Clinical features of a novel TIMP-3 mutation causing Sorsby's fundus dystrophy: implications for disease mechanism
- Michael Clarkea,
- Keith W Mitchellb,
- Judith Goodshipc,
- Sharon McDonnellc,
- Michael D Barkerd,
- Ian D Griffithse,
- Norman McKiee
- aDepartment of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, UK, bRegional Medical Physics Department, cNorthern Genetics Service, Newcastle upon Tyne, UK, dDivision of Oncology and Cellular Pathology, Pathology Section, University of Sheffield, Medical School, Sheffield SR10 2RX, UK, eDepartment of Rheumatology, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK
- M ClarkeM.P.Clarke{at}ncl.ac.uk
- Accepted 11 July 2001
Abstract
AIMS To describe the phenotype in three family members affected by a novel mutation in the gene coding for the enzyme tissue inhibitor of metalloproteinase-3 (TIMP-3).
METHODS Three members of the same family were seen with a history of nyctalopia and visual loss due to maculopathy. Clinical features were consistent with Sorsby's fundus dystrophy. Exon 5 of the gene coding for TIMP-3 was amplified by the polymerase chain reaction, single strand conformation polymorphism analysis undertaken and exon 5 amplicons were directly sequenced.
RESULTS Onset of symptoms was in the third to fourth decade. Five of six eyes had geographic macular atrophy rather than neovascularisation as a cause for central visual loss. Peripheral retinal pigmentary disturbances were present. Scotopic ERGs were abnormal in all three. Mutation analysis showed a G→T transversion in all three resulting in a premature termination codon, E139X, deleting most of the carboxy terminal domain of TIMP-3.
CONCLUSIONS The patients described had a form of Sorsby's fundus dystrophy which fell at the severe end of the spectrum of this disease. Postulated disease mechanisms include deposition of dimerised TIMP-3 protein.
