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Clinical and biochemical effects of the E139K missense mutation in the TIMP3 gene, associated with Sorsby fundus dystrophy.

Saihan Z, Li Z, Rice J, Rana NA, Ramsden S, Schlottmann PG, Jenkins SA, Blyth C, Black GC, McKie N, Webster AR - Mol. Vis. (2009)

Bottom Line: The TIMP3 p.E139K mutation is another cause of SFD.It is the second TIMP3 sequence variant reported that does not affect the number of cysteine residues in the mutant protein yet dimerizes in vitro.The clinical presentation of this family is in keeping with previous clinical reports of this disorder.

View Article: PubMed Central - PubMed

Affiliation: Moorfields Eye Hospital, London, UK. z.saihan@ucl.ac.uk

ABSTRACT

Purpose: To determine the phenotypic and biochemical characteristics of the p.E139K missense variant in tissue inhibitor of metalloproteinase 3 (TIMP3) associated with Sorsby fundus dystrophy (SFD).

Methods: The coding regions and adjacent intronic sequence of TIMP3 were amplified by polymerase chain reaction and then analyzed by bidirectional sequencing. Allele-specific PCR was used to determine the minimum allele frequency of the mutant allele in ethnically matched controls. Clinical examination and imaging of affected individuals with color fundus photography, scanning laser ophthalmoscope (fundal autofluorescence), and optical coherence tomography was performed. A mutant construct of the TIMP3 protein was created and expressed in human retinal pigment epithelium (ARPE19) cells, which were then assayed for oligomerization and intrinsic matrix metalloproteinase (MMP) inhibitory activity.

Results: Three affected individuals from a family of Welsh origin each harbored one allele of the TIMP3 missense variant c.415 G>A, (p.E139K), which was not identified in 534 ethnically matched control chromosomes and thus presumed pathogenic. The mutant protein was shown to dimerize in culture cells and retain its MMP inhibitory activity. Retinal examination was variable between eyes of affected individuals and between family members. Drusen-like deposits were common to all three affected individuals and yellow subretinal deposits, exudative maculopathy, and geographic atrophy were also observed. Optical coherence tomography (OCT) images of affected individuals demonstrated hyperreflectivity of the RPE-photoreceptor-choroid complex.

Conclusions: The TIMP3 p.E139K mutation is another cause of SFD. It is the second TIMP3 sequence variant reported that does not affect the number of cysteine residues in the mutant protein yet dimerizes in vitro. The clinical presentation of this family is in keeping with previous clinical reports of this disorder.

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Related in: MedlinePlus

Color fundus photographs of the three affected individuals. All three affected individuals demonstrated the presence of yellow drusen-like deposits bilaterally throughout their fundi, but to varying amounts. A: Individual III:1 had bilateral geographic atrophy and widespread subretinal drusen-like deposits throughout the posterior pole extending beyond the vascular arcades. B: Individual III:3 had subretinal and intraretinal fluid at the macula in the right eye extending inferiorly toward the temporal arcades. In the right eye, two extrafoveal foci of subretinal hemorrhage were also noted, inferior to the optic disc and temporal to the macula. In the left eye (poorest visual acuity), subretinal fluid and a pigment epithelial detachment were noted superior to the macula. Although not visible on this image, areas of chorioretinal atrophy were also noted nasal to the disc. C: Individual III:4 had a large subretinal fibrovascular scar visible in the right eye. Foci of subretinal hemorrhage, exudates, and secondary retinal detachment are also visible. Areas of floccular yellowish subretinal deposit can be seen throughout the fundus in the right eye. In the left eye (without visual loss) only small yellowish subretinal deposits can be seen throughout the posterior pole.
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f3: Color fundus photographs of the three affected individuals. All three affected individuals demonstrated the presence of yellow drusen-like deposits bilaterally throughout their fundi, but to varying amounts. A: Individual III:1 had bilateral geographic atrophy and widespread subretinal drusen-like deposits throughout the posterior pole extending beyond the vascular arcades. B: Individual III:3 had subretinal and intraretinal fluid at the macula in the right eye extending inferiorly toward the temporal arcades. In the right eye, two extrafoveal foci of subretinal hemorrhage were also noted, inferior to the optic disc and temporal to the macula. In the left eye (poorest visual acuity), subretinal fluid and a pigment epithelial detachment were noted superior to the macula. Although not visible on this image, areas of chorioretinal atrophy were also noted nasal to the disc. C: Individual III:4 had a large subretinal fibrovascular scar visible in the right eye. Foci of subretinal hemorrhage, exudates, and secondary retinal detachment are also visible. Areas of floccular yellowish subretinal deposit can be seen throughout the fundus in the right eye. In the left eye (without visual loss) only small yellowish subretinal deposits can be seen throughout the posterior pole.

Mentions: No anterior segment abnormalities or visually significant lens opacity were noted in any of the three affected individuals, and no history of renal or systemic disease was found to segregate with the disorder in this pedigree. Yellow drusen-like deposits were present in all eyes of the three affected individuals to varying amounts but most obvious in III:1 (see Figure 3).


