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Next generation sequencing identifies mutations in Atonal homolog 7 (ATOH7) in families with global eye developmental defects.

Human molecular genetics | Feb 15, 2012

The atonal homolog 7 (ATOH7) gene encodes a transcription factor involved in determining the fate of retinal progenitor cells and is particularly required for optic nerve and ganglion cell development. Using a combination of autozygosity mapping and next generation sequencing, we have identified homozygous mutations in this gene, p.E49V and p.P18RfsX69, in two consanguineous families diagnosed with multiple ocular developmental defects, including severe vitreoretinal dysplasia, optic nerve hypoplasia, persistent fetal vasculature, microphthalmia, congenital cataracts, microcornea, corneal opacity and nystagmus. Most of these clinical features overlap with defects in the Norrin/β-catenin signalling pathway that is characterized by dysgenesis of the retinal and hyaloid vasculature. Our findings document Mendelian mutations within ATOH7 and imply a role for this molecule in the development of structures at the front as well as the back of the eye. This work also provides further insights into the function of ATOH7, especially its importance in retinal vascular development and hyaloid regression.

Pubmed ID: 22068589 RIS Download

Mesh terms: Basic Helix-Loop-Helix Transcription Factors | Consanguinity | DNA Mutational Analysis | Eye | Eye Abnormalities | Eye Diseases | Eye Proteins | Humans | Male | Mutation | Nerve Tissue Proteins | Retina | beta Catenin

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Associated grants

  • Agency: Wellcome Trust, Id: 090224

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A non-profit academic organization for research and services in bioinformatics that provides freely available data from life science experiments, performs basic research in computational biology, and offers an extensive user training programme, supporting researchers in academia and industry. The Institute manages databases of biological data including nucleic acid, protein sequences, and macromolecular structures.

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PolyPhen: Polymorphism Phenotyping

PolyPhen is a tool which predicts possible impact of an amino acid substitution on the structure and function of a human protein using straightforward physical and comparative considerations. It is an automatic tool for prediction of possible impact of an amino acid substitution on the structure and function of a human protein. This prediction is based on straightforward empirical rules which are applied to the sequence, phylogenetic and structural information characterizing the substitution. They specifically focus on non-synonymous SNPs (nsSNPs), i.e. SNPs located in coding regions and resulting in amino acid variation in protein products of genes. It was shown in several recent studies that impact of amino acid allelic variants on protein structure/function can be reliably predicted via analysis of multiple sequence alignments and protein 3D-structures. As they demonstrated in an earlier work, these predictions correlate with the effect of natural selection seen as an excess of rare alleles. Therefore, predictions at the molecular level reveal SNPs affecting actual phenotypes. A substitution may occur at a specific site, e.g., active or binding, or in a non-globular, e.g., transmembrane, region. PolyPhen tries to identify a query protein as an entry in the hs_swall, the human proteins subset of UniProt database and use the FT (feature table) section of the corresponding entry. Information on FT records can be found in the Swiss-Prot Help. PolyPhen checks if the amino acid replacement occurs at a site. Most of human genetic variation is represented by SNPs (Single Nucleotide Polymorphisms) and many of them are believed to cause phenotypic differences between human individuals. At this step PolyPhen memorizes all positions which are annotated in the query protein as BINDING, ACT_SITE, LIPID, and METAL. At a later stage if the search for a homologous protein with known 3D structure is successful, it is checked whether the substitution site is in spatial contact with these critical for protein function residues. For hs_swall, PolyPhen augments annotation data with predictions made with TMHMM algorithm to predict transmembrane regions, Coils2 program to predict coiled coil regions and SignalP program to predict signal peptide regions of the protein sequences. For a substitution in an annotated or predicted transmembrane region, PolyPhen uses the PHAT transmembrane specific matrix score to evaluate possible functional effect of a nsSNP in the transmembrane region.

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