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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

OCT3 scans (6 mm) centered on the fovea. (A) from a normal adult individual. Landmarks such as outer nuclear layer (ONL), inner and outer photoreceptor segment junction (IS), retinal pigment epithelium (RPE), and choriocapillaris (CC) are indicated. (B) from affected individual III:1 Right eye (OD) C: Individual III:1 Left eye (OS). Both B and C demonstrate hyperreflective signals (*) at the level of the RPE-choroid complex. The foveal pit appears steep in the right eye (OD). Parafoveal intraretinal cysts (IRC) are demonstrated bilaterally. There is also evidence of parafoveal retinal atrophy in the left eye (OS).
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f4: OCT3 scans (6 mm) centered on the fovea. (A) from a normal adult individual. Landmarks such as outer nuclear layer (ONL), inner and outer photoreceptor segment junction (IS), retinal pigment epithelium (RPE), and choriocapillaris (CC) are indicated. (B) from affected individual III:1 Right eye (OD) C: Individual III:1 Left eye (OS). Both B and C demonstrate hyperreflective signals (*) at the level of the RPE-choroid complex. The foveal pit appears steep in the right eye (OD). Parafoveal intraretinal cysts (IRC) are demonstrated bilaterally. There is also evidence of parafoveal retinal atrophy in the left eye (OS).

Mentions: OCT3 images from affected eyes displayed areas of RPE detachment and intraretinal cystic spaces (IRC), consistent with the choroidal neovascularization observed clinically (Figure 4, Figure 5, and Figure 6). An additional finding in both eyes of III:1 and III:4 was increased reflectivity at the level of the RPE-choroid complex. The left eye of III:4 did not have any evidence of CNV or vision loss, but the OCT scan showed evidence of retinal atrophy, in particular the loss of the outer nuclear layer temporal to the fovea (see Figure 6B).


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)

OCT3 scans (6 mm) centered on the fovea. (A) from a normal adult individual. Landmarks such as outer nuclear layer (ONL), inner and outer photoreceptor segment junction (IS), retinal pigment epithelium (RPE), and choriocapillaris (CC) are indicated. (B) from affected individual III:1 Right eye (OD) C: Individual III:1 Left eye (OS). Both B and C demonstrate hyperreflective signals (*) at the level of the RPE-choroid complex. The foveal pit appears steep in the right eye (OD). Parafoveal intraretinal cysts (IRC) are demonstrated bilaterally. There is also evidence of parafoveal retinal atrophy in the left eye (OS).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: OCT3 scans (6 mm) centered on the fovea. (A) from a normal adult individual. Landmarks such as outer nuclear layer (ONL), inner and outer photoreceptor segment junction (IS), retinal pigment epithelium (RPE), and choriocapillaris (CC) are indicated. (B) from affected individual III:1 Right eye (OD) C: Individual III:1 Left eye (OS). Both B and C demonstrate hyperreflective signals (*) at the level of the RPE-choroid complex. The foveal pit appears steep in the right eye (OD). Parafoveal intraretinal cysts (IRC) are demonstrated bilaterally. There is also evidence of parafoveal retinal atrophy in the left eye (OS).
Mentions: OCT3 images from affected eyes displayed areas of RPE detachment and intraretinal cystic spaces (IRC), consistent with the choroidal neovascularization observed clinically (Figure 4, Figure 5, and Figure 6). An additional finding in both eyes of III:1 and III:4 was increased reflectivity at the level of the RPE-choroid complex. The left eye of III:4 did not have any evidence of CNV or vision loss, but the OCT scan showed evidence of retinal atrophy, in particular the loss of the outer nuclear layer temporal to the fovea (see Figure 6B).

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