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J Med Genet. 2017 Mar;54(3):212-216. doi: 10.1136/jmedgenet-2016-104295. Epub 2016 Dec 5.

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

Author information

  • 1National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • 2Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
  • 3Center for Gerontology and Health Care Research, Brown University, Providence, Rhode Island, USA.
  • 4Department of Pediatrics, Hasbro Children's Hospital, Providence, Rhode Island, USA.
  • 5Department of Biochemistry, The Gurdon Institute, University of Cambridge, Cambridge, UK.
  • 6Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.

Abstract

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.

KEYWORDS:

Other cardiovascular medicine; aging; lamin; mosaicism; progeria

PMID:
27920058
DOI:
10.1136/jmedgenet-2016-104295
[PubMed - in process]
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