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      A novel locus for X-linked congenital cataract on Xq24

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          Abstract

          Purpose

          This study aimed to map the genetic locus responsible for a novel X-linked congenital cataract phenotype.

          Methods

          A large three-generation family with lamellar and nuclear cataract in five affected males was identified. Linkage analysis was conducted by genotyping X-chromosome specific microsatellite markers at an average spacing of 5 cM. Analysis was conducted using the LINKAGE package under an X-linked recessive model.

          Results

          A linkage was detected on Xq24 with the maximum LOD score of 2.53 at θ=0 for DXS1001. The minimal region was defined as 11.5 Mb between markers DXS8055 and DXS8009 through critical recombination events in multiple individuals.

          Conclusions

          A gene causing this novel congenital cataract phenotype is located on the long arm of the X chromosome.

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          Most cited references16

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          The catenin p120(ctn) interacts with Kaiso, a novel BTB/POZ domain zinc finger transcription factor.

          p120(ctn) is an Armadillo repeat domain protein with structural similarity to the cell adhesion cofactors beta-catenin and plakoglobin. All three proteins interact directly with the cytoplasmic domain of the transmembrane cell adhesion molecule E-cadherin; beta-catenin and plakoglobin bind a carboxy-terminal region in a mutually exclusive manner, while p120 binds the juxtamembrane region. Unlike beta-catenin and plakoglobin, p120 does not interact with alpha-catenin, the tumor suppressor adenomatous polyposis coli (APC), or the transcription factor Lef-1, suggesting that it has unique binding partners and plays a distinct role in the cadherin-catenin complex. Using p120 as bait, we conducted a yeast two-hybrid screen and identified a novel transcription factor which we named Kaiso. Kaiso's deduced amino acid sequence revealed an amino-terminal BTB/POZ protein-protein interaction domain and three carboxy-terminal zinc fingers of the C2H2 DNA-binding type. Kaiso thus belongs to a rapidly growing family of POZ-ZF transcription factors that include the Drosophila developmental regulators Tramtrak and Bric à brac, and the human oncoproteins BCL-6 and PLZF, which are causally linked to non-Hodgkins' lymphoma and acute promyelocytic leukemia, respectively. Monoclonal antibodies to Kaiso were generated and used to immunolocalize the protein and confirm the specificity of the p120-Kaiso interaction in mammalian cells. Kaiso specifically coprecipitated with a variety of p120-specific monoclonal antibodies but not with antibodies to alpha- or beta-catenin, E-cadherin, or APC. Like other POZ-ZF proteins, Kaiso localized to the nucleus and was associated with specific nuclear dots. Yeast two-hybrid interaction assays mapped the binding domains to Arm repeats 1 to 7 of p120 and the carboxy-terminal 200 amino acids of Kaiso. In addition, Kaiso homodimerized via its POZ domain but it did not heterodimerize with BCL-6, which heterodimerizes with PLZF. The involvement of POZ-ZF proteins in development and cancer makes Kaiso an interesting candidate for a downstream effector of cadherin and/or p120 signaling.
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            Easy calculations of lod scores and genetic risks on small computers.

            A computer program that calculates lod scores and genetic risks for a wide variety of both qualitative and quantitative genetic traits is discussed. An illustration is given of the joint use of a genetic marker, affection status, and quantitative information in counseling situations regarding Duchenne muscular dystrophy.
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              Mutations in a novel gene, NHS, cause the pleiotropic effects of Nance-Horan syndrome, including severe congenital cataract, dental anomalies, and mental retardation.

              Nance-Horan syndrome (NHS) is an X-linked disorder characterized by congenital cataracts, dental anomalies, dysmorphic features, and, in some cases, mental retardation. NHS has been mapped to a 1.3-Mb interval on Xp22.13. We have confirmed the same localization in the original, extended Australian family with NHS and have identified protein-truncating mutations in a novel gene, which we have called "NHS," in five families. The NHS gene encompasses approximately 650 kb of genomic DNA, coding for a 1,630-amino acid putative nuclear protein. NHS orthologs were found in other vertebrates, but no sequence similarity to known genes was identified. The murine developmental expression profile of the NHS gene was studied using in situ hybridization and a mouse line containing a lacZ reporter-gene insertion in the Nhs locus. We found a complex pattern of temporally and spatially regulated expression, which, together with the pleiotropic features of NHS, suggests that this gene has key functions in the regulation of eye, tooth, brain, and craniofacial development.
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                Author and article information

                Journal
                Mol Vis
                MV
                Molecular Vision
                Molecular Vision
                1090-0535
                2008
                18 April 2008
                : 14
                : 721-726
                Affiliations
                [1 ]Department of Ophthalmology, Flinders University, Adelaide, SA, Australia
                [2 ]Department of Genetic Medicine, Women’s and Children’s Hospital, Adelaide, SA, Australia
                [3 ]Departments of Paediatrics and Molecular Biosciences, University of Adelaide, Adelaide, SA, Australia
                [4 ]Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
                Author notes
                Correspondence to: Dr. Kathryn P. Burdon, Department of Ophthalmology, Flinders Medical Centre, Bedford Park, SA, 5042, Australia; Phone: +61 8 82044094; FAX: +61 8 82770899; email: kathryn.burdon@flinders.edu.au
                Article
                85 2008MOLVIS0021
                2324122
                18431456
                4956ee1d-8449-4b3b-8716-85e62f2b2825
                Copyright @ 2008

                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.

                History
                : 15 January 2008
                : 27 March 2008
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                Research Article
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                Vision sciences
                Vision sciences

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