ArticlePloS one2017
Whole exome sequencing of a consanguineous family identifies the possible modifying effect of a globally rare AK5 allelic variant in celiac disease development among Saudi patients.
Article in PloS one, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 19 citations in OpenAlex.
- New Insights on Genes, Gluten, and Immunopathogenesis of Celiac Disease.Gastroenterology · 2024Review
- Article
- The role of the adenylate kinase 5 gene in various diseases and cancer.Journal of clinical and translational science · 2024Review
- Genome-Wide Association Study-Guided Exome Rare Variant Burden Analysis Identifies IL1R1 and CD3E as Potential Autoimmunity Risk Genes for Celiac Disease.Frontiers in pediatrics · 2022Article
- Complex Inheritance of Rare Missense Variants inFrontiers in pediatrics · 2022Article
- Exome Sequencing Identifies the Extremely RareFrontiers in pediatrics · 2022Article
- TagSNP approach for HLA risk allele genotyping of Saudi celiac disease patients: effectiveness and pitfalls.Bioscience reports · 2021Article
- Identification of a Rare Exon 19 Skipping Mutation in ALMS1 Gene in Alström Syndrome Patients From Two Unrelated Saudi Families.Frontiers in pediatrics · 2021Article
- Exploring celiac disease candidate pathways by global gene expression profiling and gene network cluster analysis.Scientific reports · 2020Article
- Whole exome sequencing of a Saudi family and systems biology analysis identifiesSaudi journal of biological sciences · 2020Article
- Familial/inherited cancer syndrome: a focus on the highly consanguineous Arab population.NPJ genomic medicine · 2020Review
- Exome sequencing and metabolomic analysis of a chronic kidney disease and hearing loss patient family revealed RMND1 mutation induced sphingolipid metabolism defects.Saudi journal of biological sciences · 2020Article
- Whole exome sequencing identifies rare biallelic ALMS1 missense and stop gain mutations in familial Alström syndrome patients.Saudi journal of biological sciences · 2020Article
- Genetic susceptibility for celiac disease is highly prevalent in the Saudi population.Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology AssociationArticle
- Health related quality of life among Saudi children and adolescents with celiac disease.Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology AssociationArticle
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Celiac disease (CD), a multi-factorial auto-inflammatory disease of the small intestine, is known to occur in both sporadic and familial forms. Together HLA and Non-HLA genes can explain up to 50% of CD's heritability. In order to discover the missing heritability due to rare variants, we have exome sequenced a consanguineous Saudi family presenting CD in an autosomal recessive (AR) pattern. We have identified a rare homozygous insertion c.1683_1684insATT, in the conserved coding region of AK5 gene that showed classical AR model segregation in this family. Sequence validation of 200 chromosomes each of sporadic CD cases and controls, revealed that this extremely rare (EXac MAF 0.000008) mutation is highly penetrant among general Saudi populations (MAF is 0.62). Genotype and allelic distribution analysis have indicated that this AK5 (c.1683_1684insATT) mutation is negatively selected among patient groups and positively selected in the control group, in whom it may modify the risk against CD development [p<0.002]. Our observation gains additional support from computational analysis which predicted that Iso561 insertion shifts the existing H-bonds between 400th and 556th amino acid residues lying near the functional domain of adenylate kinase. This shuffling of amino acids and their H-bond interactions is likely to disturb the secondary structure orientation of the polypeptide and induces the gain-of-function in nucleoside phosphate kinase activity of AK5, which may eventually down-regulates the reactivity potential of CD4+ T-cells against gluten antigens. Our study underlines the need to have population-specific genome databases to avoid false leads and to identify true candidate causal genes for the familial form of celiac disease.
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