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

• Published in: PloS one Vol. 12; no. 5; p. e0176664
• Main Authors: Al-Aama, Jumana Yousuf, Shaik, Noor Ahmad, Banaganapalli, Babajan, Salama, Mohammed A, Rashidi, Omran, Sahly, Ahmed N, Mohsen, Mohammed O, Shawoosh, Harbi A, Shalabi, Hebah Ahmad, Edreesi, Mohammad Al, Alharthi, Sameer E, Wang, Jun, Elango, Ramu, Saadah, Omar I
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.05.2017; Public Library of Science (PLoS)
• Subjects: Adenylate kinase; Adenylate Kinase - chemistry; Adenylate Kinase - genetics; Alleles; Amino acids; Antigens; Autoimmune diseases; Biology and Life Sciences; CD4 antigen; Celiac disease; Celiac Disease - genetics; Chromosome Mapping; Chromosomes; Computational Biology; Computer applications; Consanguinity; Development and progression; Evolution, Molecular; Exome; Exome sequencing; Female; Gastroenterology; Gene loci; Genes; Genetic aspects; Genetic Variation; Genomes; Genotype; Gluten; Heritability; High-Throughput Nucleotide Sequencing; Histocompatibility antigen HLA; Humans; Hydrogen Bonding; Inheritance Patterns; Insertion; Lymphocytes T; Male; Medicine; Medicine and Health Sciences; Models, Molecular; Mutation; Pediatrics; Pedigree; Penetrance; Phosphates; Protein Conformation; Protein structure; Proteins; Research and Analysis Methods; Saudi Arabia; Secondary structure; Small intestine; Social Sciences; Saudi Arabia; Middle East
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0176664

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.