title: A novel somatic mutation achieves partial rescue in a child with Hutchinson-Gilford progeria syndrome.
abstract: 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 theLMNAgene. The resultant disease-causing protein, progerin, acts as a dominant negative. Disease severity relies partly on progerin levels.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Daniel Z
authors.initials: DZ
authors.lastname: Bar
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Arlt
authors.affiliation: Center for Gerontology and Health Care Research, Brown University, Providence, Rhode Island, USA.
authors.forename: Joan F
authors.initials: JF
authors.lastname: Brazier
authors.affiliation: Department of Pediatrics, Hasbro Children's Hospital, Providence, Rhode Island, USA.
authors.forename: Wendy E
authors.initials: WE
authors.lastname: Norris
authors.affiliation: Center for Gerontology and Health Care Research, Brown University, Providence, Rhode Island, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Campbell
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Chines
authors.affiliation: Department of Biochemistry, The Gurdon Institute, University of Cambridge, Cambridge, UK.
authors.forename: Delphine
authors.initials: D
authors.lastname: Larrieu
authors.affiliation: Department of Biochemistry, The Gurdon Institute, University of Cambridge, Cambridge, UK.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Jackson
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Glover
authors.affiliation: Department of Pediatrics, Hasbro Children's Hospital, Providence, Rhode Island, USA.|Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Gordon
mesh_terms: D000293:Adolescent; D002467:Cell Nucleus / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005091:Exons / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D009030:Mosaicism; D011371:Progeria / Q000235:genetics* / Q000473:pathology
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A; C090764:prelamin A
keywords: Other cardiovascular medicine; aging; lamin; mosaicism; progeria