Six novel rare non-synonymous mutations for migraine without aura identified by exome sequencing

Abstract

Migraine without aura (MWO) is the most common among migraine group, and is mainly associated with genetic, physical and chemical factors, and hormonal changes. We aimed to identify novel non-synonymous mutations predisposing to the susceptibility to MWO in a Chinese sample using exome sequencing. Four patients with MWO from a family and four non-migraine subjects unrelated with these patients were genotyped using whole-exome sequencing. Bioinformatics analysis was used to screen possible susceptibility gene mutations, which were then verified by PCR. In four patients with MWO, six novel rare non-synonymous mutations were observed, including EDA2R (G170A), UBE2NL (T266G), GBP2 (A907G), EMR1 (C264G), CLCNKB (A1225G), and ARHGAP28 (C413G). It is worth stressing that GBP2 (A907G) was absent in any control subject. Multiple genes predispose to the susceptibility to MWO. ARHGAP28-, EMR1-, and GBP2-encoded proteins may affect angiokinesis, which supports vasogenic theory for the etiological hypothesis of this disease. CLCNKB-encoded protein may affect cell membrane potential, which is consistent with the cortical spreading depression theory. UBE2NL-encoded protein may regulate cellular responses to 5-hydroxytryptamine, which is in accordance with trigeminovascular reflex theory. EDA2R and UBE2NL are located on the X chromosome, which supports that this disease may have gender differences in genetic predisposition. