PMID: 25390527

Gene: TIMP3

HGNC: 11822

Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy

MONDO: 0007640

InheritancePattern: Autosomal Dominant

Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)

Penetrance: Fully penetrant, onset between the third and sixth decades of life

Case: Weber_1994_Family_M_Patient_IV-2, male, age 28 at onset of symptoms

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo:

CasePresentingHPOs: HP:0011506 (Choroidal neovascularization), HP:0025094 (Disciform macular scar), HP:0007663 (Reduced visual acuity), HP:0000819 (Diabetes mellitus), HP:0007703 (Abnormality of retinal pigmentation), HP:0012805 (Iris transillumination defect), HP:0012231 (Exudative retinal detachment), HP:0030604 (Abnormal fundus fluorescein angiography), HP:0011506 (Choroidal neovascularization), HP:0000603 (Central scotoma), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude)

CaseHPOFreeText: Choroidal neovascular invasion of the macula was bilateral. This occurred early in the presentation and led to the disciform scar and loss of central vision. Granularity / abnormalities of the RPE were present in both eyes and preceded the onset of visual problems in the initially-unaffected eye. Serous detachment of sensory retina had underlying pigment epithelial detachment. CNV was accompanied by leakage from foveal avascular zone. Loss of visual acuity was progressive but possibly stabilized by argon green laser photocoagulation treatment.

CaseNOTHPOs: HP:0030584 (Color vision test abnormality), HP:0007957 (Corneal opacity), HP:0000518 (Cataract)

CaseNOTHPOFreeText: N/A

CasePreviousTesting: N/A

GenotypingMethod: Sanger sequencing of Weber_1994_Family_M_patient_IV-2

PreviouslyPublished: PMID:2000899

SupplementalData: N/A

Variant: The variant is NM_000362.5(TIMP3):c.572A>G, p.Tyr191Cys, which was first referred to in PMID:7894485 as "Tyr168Cys" (due to the removal of a 23-amino acid N-terminal signal peptide from the polypeptide sequence) but encodes Tyr191Cys in the full/updated polypeptide sequence.

ClinVar: 12677

gnomAD: Variant is absent from gnomAD.

VariantEvidence: Variant adds a Cys residue to TIMP3 and is predicted to disrupt tertiary structure.

NonPatientCell: ARPE-19 (human retinal pigment epithelial) cell line (CLO:0001749, CL:0009004)

GeneFunction: GO:0008191 (metalloendopeptidase inhibitor activity), GO:0046872 (metal ion binding), GO:0002020 (protease binding), GO:0005615 (active in extracellular space), GO:0031012 (active in extracellular matrix)

GeneAlteration: A TIMP3 expression construct encoding the Glu162Lys variant (referred to in the paper as "Glu139Lys") was generated by PCR-based mutagenesis of the wild-type pCDNA3-TIMP3.

FunctionalEvidence: The TIMP3 variant was exogenously expressed in ARPE-19 cells alongside a mock transfected control (not a wild-type control). Immunoblotting of non-reduced samples detected both monomeric (24 kDa) and dimeric (48 kDa) forms of the variant (Figure 8). Reverse zymographs of extracellular matrix from both wild-type TIMP3- and variant TIMP3-transfected cells revealed the presence of the dimeric species for the variant but not the wild-type, and confirmed its intact metalloproteinase inhibitory activity (Figure 9). This indicated that the free cysteine present in the variant may not have compromised metalloproteinase inhibitory activity, but likely facilitated an intramolecular disfulfide bonding interaction with another TIMP3 molecule. This gain-of-function interpretation of the variant effect would be consistent with the autosomal dominant mechanism of inheritance.

FAVariants: Variant used was NM_000362.5(TIMP3):c.484G>A (p.Glu162Lys) (CAID:CA411540222). The variant is referred to in this publication as "Glu139Lys" (due to the removal of a 23-amino acid N-terminal signal peptide from the polypeptide sequence) but encodes Glu162Lys in the full/updated polypeptide sequence.

