摘要
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.
- 出版日期2017-3