A new autosomal dominant eye and lung syndrome linked to mutations in TIMP3 gene

Meunier, Isabelle; Bocquet, Béatrice; Labesse, Gilles; Zeitz, Christina; Defoort‐Dhellemmes, Sabine; Lacroux, Annie; Mauget‐Faÿsse, Martine; Drumare, Isabelle; Gamez, Anne‐Sophie; Mathieu, Cyril; Marquette, Virginie; Sagot, Lola; Dhaenens, Claire‐Marie; Arndt, Carl; Carroll, Patrick; Rémy‐Jardin, Martine; Cohen, Salomon Y.; Sahel, José‐Alain; Puech, Bernard; Audo, Isabelle; Mrejen, Sarah; Hamel, Christian

doi:10.1038/srep32544

Cited by 18 publications

(18 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mutation in fibulin-3 leads to proteoglycan accumulation in the Bruch membrane and the disruption of diffusion, which can impair nutrient and oxygen movement to the retina (91). TIMP3 is also found in the ECM of the lung and kidney, and a unique Ser to Cys mutation in the N-domain of TIMP3 has been linked to a late-onset human disease affecting lungs and eyes (92). These findings suggest that TIMP3 may be important for ECM structure and function in both organs.…”

Section: Structural Roles In Ecmmentioning

confidence: 99%

Reflections on the evolution of the vertebrate tissue inhibitors of metalloproteinases

Brew

2018

The FASEB Journal

View full text Add to dashboard Cite

Jawed vertebrates (Gnathostomes) have 4 tissue inhibitors of metalloproteinases (TIMPs), multifunctional proteins that all inhibit members of the large matrix metalloproteinase (MMP) family but differ in their other roles, including the regulation of pro-MMP activation, cell growth, apoptosis and angiogenesis, and the structure of extracellular matrices (ECMs). Molecular phylogeny analyses indicate that vertebrate TIMP genes arose from an invertebrate ancestor through 3 successive duplications, possibly including 2 whole genome duplications, during early vertebrate phylogeny. TIMPs from invertebrates also inhibit metalloproteinases, bind to pro-MMPs, and contribute to ECM structures but are not orthologs of any particular vertebrate TIMP. The most ancient vertebrate superclass, the Agnatha (jawless fish), seems to provide a snapshot of a stage in TIMP evolution preceding the third gene duplication. This review examines the structures of TIMPs from different vertebrate orders using information relating to the structural basis of their various functions. Provisional conclusions are that during their evolutionary divergence, various TIMPs lost inhibitory activity toward some metalloproteinases, specialized in effects on different pro-MMPs, and developed new interactions with discrete targets (including integrins and receptors), while recapitulating a role in ECM structure. The analysis is limited by the sparse information available regarding the functional properties of nonmammalian TIMPs.-Brew, K. Reflections on the evolution of the vertebrate tissue inhibitors of metalloproteinases.

show abstract

Section: Structural Roles In Ecmmentioning

confidence: 99%

Reflections on the evolution of the vertebrate tissue inhibitors of metalloproteinases

Brew

2018

The FASEB Journal

View full text Add to dashboard Cite

show abstract

“…However, recent findings described two SFD families with a history of pulmonary disease, where individuals over 50 years in one family (carrying the TIMP-3 p.Y191C mutation) were diagnosed with severe emphysema. Similarly, both members of the second family (carrying the TIMP-3 p.S38C mutation) exhibited moderate bronchiectasis [74]. This suggests that some TIMP-3 mutations may be more severe compared to others, or indeed behave very differently than has been previously thought.…”

Section: Timp-3 and Other Ecm Changes In The Aging Retinamentioning

confidence: 68%

“…A question which has arisen frequently is why do mutations in TIMP-3 drive pathology so prominently in the retina, but not in other tissues to the same extent? This was partly answered by an important finding, which showed that individuals carrying the TIMP-3 p.Y191C mutation presented with bronchiectasis and emphysema before developing SFD [74]. This discovery prompted SFD patients attending ophthalmology clinics at Southampton to be screened for any respiratory abnormalities by a specialist.…”

Section: Discussionmentioning

confidence: 99%

The Diverse Roles of TIMP-3: Insights into Degenerative Diseases of the Senescent Retina and Brain