FamilyLabel: Saihan_2009_Family

Family#PresentingHPOs: HP:0000662 (Nyctalopia), HP:0000529 (Progressive visual loss), HP:0000572 (Visual loss), HP:0011510 (Drusen), HP:0011506 (Choroidal neovascularization)

FamilyHPOFreeText: First presenting phenotypes were reduction of night vision and slow dark adaptation (with onset in fifth decade, 1 to 11 years prior to vision loss). Nyctalopia was progressive, with onset in the fifth decade of life (age 45-47). Vision loss was sudden, in some cases bilateral, and occurred in the fifth or sixth decade of life (age 48-56). Drusen-like deposits were present at the posterior pole in all three patients but varied in severity (possibly in proportion to age at examination). The degree of vision loss also varied in severity between patients and between the left and right eyes of each patient. Choroidal neovascularization was hemorrhagic and initiated loss of central vision.

FamilyNotHPOs: HP:0004328 (Abnormal anterior eye segment morphology), HP:0000518 (Cataract)

FamilyNotHPOFreeText: No history of renal disease or systemic disease was consistently observed among the affected family members.

CountryOrigin: British (of Welsh origin)

Family#PreviousTesting: Family history (indicating autosomal dominant inheritance of retinal degeneration) and ophthalmic exams (including LogMAR visual acuities, slit-lamp biomicroscopy, color fundus photography, optical coherence tomography scans of the fovea, and autofluorescent imaging of the fundus)

Family#GenotypingMethod: Mutational screening of TIMP3 by bidirectional Sanger sequencing

Affected: 3

Unaffected: 2

Segregations: 2

PublishedLOD: N/A

eLOD: Insufficient information available

AddSegregationInfo: N/A

ProbandLabel: Saihan_2009_Family_patient_III:4

Variant: Variant used was NM_000362.5(TIMP3):c.484G>A (p.Glu162Lys) (CAID:CA411540222). The variant is referred to in this publication as "Glu139Lys" (due to the removal of a 23-amino acid N-terminal signal peptide from the polypeptide sequence) but encodes Glu162Lys in the full/updated polypeptide sequence.

CAID: CA411540222

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: The mother of the proband and affected siblings was unaffected and negative for the variant, while the father was affected but not genotyped.

FamilyPMIDs: N/A

PMID: 30668888

Gene: TIMP3

HGNC: 11822

Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy

MONDO: 0007640

InheritancePattern: Autosomal Dominant

Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)

Penetrance: Fully penetrant, onset between the third and sixth decades of life

Case: Naessens_2019_Family_2_Patient_II:1, female, age of onset 53 years old, country of origin France (northern)

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: Familial variant appears to come from a founder mutation shared by other families in Belgium and northern France with a distant common ancestor.

CasePresentingHPOs: HP:0011510 (Drusen), , HP:0000572 (Visual loss), HP:0007401 (Macular atrophy), HP:0007769 (Peripheral retinal degeneration), HP:0011506 (Choroidal neovascularization), HP:0007777 (Chorioretinal scar)

CaseHPOFreeText: Relatively late onset of phenotypes (at age 53, presenting with nyctalopia). Drusen was described as widespread and partially calcified. Macular atrophy was patchy, with round atrophic patches outside the vascular arcades.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: Pulmonary involvement

CasePreviousTesting: N/A

GenotypingMethod: PCR amplification of all 5 coding exons of TIMP3, followed by Sanger sequencing

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S3 from this paper (PMID: 30668888) provides some of the proband phenotype details.

Variant: The variant is NM_000362.5(TIMP3):c.113C>G (p.Ser38Cys), a missense variant predicted to introduce a new cysteine-encoding codon into exon 1.

ClinVar: 843268

gnomAD: Variant is absent from gnomAD.

VariantEvidence: Variant adds a Cys residue to TIMP3 and is predicted to disrupt tertiary structure. Patient fibroblasts reveal no change in expression of the variant at the mRNA level, no dimerization of the variant under non-reducing conditions, and no defect in its localization to the ECM. Variant showed a minor increase in glycosylation. An in vitro transcription and translation study found that the variant forms an aberrant intramolecular disulfide bond between the introduced Ser38Cys residue and Cys36 of TIMP3 (Figure 7). Aberrant intramolecular disulfide bonding caused by this variant would be consistent gain-of-function and an autosomal dominant mechanism of inheritance.

