Isolation and characterization of a candidate gene for Norrie disease

Zy, Chen; Rw, Hendriks; Jobling, Mark A.; Powell, John; Xo, Breakefield; Kb, Sims; Craig, Ian W.

doi:10.1038/ng0692-204

Cited by 178 publications

(86 citation statements)

References 27 publications

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“…1) and a tertiary structure similar to that of TGF-b (Meitinger et al 1993). Mutations in Norrin cause Norrie disease Chen et al 1992;Meindl et al 1992), an X-linked disorder characterized by vascular abnormalities in the eye and blindness, often accompanied by progressive hearing loss and mental retardation (Berger 1998). …”

Section: Norrinmentioning

confidence: 99%

Secreted and Transmembrane Wnt Inhibitors and Activators

Cruciat

Niehrs

2012

Cold Spring Harbor Perspectives in Biology

526

450

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Section: Norrinmentioning

confidence: 99%

Secreted and Transmembrane Wnt Inhibitors and Activators

Cruciat

Niehrs

2012

Cold Spring Harbor Perspectives in Biology

526

450

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“…The carboxyl terminus of submaxillary mucin is formed by a 240-residue disulfide-rich domain, which has significant sequence identity with similar domains at the carboxyl terminus of human prepro-von Willebrand factor (3), frog integumentary mucin FIMB.1 (6), and human mucins secreted by different tissues, including MUC2, MUC5AC, 4 MUC5B, 5 and MUC6 6 (5,(7)(8)(9)(10). Moreover, the 11 half-cystines in a 133-residue protein (norrin) 7 associated with Norrie disease in humans (11,12) are conserved in the carboxyl-terminal disulfide-rich domains of human prepro-von Willebrand factor, porcine submaxillary mucin, and several human mucins (13). It has been shown that the disulfide-rich domain of prepro-von Willebrand factor (14), porcine submaxillary mucin (15), and norrin (16) forms interchain disulfide bonds between two polypeptide chains in these molecules.…”

mentioning

confidence: 99%

The Carboxyl-terminal 90 Residues of Porcine Submaxillary Mucin Are Sufficient for Forming Disulfide-bonded Dimers

Pérez-Vilar

Hill

1998

Journal of Biological Chemistry

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COS-7 cells transfected with expression vectors encoding 90 and 154 amino acid residues, respectively, from the carboxyl terminus of the disulfide-rich domain (240 residues) of porcine submaxillary mucin were shown to form disulfide-bonded dimers. Cells with expression vectors that encoded the disulfide-rich domain lacking the last 90 and 150 carboxyl-terminal residues, respectively, from the carboxyl terminus of the disulfide-rich domain were unable to secrete truncated domains. These results indicate that the information required to form disulfide-bonded dimers resides in only 90 residues, including 11 half-cystines. Site-specific mutagenesis was employed to change, one at a time, each codon for the 11 half-cystines to serine. Eight of the 11 mutants formed disulfide-bonded dimers indistinguishable from those produced by unmutated vector, although 6 of the 8 mutants also produced aggregates thought to be misfolded protein with scrambled disulfide bonds. Two additional mutant vectors encoding serine instead of half-cystine at residues 13244 and 13246 in submaxillary mucin expressed both monomers and dimers of the disulfide-rich domain but no aggregates. The final mutant vector, C13223S, expressed protein aggregates that were poorly secreted from transfected cells. A mutant vector with two codon changes, C13244A/ C13246A, expressed both monomers and dimers, just like the single mutants at these half-cystines. These results suggest that three half-cystine residues (Cys 13223 , Cys 13244 , and Cys 13246 ) may be involved in forming interchain disulfide bonds in mucin dimers. Two of these half-cystines, Cys 13244 and Cys 13246 , are in the highly conserved sequence C 13244 LC 13246 C in the disulfide-rich domain of several other human mucins and in preprovon Willebrand factor and norrin, a protein that in mutant forms gives rise to Norrie disease. Support for the involvement of these half-cystines in formation of disulfide-bonded dimers of these molecules is also provided by known mutations in prepro-von Willebrand factor and norrin.Porcine submaxillary mucin contains a polypeptide chain of 13,288 residues, 1 which can be divided into domains typical of those found in several other mucins secreted by various human tissues (1). Most of the polypeptide chain is comprised of 81 residue tandem repeats that are rich in serine, threonine, glycine, and alanine, and together account for 75% of the residues in this domain. There are at least three different genes encoding porcine submaxillary mucin that differ from one another in the number (90, 125, and 135) of repeats they encode (1). The tandem repeat domain is flanked on either end by unique sequences that are similar in composition to the repeat domains but exhibit no sequence identity to one another or to the tandem repeat domains. The hydroxyl groups of serine and threonine in the tandem repeat domain (2), and presumably the unique sequences flanking this domain, are in O-glycosidic linkage with oligosaccharides, which account for about 75% of the weight of native mu...

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“…Norrin acts as a tissue-specific ligand for Frizzled 4 (Fz4) to help direct retinal vascular development (Xu et al, 2004). Mutations in Norrin result in Norrie Disease (Berger et al, 1992;Chen et al, 1992), in which retinal vascular development is incomplete resulting in large areas of avascular retina, neovascularization, scarring, and retinal detachment. Heterozygosity for mutations in Fz4, result in familial exudative vitreoretinopathy (FEVR) (Toomes et al, 2004), in which retinal vascular development is perturbed, but often not as severely as in Norrie disease, resulting in areas of avascular retina, neovascularization, and a spectrum that ranges from focal traction retinal detachments to severe detachments and blindness.…”

Section: Retinal Vascular Developmentmentioning

confidence: 99%

Seeing the light: New insights into the molecular pathogenesis of retinal diseases

Campochiaro

2007

Journal Cellular Physiology

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In the past, most treatments for retinal diseases have been empirical. Steroids and/or laser photocoagulation and/or surgery have been tried for almost every condition with little or no understanding of the underlying disease. Over the past several years vision researchers have uncovered molecular components of processes, such as visual transduction and the visual cycle, that are critical for visual function, and identified other molecules that lead to dysfunction and disease processes such as neovascularization and macular edema. It is becoming clear that dysregulation of certain molecules can have major effects on retinal structure and function. Studies in animal models have suggested that inhibiting or augmenting levels of a single molecule can have major effects in complex disease processes. Although several molecules probably contribute to neovascularization and excessive vascular permeability in the eye, blockade of vascular endothelial growth factor (VEGF) has remarkable beneficial effects in animal models that have now been proven to apply to human diseases in clinical trials. Intraocular injection of VEGF antagonists has revolutionized the treatment of choroidal neovascularization (CNV) and macular edema and serves as a model of targeted ocular pharmacotherapy. Significant progress elucidating the molecular pathogenesis of several disease processes in the eye may soon lead to new treatments following the lead of VEGF antagonists. Initial treatments that provide benefit from frequent intraocular injections are likely to be followed by sustained delivery of drugs and/or prolonged protein delivery by gene transfer. The eye has entered the era of molecular therapy. J. Cell. Physiol. 213: 348–354, 2007. © 2007 Wiley‐Liss, Inc.

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Isolation and characterization of a candidate gene for Norrie disease

Cited by 178 publications

References 27 publications

Secreted and Transmembrane Wnt Inhibitors and Activators

Secreted and Transmembrane Wnt Inhibitors and Activators

The Carboxyl-terminal 90 Residues of Porcine Submaxillary Mucin Are Sufficient for Forming Disulfide-bonded Dimers

Seeing the light: New insights into the molecular pathogenesis of retinal diseases

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