormalities integumentary system Other cardiovascular medicine Adolescent Mosaicism aging progeria High-Throughput Nucleotide Sequencing Infant Exons Fibroblasts Lamin Type A Child Preschool Humans lamin Female Genetic Predisposition to Disease Somatic Mosaicism Child Cells Cultured Germ-Line Mutation |
| Zdroj: | Journal of Medical Genetics |
| ISSN: | 1468-6244 0022-2593 |
| Popis: | BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) is a fatal sporadic autosomal dominant premature ageing disease caused by single base mutations that optimise a cryptic splice site within exon 11 of the LMNA gene. The resultant disease-causing protein, progerin, acts as a dominant negative. Disease severity relies partly on progerin levels. METHODS AND RESULTS: We report a novel form of somatic mosaicism, where a child possessed two cell populations with different HGPS disease-producing mutations of the same nucleotide-one producing severe HGPS and one mild HGPS. The proband possessed an intermediate phenotype. The mosaicism was initially discovered when Sanger sequencing showed a c.1968+2T>A mutation in blood DNA and a c.1968+2T>C in DNA from cultured fibroblasts. Deep sequencing of DNA from the proband's blood revealed 4.7% c.1968+2T>C mutation, and 41.3% c.1968+2T>A mutation. CONCLUSIONS: We hypothesise that the germline mutation was c.1968+2T>A, but a rescue event occurred during early development, where the somatic mutation from A to C at 1968+2 provided a selective advantage. This type of mosaicism where a partial phenotypic rescue event results from a second but milder disease-causing mutation in the same nucleotide has not been previously characterised for any disease. |
| Databáze: | OpenAIRE |
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