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Null mutations in LTBP2 cause primary congenital glaucoma.

Primary congenital glaucoma (PCG) is an autosomal-recessive condition characterized by high intraocular pressure (IOP), usually within the first year of life, which potentially could lead to optic nerve damage, globe enlargement, and permanent loss of vision. To date, PCG has been linked to three loci: 2p21 (GLC3A), for which the responsible gene is CYP1B1, and 1p36 (GLC3B) and 14q24 (GLC3C), for which the genes remain to be identified. Here we report that null mutations in LTBP2 cause PCG in four consanguineous families from Pakistan and in patients of Gypsy ethnicity. LTBP2 maps to chromosome 14q24.3 but is around 1.3 Mb proximal to the documented GLC3C locus. Therefore, it remains to be determined whether LTBP2 is the GLC3C gene or whether a second adjacent gene is also implicated in PCG. LTBP2 is the largest member of the latent transforming growth factor (TGF)-beta binding protein family, which are extracellular matrix proteins with multidomain structure. It has homology to fibrillins and may have roles in cell adhesion and as a structural component of microfibrils. We confirmed localization of LTBP2 in the anterior segment of the eye, at the ciliary body, and particularly the ciliary process. These findings reveal that LTBP2 is essential for normal development of the anterior chamber of the eye, where it may have a structural role in maintaining ciliary muscle tone.

Pubmed ID: 19361779 RIS Download

Mesh terms: Chromosome Mapping | Ciliary Body | Consanguinity | Glaucoma | Humans | Latent TGF-beta Binding Proteins | Mutation | Pedigree

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Associated grants

  • Agency: Medical Research Council, Id: G0501050

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HGMD

It represents an attempt to collate known (published) gene lesions responsible for human inherited disease. More specifically, this database is a comprehensive core collection of germline mutations in nuclear genes that underlie or are associated with human inherited disease. This database, whilst originally established for the study of mutational mechanisms in human genes (Cooper and Krawczak 1993), has now acquired a much broader utility in that it embodies an up-to-date and comprehensive reference source to the spectrum of inherited human gene lesions. Thus, HGMD provides information of practical diagnostic importance to (i) researchers and diagnosticians in human molecular genetics, (ii) physicians interested in a particular inherited condition in a given patient or family, and (iii) genetic counselors. The Human Gene Mutation Database comprises various types of mutation within the coding regions, splicing and regulatory regions of human nuclear genes causing inherited disease. Somatic mutations and mutations in the mitochondrial genome are thus not included, although in the latter case, links to Mitomap are now provided. Each mutation is entered only once in order to avoid confusion between recurrent and identical-by-descent lesions. Mutations inferred from amino acid sequencing have been excluded since, in the absence of direct DNA analysis, some ambiguity may exist as to the DNA sequence changes involved. Silent mutations within the coding region which do not alter the encoded amino acid are also not recorded. If such mutations are known to adversely affect mRNA splicing or gene expression, or have been reported in significant association with disease, they may be included. Sponsors: This Database is supported by Celera, Macmillan, The Genome Database, DFG, BIOS Scientific Publishers, Research Genetics, ScotLab bioscience, MB Biochemicals, Phzer, Sun Life, GFH, Springer, SmithKline Beecham, Hybaid.

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NCBI BLAST

Web search tool to find regions of similarity between biological sequences. The program compares nucleotide or protein sequences to sequence databases and calculates the statistical significance.

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UCSC Genome Browser

A collection of genomes which include reference sequences and working draft assemblies, as well as a variety of tools to explore these sequences. The Genome Browser zooms and scrolls over chromosomes, showing the work of annotators worldwide. The Gene Sorter shows expression, homology and other information on groups of genes that can be related in many ways. Blat quickly maps your sequence to the genome. The Table Browser provides access to the underlying database. VisiGene lets you browse through a large collection of in situ mouse and frog images to examine expression patterns. Genome Graphs allows you to upload and display genome-wide data sets. Also provided is a portal to the Encyclopedia of DNA Elements (ENCODE) and Neandertal projects.

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