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Benjamin Bakall, Elliott H Sohn, Janet Riley, Dianna Brack, Edwin M Stone; Novel mutations and change of nomenclature for pathogenic variants in the TIMP3 gene causing Sorsby fundus dystrophy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3290.
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© ARVO (1962-2015); The Authors (2016-present)
Sorsby Fundus Dystrophy (SFD) is an autosomal dominant macular dystrophy caused by mutations in the TIMP3 gene on 22q12.3. The purpose of the study was to identify variants in the TIMP3 gene in patients SFD and to modify the nomenclature to conform to the Human Genome Variation Society (HGVS) guidelines.
Ophthalmic exam and available standard imaging techniques, including fundus photography, fluorescein angiography and ocular coherence tomography were applied to six individuals from five families. After informed consent, peripheral venous blood was obtained for DNA extraction. Sanger sequencing was initially performed for exon 5 and flanking intronic regions of the TIMP3 gene. If negative, the first four exons were analyzed for variants. Identified pathogenic variants were numbered with the start codon as +1.
By exam, six individuals from five families were diagnosed with SFD including signs of early onset choroidal neovascularization. Molecular analysis revealed three novel variants in the TIMP3 protein: Cys24Arg, Tyr151Cys and Trp198Cys; and two previously published variants: Ser38Cys and Tyr191Cys.
The three novel mutations broaden the spectrum of the known pathogenic variants in the TIMP3 protein. All the identified variants caused formation or loss of a cysteine residue, consistent with the theory that pathogenic variants create an unpaired disulfide bond resulting in dimerization of the TIMP3 protein. In addition, we propose that all pathogenic variants are numbered from the translation initiation site according to HGVS guidelines.
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