Familial Exudative Vitreoretinopathy caused by a Homozygous Mutation in<i>TSPAN12</i>in a Cystic Fibrosis Infant

Savarese, Marco; Spinelli, Elide; Gandolfo, Federico; Lemma, Valentina; Fruscio, Giuseppina Di; Padoan, Rita; Morescalchi, Francesco; D’Agostino, Massimo; Savoldi, Gianfranco; Semeraro, Francesco; Nigro, Vincenzo; Bonatti, Stefano

doi:10.3109/13816810.2013.811270

Cited by 14 publications

(13 citation statements)

References 12 publications

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“…FEVR can be caused by mutations in NDP, FZD4, LRP5, TSPAN12 , and ZNF408 – a zinc finger protein recently implicated in vascular biology (Collin et al, 2013; Nikopoulos et al, 2010b). TSPAN12 mutations have been predominantly reported in autosomal dominant FEVR (Kashani et al, 2014b; Kondo et al, 2011; Nikopoulos et al, 2010a; Poulter et al, 2010; Yang et al, 2011 Xu 14) but also in homozygous patients with an autosomal recessive inheritance pattern (Gal et al, 2014; Poulter et al, 2012; Savarese et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

TSPAN12 Is a Norrin Co-receptor that Amplifies Frizzled4 Ligand Selectivity and Signaling

et al. 2017

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Summary Accessory proteins in Frizzled (FZD) receptor complexes are thought to determine ligand selectivity and signaling amplitude. Genetic evidence indicates that specific combinations of accessory proteins and ligands mediate vascular beta-catenin signaling in different CNS structures. In the retina, the tetraspanin TSPAN12 and the ligand norrin (NDP) mediate angiogenesis and both genes are linked to familial exudative vitreoretinopathy (FEVR). Yet, the molecular function of TSPAN12 remains poorly understood. Here, we report that TSPAN12 is an essential component of the NDP-receptor complex and interacts with FZD4 and NDP via its extracellular loops, consistent with an action as co-receptor that enhances FZD4 ligand selectivity for NDP. FEVR-linked mutations in TSPAN12 prevent the incorporation of TSPAN12 into the NDP-receptor complex. In vitro and in Xenopus embryos, TSPAN12 alleviates defects of FZD4 M105V, a mutation that destabilizes the NDP/FZD4 interaction. This study sheds light on the poorly understood function of accessory proteins in FZD signaling.

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Section: Introductionmentioning

confidence: 99%

TSPAN12 Is a Norrin Co-receptor that Amplifies Frizzled4 Ligand Selectivity and Signaling

et al. 2017

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“…In literature on Italian FEVR patients, only three genetic association studies describing a total of six probands are reported [13–15]. Here, we present the results of clinical and genetic characterization of the largest Italian FEVR population, consisting of six probands and ten relatives, as a contribution to the FEVR disease molecular epidemiology in our country.…”

Section: Introductionmentioning

confidence: 93%

Genotype-Phenotype Characterization of Novel Variants in Six Italian Patients with Familial Exudative Vitreoretinopathy

Iarossi

Bertelli²,

Maltese³

et al. 2017

Journal of Ophthalmology

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Familial exudative vitreoretinopathy (FEVR) is a complex disorder characterized by incomplete development of the retinal vasculature. Here, we report the results obtained on the spectrum of genetic variations and correlated phenotypes found in a cohort of Italian FEVR patients. Eight probands (age range 7–19 years) were assessed by genetic analysis and comprehensive age-appropriate ophthalmic examination. Genetic testing investigated the genes most widely associated in literature with FEVR: FZD4, LRP5, TSPAN12, and NDP. Clinical and genetic evaluations were extended to relatives of probands positive to genetic testing. Six out of eight probands (75%) showed a genetic variation probably related to the phenotype. We identified four novel genetic variants, one variant already described in association with Norrie disease and one previously described linked to autosomal dominant FEVR. Pedigree analysis of patients led to the classification of four autosomal dominant cases of FEVR (caused by FZD4 and TSPAN12 variants) and two X-linked FEVR probands (NDP variants). None of the patients showed variants in the LRP5 gene. This study represents the largest cohort study in Italian FEVR patients. Our findings are in agreement with the previous literature confirming that FEVR is a clinically and genetically heterogeneous retinal disorder, even when it manifests in the same family.

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“…Interestingly, the tetraspanin 12 protein (TSPAN12), expressed in the retinal vasculature, phenocopies the depletion of FZD 4 , LRP5 and Norrin (Junge et al, 2009). As with FZD 4 and LRP5, several TSPAN12 mutations are associated with familial exudative vitreoretinopathy (Gal et al, 2014;Knoblich et al, 2014;Savarese et al, 2014;Ye et al, 2010). Although the mechanism is not fully understood, TSPAN12 selectively mediates Norrin over WNT-3A signaling indicating a possible role for conveying ligand selectivity to the FZD 4 /LRP5 receptor complex.…”

Section: Required Transmembrane Components As Cofactors (Tspan12 Gprmentioning

confidence: 97%

Frizzleds and WNT/β-catenin signaling – The black box of ligand–receptor selectivity, complex stoichiometry and activation kinetics

Schulte

2015

European Journal of Pharmacology

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Familial Exudative Vitreoretinopathy caused by a Homozygous Mutation inTSPAN12in a Cystic Fibrosis Infant

Cited by 14 publications

References 12 publications

TSPAN12 Is a Norrin Co-receptor that Amplifies Frizzled4 Ligand Selectivity and Signaling

TSPAN12 Is a Norrin Co-receptor that Amplifies Frizzled4 Ligand Selectivity and Signaling

Genotype-Phenotype Characterization of Novel Variants in Six Italian Patients with Familial Exudative Vitreoretinopathy

Frizzleds and WNT/β-catenin signaling – The black box of ligand–receptor selectivity, complex stoichiometry and activation kinetics

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