The study, “Identification of RELN varient p.(Ser2486Gly) in an Iranian family with ankylosing spondylitis: the first association of RELN and AS,” was published in the European Journal of Human Genetics.
Genes, which are composed of DNA sequences, are transcribed into RNA molecules. In turn, these RNA molecules are used as templates to make proteins, which carry out various functions in a cell.
Variations in more than 30 genes have been associated with AS. However, these variants can explain only about 25% of the heritability of AS. Most of the identified variants have been found in more than 5% of the general population. Yet, rarer variants (occurring in less than 1% of the population) have not yet been connected with AS.
Researchers hypothesized that unidentified changes in genes may alter the risk of a person developing AS and influence its progression.
Whole exome sequencing (WES), in particular, analyzes the protein-coding regions of the human genome, or the information in a person’s genes that will be converted into proteins. Variants in coding regions are predicted to include approximately 85% of disease-causing mutations. Determining new variants for AS is important for understanding its onset and progression, as well as aiding in diagnosis and treatments.
Researchers studied a large Iranian-Kurdish family with seven family members diagnosed with AS.
DNA samples from three patients and two healthy family members were analyzed by WES. After excluding for over 1% of variants found in the general population, the analysis revealed eight variants in protein-coding regions within six genes: RELN, DNMT1, TAF4β, MUC16, DLG2, and FAM208.
Further analysis revealed that only one variant, known as c.7456A>G; p.(Ser2486Gly), in the RELN gene was found in family members with AS, while it was absent from all healthy controls.
The RELN gene provides instructions for making the reelin protein, which is important for regulating cell-cell interactions, migration and maturation of nerve cells, as well as cell positioning during brain development.
Computational analysis indicated that the mutation may decrease the stability of reelin.
Although this protein’s involvement in AS is not yet understood, researchers hypothesize that it may be involved in inflammation and osteogenesis (bone formation). They suggest that the variant in reelin may alter pathways in macrophages (immune cells that are essential in AS) to induce inflammation.
“In the present study, we utilized WES to identify gene causality in a familial case of AS,” the researchers wrote.
“This association suggests potential insights into the pathophysiological bases of AS and it could broaden horizons toward new therapeutic strategies,” they stated.
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