A novel His158Arg mutation in TIMP3 causes a late-onset form of Sorsby fundus dystrophy.
OBJECTIVE
To describe the phenotype and genotype of a family with suspected Sorsby fundus dystrophy (SFD).


METHODS
Case reports and results of deoxyribonucleic acid (DNA) analysis.


METHODS
Clinical features were determined by complete ophthalmologic examination or by review of medical records. Mutational analysis of the tissue inhibitor of metalloproteinase (TIMP)3 gene was performed by DNA resequencing. Biochemical properties of the mutant TIMP3 protein were studied, and phylogenetic and molecular modeling analyses of TIMP proteins were performed.


RESULTS
Fundi of four affected family members demonstrated active or regressed bilateral choroidal neovascularization, whereas another affected individual displayed severe diffuse pigmentary degeneration associated with nyctalopia characteristic of SFD. Onset of disease occurred in the fifth to seventh decades of life. A heterozygous His158Arg mutation was found in seven affected family members and was absent from an unaffected member and 98 unrelated controls. Bioinformatic analyses indicate that histidine 158 is an evolutionarily conserved residue in most vertebrate TIMP homologs and predict that substitution by arginine disrupts TIMP3 function. The mutant protein appears to be expressed by fibroblasts from an affected family member. Molecular modeling suggests that TIMP3 residue 158 may be part of a protein-protein interaction interface.


CONCLUSIONS
A novel mutation in TIMP3 causes a late-onset form of SFD in this family. His158Arg is the first reported TIMP3 SFD coding sequence mutation that does not create an unpaired cysteine. Further study of this unusual mutation may provide insight into the mechanism of SFD pathogenesis.
Lin
Ruth J
RJ
Department of Genetics, Stanford University School of Medicine, Stanford, California 94305-5120, USA.
Blumenkranz
Mark S
MS
Binkley
Jonathan
J
Wu
Kathy
K
Vollrath
Douglas
D
D000595:Amino Acid Sequence; D020256:Choroidal Neovascularization / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005654:Fundus Oculi; D005799:Genes, Dominant; D005838:Genotype; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012867:Skin / Q000166:cytology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics*; D014162:Transfection
C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3