PATHOGENICITY ANALYSIS OF THE NEW MISSENSE MUTATION IN THE MYOF GENE DETECTED IN A FEMALE PATIENT WITH HEREDITARY ANGIOEDEMA WITH NORMAL LEVEL OF C1-INHIBITOR

Abstract

Hereditary angioedema (HAE) is a genetically determined disorder accompanied by specific symptoms associated with sporadic subcutaneous and submucosal edema. The described cases of type III HAE not associated with mutations in the SERPING1 gene are characterized by the corresponding clinical picture with normal values and functional activity of the C1-inhibitor. Type III HAE is associated with mutations in the F12, PLG, ANGPT1, KNG1, MYOF, and HS3ST6 genes. Mutations in the MYOF and HS3ST6 genes remain the least studied as yet. And as for the MYOF gene, a single mutation, Arg217Ser, is known to be associated with the development of HAE. The purposes of this research were to study the new missense mutation NC_000010.10:g.95093020C>T in the MYOF gene and predictive assessment of its contribution to the HAE pathogenesis using the bioinformatics analysis. There was a blood sample obtained from a 14 y/o female patient with HAE clinical manifestations and without a decrease in the level and the lack in function of the C1-inhibitor. The research methods included sequencing of the patient's complete exome, bioinformatic analysis of the MYOF gene mutation using a number of databases and Internet resources with the purpose of assessing the conservation of the amino acid position of the substitution and predicting the effect of the mutation on the protein. Results: the girl had a previously undescribed missense mutation NC_000010.10:g.95093020C>T in exon 42 of the MYOF gene (isoform A) in the heterozygous state. The mutation resulted in the replacement of arginine with glutamine at position 1590 of the amino acid sequence (p.Arg1590Gln, rs201619869). The use of bioinformatics analysis allowed assuming the potential pathogenicity of the detected missense mutation, which could cause the observed edema. The possible pathways for the involvement of myoferlin with the detected mutation in the HAE pathogenesis are discussed in the Article. The use of in silico analysis allowed conducting the detailed study of the detected mutation considering its effect on the protein structure, which is the basis of its normal functioning. According to the results of the study, rare mutations in the MYOF gene can be involved in the HAE pathogenesis provoking edema through various cascades of biochemical reactions. In the course of the study, a new missense mutation in the MYOF gene, pathogenetically significant for the HAE development, was described for the first time.