Pedigree of a family with Sorsby fundus dystrophy. Squares indicate males; circles, females; filled symbols, affected family members; open symbols, unaffected family members; diagonal line, deceased; and arrow, proband. Only affected individuals carried the dominant Ser170Cys tissue inhibitor of metalloproteinases 3 mutation.
Fundus images of individuals III:1 (A and B) and II:2 (C and D). A, Fundus photograph showing juxtafoveal choroidal neovascularization in the left eye of the proband (individual III:1). B, Fluorescein angiography confirming classic choroidal neovascularization in the same eye. C and D, Composite fundus photographs of individual II:2 showing diffuse retinal degeneration with central retinal atrophy, disciform scarring, and pigment clumping in the left (C) and right (D) eyes.
Barbazetto IA, Hayashi M, Klais CM, Yannuzzi LA, Allikmets R. A Novel TIMP3 Mutation Associated With Sorsby Fundus Dystrophy. Arch Ophthalmol. 2005;123(4):542-543. doi:10.1001/archopht.123.4.542
WIGGSJANEY LMD, PhD
Sorsby fundus dystrophy (SFD), originally described by Sorsby and Mason in 1949,1 is a rare autosomal dominant retinal degeneration. To date, 8 mutations in the tissue inhibitor of metalloproteinases 3 (TIMP3) gene on chromosome 22q13 have been described in patients with SFD.2 Herein we describe clinical features in a family of Eastern European–Jewish ancestry with a novel TIMP3 mutation.
Blood samples were obtained from 2 affected and 2 unaffected family members (Figure 1). Genomic DNA was extracted, and mutational analysis was performed by direct sequencing for all exons of the TIMP3 gene, as described elsewhere.3 Patients underwent a standard ophthalmologic examination including fundus photography and fluorescein angiography. The study was approved by the institutional review board at Columbia University, New York, NY.
Sequence analysis showed a single base pair change (508A→T), resulting in a Ser170Cys mutation in exon 5 of TIMP3 in both affected family members; that is, the mutation segregated with the disease in the family (Figure 1). The proband (III:1), was initially seen at age 31 years with progressing distortions in his left eye. Visual acuity measured 20/20 OD and 20/60 OS. Ophthalmoscopy showed a juxtafoveal choroidal neovascularization in the left eye (Figure 2A) and small areas of retinal pigment epithelial hypopigmentation in the right eye. Fluorescein angiography confirmed classic choroidal neovascularization in the left eye (Figure 2B).
The proband’s mother, individual II:2, examined at the same time, was 55 years of age. Visual acuity was 20/70 OD and 20/400 OS. The ophthalmoscopic examination results showed mild attenuation of the retinal vasculature, with bilateral loss of retinal pigment epithelium and choriocapillaris extending from the macula into the midperiphery combined with irregular pigment clumping that exceeded the atrophic areas. Both eyes showed disciform scarring in the macula. In addition, small, drusenlike deposits could be seen throughout the posterior pole (Figure 2C and D).
Almost all mutations associated with SFD have been identified in the carboxyl terminus of the protein, leading to the formation of unpaired cysteine residues.3 The novel TIMP3 mutation (Ser170Cys) described herein is located in the same region and results in changing an amino acid to cysteine, which implies a similar if not identical pathologic mechanism. The unpaired cysteine residues in the carboxyl terminus of the protein have been suggested to cause an erroneous disulfide bond formation and abnormal tertiary protein structure.3
The intrafamilial and interfamilial variability in the disease progression, similar to that seen in this family (rapid onset of central vision loss due to choroidal neovascularization in the son and a more gradual visual deterioration over the years in the mother), have also been emphasized in other studies,2- 4 suggesting the involvement of modifying factors, such as variation in other genes. To our knowledge, this is the first case in which SFD was clinically and genetically confirmed in a family of Eastern European–Jewish ancestry. This adds to the notion that not all affected families trace back to a common ancestor who transmitted the mutant TIMP3 gene, as originally suggested.1,4 The novel mutation described in this study continues to broaden the genetic spectrum of SFD and reemphasizes the importance of considering this disease as a differential diagnosis in patients with early-onset retinal and macular degeneration.
Correspondence: Rando Allikmets, PhD, Department of Ophthalmology, Columbia University, Eye Institute Research, Room 715, 630 W 168th St, New York, NY 10032 (email@example.com).
Submitted for Publication: March 30, 2004; final revision received November 17, 2004; accepted November 22, 2004.
Financial Disclosure: None.
Funding/Support: This study was supported in part by the Eye Surgery Fund, Inc, New York, NY (to Dr Barbazetto); and Research to Prevent Blindness, New York; the Macular Foundation, Inc, New York; and grant EY13435 from the National Institutes of Health, Bethesda, Md (to Dr Allikmets).