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King, Kathy, Sheikh, Mohammed F, Cuthbert, Andrew P, Fisher, Sheila A, Onnie, Clive M, Mirza, Muddassar M, Pattni, Reenal C, Sanderson, Jeremy, Forbes, Alastair 
ORCID: https://orcid.org/0000-0001-7416-9843, Mansfield, John, Lewis, Cathryn M, Roberts, Roland G and Mathew, Christopher G
(2006)
Mutation, selection, and evolution of the Crohn disease susceptibility gene CARD15.
Human Mutation, 27 (1).
pp. 44-54.
ISSN 1059-7794
Abstract
Three common mutations in the CARD15 (NOD2) gene are known to be associated with susceptibility to Crohn disease (CD), and genetic data suggest a gene dosage model with an increased risk of 2-4-fold in heterozygotes and 20-40-fold in homozygotes. However, the discovery of numerous rare variants of CARD15 indicates that some heterozygotes for the common mutations have a rare mutation on the other CARD15 allele, which would support a recessive model for CD. We addressed this issue by screening CARD15 for mutations in 100 CD patients who were heterozygous for one of the three common mutations. We also developed a strategy for evaluating potential disease susceptibility alleles (DSAs) that involves assessing the degree of evolutionary conservation of involved residues, predicted effects on protein structure and function, and genotyping in a large sample of cases and controls. The evolutionary analysis was aided by sequencing the entire coding region of CARD15 in three primates (chimp, gibbon, and tamarin) and aligning the human sequence with these and orthologs from other species. We found that 11 of the 100 CD patients screened had a second potential pathogenic mutation within the exonic and periexonic sequences examined. Assuming that there are no additional pathogenic mutations in noncoding regions, our study suggests that most carriers of the common DSAs are true heterozygotes, and supports previous evidence for a gene dosage model. Four novel nonsynonymous mutations were detected, one of which would produce premature termination of translation c.2686C>T (p.Arg896X). Two potential DSAs--c.2107C>T (p.Arg703Cys) and g.2238T>A (c.74-7T>A)--were significantly associated with CD in the case control sample. Analysis of the evolution of CARD15 revealed strong conservation of the encoded protein, with identity to the human sequence ranging from 99.1% in the chimp to 44.5% in fugu. Higher primates possess an open reading frame (ORF) upstream of the putative initiation site in other species that encodes a further 27 N-terminal amino acids, while four regions of high conservation are observed outside of the known domains of CARD15, indicative of additional residues of functional importance. The strategy developed here may have general application to the assessment of mutation pathogenicity and genetic models in other complex disorders.
| Item Type: | Article |
|---|---|
| Additional Information: | 2005 Wiley-Liss, Inc. |
| Uncontrolled Keywords: | alleles,amino acid sequence,animals,case-control studies,crohn disease,dna mutational analysis,evolution, molecular,exons,genetic predisposition to disease,genetic testing,genotype,humans,introns,molecular sequence data,mutation,nod2 signaling adaptor protein,primates,selection, genetic,sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School |
| UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology Faculty of Medicine and Health Sciences > Research Groups > Nutrition and Preventive Medicine |
| Depositing User: | Pure Connector |
| Date Deposited: | 06 Aug 2014 10:48 |
| Last Modified: | 20 Oct 2022 23:59 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/49642 |
| DOI: | 10.1002/humu.20264 |
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