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Clinical and biochemical effects of the E139K missense mutation in the TIMP3 gene, associated with Sorsby fundus dystrophy
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 chai...
Autores principales: | , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Molecular Vision
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697491/ https://www.ncbi.nlm.nih.gov/pubmed/19536307 |
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author | Saihan, Z. Li, Z. Rice, J. Rana, N.A. Ramsden, S. Schlottmann, P.G. Jenkins, S.A. Blyth, C. Black, G.C. McKie, N. Webster, A.R. |
author_facet | Saihan, Z. Li, Z. Rice, J. Rana, N.A. Ramsden, S. Schlottmann, P.G. Jenkins, S.A. Blyth, C. Black, G.C. McKie, N. Webster, A.R. |
author_sort | Saihan, Z. |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-2697491 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Molecular Vision |
record_format | MEDLINE/PubMed |
spelling | pubmed-26974912009-06-16 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, N.A. Ramsden, S. Schlottmann, P.G. Jenkins, S.A. Blyth, C. Black, G.C. McKie, N. Webster, A.R. Mol Vis Research Article 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. Molecular Vision 2009-06-15 /pmc/articles/PMC2697491/ /pubmed/19536307 Text en http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Saihan, Z. Li, Z. Rice, J. Rana, N.A. Ramsden, S. Schlottmann, P.G. Jenkins, S.A. Blyth, C. Black, G.C. McKie, N. Webster, A.R. Clinical and biochemical effects of the E139K missense mutation in the TIMP3 gene, associated with Sorsby fundus dystrophy |
title | Clinical and biochemical effects of the E139K missense mutation in the TIMP3 gene, associated with Sorsby fundus dystrophy |
title_full | Clinical and biochemical effects of the E139K missense mutation in the TIMP3 gene, associated with Sorsby fundus dystrophy |
title_fullStr | Clinical and biochemical effects of the E139K missense mutation in the TIMP3 gene, associated with Sorsby fundus dystrophy |
title_full_unstemmed | Clinical and biochemical effects of the E139K missense mutation in the TIMP3 gene, associated with Sorsby fundus dystrophy |
title_short | Clinical and biochemical effects of the E139K missense mutation in the TIMP3 gene, associated with Sorsby fundus dystrophy |
title_sort | clinical and biochemical effects of the e139k missense mutation in the timp3 gene, associated with sorsby fundus dystrophy |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697491/ https://www.ncbi.nlm.nih.gov/pubmed/19536307 |
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