PMID: 11879143

Gene: TIMP3

HGNC: 11822

Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy

MONDO: 0007640

InheritancePattern: Autosomal Dominant

Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)

Penetrance: Fully penetrant, onset between the third and sixth decades of life

Case: Lin_2006_Family_1_patient_IV-8, female, 62 years of age at presentation, Eastern European Jewish ancestry

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: N/A

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0012508 (Metamorphopsia), HP:0011510 (Drusen), HP:0025148 (Dark choroid), HP:0011506 (Choroidal neovascularization), HP:0025094 (Disciform macular scar), HP:0000662 (Nyctalopia), HP:0007703 (Abnormality of retinal pigmentation),

CaseHPOFreeText: Patient presented with central visual field loss and metamorphopsia in one eye, 10 years after a normal results from fundus and vision exam. Fluorescein angiography of the other eye revealed drusen and dark choroid. Choroidal neovascularization progressed to a central disc-shaped scar despite several treatments with argon laser thermal photocoagulation. The less affected eye initially showed mild nyctalopia only, but progressed within 2 years to fibrovascular pigment epithelial detachment, circular blocking lesion, choroidal neovascularization, and visual acuity loss.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

CasePreviousTesting: Complete ophthalmological exam to define clinical features.

CaseGenotypingMethod: Bidirectional Sanger sequencing of PCR products from exons 1 through 5.

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: NM_000362.5(TIMP3):c.542A>G, p.His181Arg is a missense variant predicted to replace a conserved histidine residue in exon 5 with arginine (conservative substitution).

CAID: CA411540357

gnomAD: Variant is absent from gnomAD.

VariantEvidence: p.His181Arg is a missense variant predicted to replace a conserved histidine residue in exon 5 with arginine (conservative substitution). Molecular modeling predicts that the affected amino acid is located on a protein-protein interaction interface.

FamilyLabel: Felbor_1995_Family_1

Family#PresentingHPOs: HP:0030666 (Retinal neovascularization), HP:0007777 (Chorioretinal scar), HP:0000603 (Central scotoma), HP:0000556 (Retinal dystrophy), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000630 (Abnormal retinal artery morphology), HP:0030491 (Choriocapillaris atrophy), HP:0007994 (Peripheral visual field loss), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0008275 (Abnormal light-adapted electroretinogram),

FamilyHPOFreeText: Patients were considered to exhibit early-onset SFD with a mean age of 25. The presenting symptom was central subretinal neovascularisation, which preceded extensive scarring. Second eye involvement generally occurred months later, indicating rapid progression. Retinal dystrophy was reported to be tapetal. Intraretinal arteries were attenuated. Dark adaptation was decreased.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: The family is described as German-Czech.

Family#PreviousTesting: Genetic linkage testing / genotyping of affected and unaffected family members with three microsatellite markers that were previously associated with SFD and that flank the TIMP3 locus. This was followed by single-stranded conformational polymorphism (SSCP) of all five TIMP3 exons, detecting a mobility shift in exon 5.

Family#GenotypingMethod: Bidirectional Sanger sequencing of exon 5 PCR products from two affected individuals.

Affected: 2 (Sanger sequenced)

Unaffected: 1 (Sanger sequenced)

Segregations: N/A

PublishedLOD: Maximum two-point LOD score of 4.75 was reported for marker D22S280 at a recombination fraction of 0.001. D22S280 is also tightly associated with the TIMP3 locus.

eLOD: Insufficient information available

AddSegregationInfo: Family pedigree (from microsatellite-based linkage testing) mapping the disease locus to chr22q13-qter is shown in Figure 1.

ProbandLabel: Felbor_1995_Family_1_patient_1

Variant: NM_000362.5(TIMP3):c.536C>G, (p.Ser179Cys) is a missense variant predicted to substitute a new cysteine residue into exon 5.

