A novel somatic mutation achieves partial rescue in a child with Hutchinson-Gilford progeria syndrome.

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Bar, Daniel Z 
Arlt, Martin F 
Brazier, Joan F 
Norris, Wendy E 
Campbell, Susan E 

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.

Other cardiovascular medicine, aging, lamin, mosaicism, progeria, Adolescent, Cell Nucleus, Cells, Cultured, Child, Child, Preschool, Exons, Female, Fibroblasts, Genetic Predisposition to Disease, Germ-Line Mutation, High-Throughput Nucleotide Sequencing, Humans, Infant, Lamin Type A, Male, Mosaicism, Progeria
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J Med Genet
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Cancer Research UK (18796)
Medical Research Council (MR/L019116/1)
Wellcome Trust (092096/Z/10/Z)
Progeria experiments were funded by The Progeria Research Foundation grants PRF-2002-CB and PRF-2002-MRD (JFB, WEN, SEC, LBG), and by the Medical Research Council UK grant MR/L019116/1 (DL). Core and general laboratory grants are as follows: Kilguss Research Core of Women & Infants Hospital of Rhode Island through an Institutional Development Award from the NIGMS of the NIH (P30GM114750), intramural funds to the NHGRI (ZIA-HG200305), Cancer Research UK programme grant C6/A18796 and Wellcome Trust (WT092096).