Clinical and biochemical effects of the E139K missense mutation in the TIMP3 gene, associated with Sorsby fundus dystrophy.

Saihan Z, Li Z, Rice J, Rana NA, Ramsden S, Schlottmann PG, Jenkins SA, Blyth C, Black GC, McKie N, Webster AR - Mol. Vis. (2009)

Color fundus photographs of the three affected individuals. All three affected individuals demonstrated the presence of yellow drusen-like deposits bilaterally throughout their fundi, but to varying amounts. A: Individual III:1 had bilateral geographic atrophy and widespread subretinal drusen-like deposits throughout the posterior pole extending beyond the vascular arcades. B: Individual III:3 had subretinal and intraretinal fluid at the macula in the right eye extending inferiorly toward the temporal arcades. In the right eye, two extrafoveal foci of subretinal hemorrhage were also noted, inferior to the optic disc and temporal to the macula. In the left eye (poorest visual acuity), subretinal fluid and a pigment epithelial detachment were noted superior to the macula. Although not visible on this image, areas of chorioretinal atrophy were also noted nasal to the disc. C: Individual III:4 had a large subretinal fibrovascular scar visible in the right eye. Foci of subretinal hemorrhage, exudates, and secondary retinal detachment are also visible. Areas of floccular yellowish subretinal deposit can be seen throughout the fundus in the right eye. In the left eye (without visual loss) only small yellowish subretinal deposits can be seen throughout the posterior pole.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2697491&req=5

f3: Color fundus photographs of the three affected individuals. All three affected individuals demonstrated the presence of yellow drusen-like deposits bilaterally throughout their fundi, but to varying amounts. A: Individual III:1 had bilateral geographic atrophy and widespread subretinal drusen-like deposits throughout the posterior pole extending beyond the vascular arcades. B: Individual III:3 had subretinal and intraretinal fluid at the macula in the right eye extending inferiorly toward the temporal arcades. In the right eye, two extrafoveal foci of subretinal hemorrhage were also noted, inferior to the optic disc and temporal to the macula. In the left eye (poorest visual acuity), subretinal fluid and a pigment epithelial detachment were noted superior to the macula. Although not visible on this image, areas of chorioretinal atrophy were also noted nasal to the disc. C: Individual III:4 had a large subretinal fibrovascular scar visible in the right eye. Foci of subretinal hemorrhage, exudates, and secondary retinal detachment are also visible. Areas of floccular yellowish subretinal deposit can be seen throughout the fundus in the right eye. In the left eye (without visual loss) only small yellowish subretinal deposits can be seen throughout the posterior pole.
Mentions: No anterior segment abnormalities or visually significant lens opacity were noted in any of the three affected individuals, and no history of renal or systemic disease was found to segregate with the disorder in this pedigree. Yellow drusen-like deposits were present in all eyes of the three affected individuals to varying amounts but most obvious in III:1 (see Figure 3).

Bottom Line: The TIMP3 p.E139K mutation is another cause of SFD.It is the second TIMP3 sequence variant reported that does not affect the number of cysteine residues in the mutant protein yet dimerizes in vitro.The clinical presentation of this family is in keeping with previous clinical reports of this disorder.

View Article: PubMed Central - PubMed

Affiliation: Moorfields Eye Hospital, London, UK. z.saihan@ucl.ac.uk

ABSTRACT

Purpose: To determine the phenotypic and biochemical characteristics of the p.E139K missense variant in tissue inhibitor of metalloproteinase 3 (TIMP3) associated with Sorsby fundus dystrophy (SFD).

Methods: The coding regions and adjacent intronic sequence of TIMP3 were amplified by polymerase chain reaction and then analyzed by bidirectional sequencing. Allele-specific PCR was used to determine the minimum allele frequency of the mutant allele in ethnically matched controls. Clinical examination and imaging of affected individuals with color fundus photography, scanning laser ophthalmoscope (fundal autofluorescence), and optical coherence tomography was performed. A mutant construct of the TIMP3 protein was created and expressed in human retinal pigment epithelium (ARPE19) cells, which were then assayed for oligomerization and intrinsic matrix metalloproteinase (MMP) inhibitory activity.

Results: Three affected individuals from a family of Welsh origin each harbored one allele of the TIMP3 missense variant c.415 G>A, (p.E139K), which was not identified in 534 ethnically matched control chromosomes and thus presumed pathogenic. The mutant protein was shown to dimerize in culture cells and retain its MMP inhibitory activity. Retinal examination was variable between eyes of affected individuals and between family members. Drusen-like deposits were common to all three affected individuals and yellow subretinal deposits, exudative maculopathy, and geographic atrophy were also observed. Optical coherence tomography (OCT) images of affected individuals demonstrated hyperreflectivity of the RPE-photoreceptor-choroid complex.

Conclusions: The TIMP3 p.E139K mutation is another cause of SFD. It is the second TIMP3 sequence variant reported that does not affect the number of cysteine residues in the mutant protein yet dimerizes in vitro. The clinical presentation of this family is in keeping with previous clinical reports of this disorder.

Show MeSH
Related in: MedlinePlus