ClinVar: 12678

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

PMID: 9924344

Gene: TIMP3

HGNC: 11822

Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy

MONDO: 0007640

InheritancePattern: Autosomal Dominant

Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)

Penetrance: Fully penetrant, onset between the third and sixth decades of life

PMID: 9400791

Gene: TIMP3

HGNC: 11822

Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy

MONDO: 0007640

InheritancePattern: Autosomal Dominant

Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)

Penetrance: Fully penetrant, onset between the third and sixth decades of life

PMID: 8919688

Gene: TIMP3

HGNC: 11822

Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy

MONDO: 0007640

InheritancePattern: Autosomal Dominant

Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)

Penetrance: Fully penetrant, onset between the third and sixth decades of life

ExperimentName: Functional testing of Ser179Cys, Gly190Cys, Tyr191Cys and Ser204Cys variants of TIMP3 in baby hamster kidney (BHK) cells

NonPatientCell: Baby hamster kidney (BHK) cells, EFO:0001643 (kidney-derived cell line), CLO:0000696 (immortal hamster kidney-derived cell line), CLO:0001965 (BHK-21 cell line)

GeneFunction: GO:0008191 (metalloendopeptidase inhibitor activity), GO:0046872 (metal ion binding), GO:0002020 (protease binding), GO:0005615 (active in extracellular space), GO:0031012 (active in extracellular matrix)

GeneAlteration: TIMP3 expression constructs encoding the Ser179Cys, Gly190Cys, Tyr191Cys, and Ser204Cys variants (referred to in the paper as "Ser156Cys", "Gly167Cys", "Tyr166Cys", and "Ser181Cys") were generated by PCR-based mutagenesis of wild-type TIMP3 and cloned into the pNUT expression vector.

FunctionalEvidence: BHK cells were stably transfected with each of four variants or wild-type TIMP3. All variants expressed and localized successfully to the extracellular matrix (western blotting), Both variants tested exhibited intact metalloproteinase inhibitor activity in ECM fractions (reverse zymography). All four of the variants accumulated as higher molecular weight species (Figure 1A, Figure 2), with Ser179Cys and Ser204Cys in particular accumulating to a much greater degree than the other variants or the wild-type control (Figure 2). Cell morphology and adherence were affected within the variant-expressing cells. While wild-type-transfected cells were more adherent to the ECM than the untransfected controls were, both variant-transfected cells (Ser179Cys, Ser204Cys) were even more ECM-adherent (Figure 5). Association constants were measured for TIMP3 interaction with a series of metalloproteinases, calculating their values for wild-type TIMP3 and for the Ser156Cys variant, which exhibited a 2- or 3-fold loss of reduction, depending on the substrate (Table 2).

FAVariants: The four variants used were NM_000362.5(TIMP3):c.536C>G, p.Ser179Cys (ClinVar:12678), NM_000362.5(TIMP3):c.568G>T, p.Gly190Cys (CA411540415), NM_000362.5(TIMP3):c.572A>G, p.Tyr191Cys (ClinVar:12677), and NM_000362.5(TIMP3):c.610A>T, p.Ser204Cys (ClinVar:12676).

FamilyLabel: Langton_2000_Family_1

Family#PresentingHPOs: HP:0031609 (Geographic atrophy), HP:0007663 (Reduced visual acuity), HP:0007703 (Abnormality of retinal pigmentation), HP:0000512 (Abnormal electroretinogram)

FamilyHPOFreeText: First presentation of symptoms was in the 3rd or 4th decade of life. Geographic macular atrophy was the cause of central vision loss. Retinal pigmentary disturbances were peripheral. Scotopic ERGs were abnormal. Other common SFD phenotypes were seen in some affected individuals but not uniformly across all affected family members.

FamilyNotHPOs: N/A

CountryOrigin: British (PMID:11734514)

Family#PreviousTesting: Family previously diagnosed with SFD, with details provided in PMID:11734514.

Family#GenotypingMethod: Sanger sequencing of PCR product from Exon 5 of the TIMP3 gene.

Affected: 3

Unaffected: 2

Segregations: N/A

PublishedLOD: N/A

eLOD: Insufficient information available

AddSegregationInfo: N/A

ProbandLabel: Langton_2000_Family_1_patient_II2

Variant: The NM_000362.5(TIMP3):c.484G>T, p.Glu139X variant converts the GAG codon to a TAG, resulting in early termination of the transcript. This nonsense substitution affects the final exon 5, so that truncation of the protein product is predicted but not nonsense-mediated decay of the transcript.

ClinVar: 12680

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: Variant is referred to in the paper as "Glu139X" but encodes Glu162X in the updated polypeptide sequence (which includes the 23-amino acid N-terminal signal peptide).

FamilyPMIDs: PMID:11734514