The role of small in-frame insertions/deletions in inherited eye disorders and how structural modelling can help estimate their pathogenicity.
Background: Although the majority of small in-frame insertions/deletions (indels) has no/little affect on protein function, a small subset of these changes has been causally associated with genetic disorders. Notably, the molecular mechanisms and frequency by which they give rise to disease phenotyp...
| Publicado en: | Orphanet Journal of Rare Diseases Vol. 11; pp. 1 - 9 |
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| Autores principales: | , , , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
BioMed Central
9/14/2016
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=118103694&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 118103694 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 17501172 38NP jtl: Orphanet Journal of Rare Diseases issn: 17501172 maglogo: N pubinfo: dt: 9/14/2016 vid: 11 pid: 24147 pub: BioMed Central artinfo: ui: 118103694 118103694 NLM27628848 118103694 10.1186/s13023-016-0505-0 NLM27628848 118103694 ppf: 1 ppct: 8 formats: tig: atl: The role of small in-frame insertions/deletions in inherited eye disorders and how structural modelling can help estimate their pathogenicity. aug: au: Sergouniotis, Panagiotis I. Barton, Stephanie J. Waller, Sarah Perveen, Rahat Ellingford, Jamie M. Campbell, Christopher Hall, Georgina Gillespie, Rachel L. Bhaskar, Sanjeev S. Ramsden, Simon C. Black, Graeme C. Lovell, Simon C. affil: Manchester Royal Eye Hospital, Manchester Academic Health Science Centre, Manchester, UK sug: subj: Mutation Eye Diseases Genes Retinal Diseases Human Bioinformatics Cataract Validation Studies Comparative Studies Evaluation Research Multicenter Studies Funding Source ab: Background: Although the majority of small in-frame insertions/deletions (indels) has no/little affect on protein function, a small subset of these changes has been causally associated with genetic disorders. Notably, the molecular mechanisms and frequency by which they give rise to disease phenotypes remain largely unknown. The aim of this study is to provide insights into the role of in-frame indels (≤21 nucleotides) in two genetically heterogeneous eye disorders.Results: One hundred eighty-one probands with childhood cataracts and 486 probands with retinal dystrophy underwent multigene panel testing in a clinical diagnostic laboratory. In-frame indels were collected and evaluated both clinically and in silico. Variants that could be modeled in the context of protein structure were identified and analysed using integrative structural modeling. Overall, 55 small in-frame indels were detected in 112 of 667 probands (16.8 %); 17 of these changes were novel to this study and 18 variants were reported clinically. A reliable model of the corresponding protein sequence could be generated for 8 variants. Structural modeling indicated a diverse range of molecular mechanisms of disease including disruption of secondary and tertiary protein structure and alteration of protein-DNA binding sites.Conclusions: In childhood cataract and retinal dystrophy subjects, one small in-frame indel is clinically reported in every ~37 individuals tested. The clinical utility of computational tools evaluating these changes increases when the full complexity of the involved molecular mechanisms is embraced. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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