Dewing

Carare

Lotery

et al. 2019

Cells

View full text Add to dashboard Cite

Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a component of the extracellular environment, where it mediates diverse processes including matrix regulation/turnover, inflammation and angiogenesis. Rare TIMP-3 risk alleles and mutations are directly linked with retinopathies such as age-related macular degeneration (AMD) and Sorsby fundus dystrophy, and potentially, through indirect mechanisms, with Alzheimer's disease. Insights into TIMP-3 activities may be gleaned from studying Sorsby-linked mutations. However, recent findings do not fully support the prevailing hypothesis that a gain of function through the dimerisation of mutated TIMP-3 is responsible for retinopathy. Findings from Alzheimer's patients suggest a hitherto poorly studied relationship between TIMP-3 and the Alzheimer's-linked amyloid-beta (Aβ) proteins that warrant further scrutiny. This may also have implications for understanding AMD as aged/diseased retinae contain high levels of Aβ. Findings from TIMP-3 knockout and mutant knock-in mice have not led to new treatments, particularly as the latter does not satisfactorily recapitulate the Sorsby phenotype. However, recent advances in stem cell and in vitro approaches offer novel insights into understanding TIMP-3 pathology in the retina-brain axis, which has so far not been collectively examined. We propose that TIMP-3 activities could extend beyond its hitherto supposed functions to cause age-related changes and disease in these organs.

show abstract

“…This revealed a mutation in the first exon of family 1: c.113C>G, p.(Ser38Cys) (NM_000362.4) (Figure d). This is a known pathogenic variant in the TIMP3 gene and one of only two mutations currently identified in the N‐terminal region of the protein (Meunier et al., ; Schoenberger & Agarwal, ; Warwick, Gibson, Sood, & Lotery, ) (Figure ). Segregation analysis in 60 family members showed co‐segregation with disease in 47 individuals of family 1 (Figure a).…”

Section: Resultsmentioning

confidence: 99%

“…All affected individuals are heterozygous for the c.113C>G, p.(Ser38Cys) mutation in exon 1 of the TIMP3 gene, which was previously missed in family 1 due to less sensitive screening methods (Figure ). This mutation has been associated with relatively late onset SFD leading to choroidal neovascularization, with or without pulmonary involvement (Meunier et al., ; Schoenberger & Agarwal, ; Warwick et al., ). We confirm a later onset in the families identified here, segregating the p.(Ser38Cys) mutation.…”

Section: Discussionmentioning

confidence: 99%

The N‐terminal p.(Ser38Cys) TIMP3 mutation underlying Sorsby fundus dystrophy is a founder mutation disrupting an intramolecular disulfide bond

et al. 2019

View full text Add to dashboard Cite

Sorsby fundus dystrophy (SFD) is a macular degeneration caused by mutations in TIMP3, the majority of which introduce a novel cysteine. However, the exact molecular mechanisms underlying SFD remain unknown. We aimed to provide novel insights into the functional consequences of a distinct N‐terminal mutation. Haplotype reconstruction in three SFD families revealed that the identified c.113C>G, p.(Ser38Cys) mutation is a founder in Belgian and northern French families with a late‐onset SFD phenotype. Functional consequences of the p.(Ser38Cys) mutation were investigated by high‐resolution Western blot analysis of wild type and mutant TIMP3 using patient fibroblasts and in vitro generated proteins, and by molecular modeling of TIMP3 and its interaction partners. We could not confirm a previous hypothesis on dimerization of mutant TIMP3 proteins. However, we identified aberrant intramolecular disulfide bonding. Our data provide evidence for disruption of the established Cys36‐Cys143 disulfide bond and formation of a novel Cys36‐Cys38 bond, possibly associated with increased glycosylation of the protein. In conclusion, we propose a novel pathogenetic mechanism underlying the p.(Ser38Cys) TIMP3 founder mutation involving intramolecular disulfide bonding. These results provide new insights into the pathogenesis of SFD and other retinopathies linked to mutations in TIMP3, such as age‐related macular degeneration.

show abstract

A new autosomal dominant eye and lung syndrome linked to mutations in TIMP3 gene

Cited by 18 publications

References 29 publications

Reflections on the evolution of the vertebrate tissue inhibitors of metalloproteinases

Reflections on the evolution of the vertebrate tissue inhibitors of metalloproteinases

The Diverse Roles of TIMP-3: Insights into Degenerative Diseases of the Senescent Retina and Brain

The N‐terminal p.(Ser38Cys) TIMP3 mutation underlying Sorsby fundus dystrophy is a founder mutation disrupting an intramolecular disulfide bond

Contact Info

Product

Resources

About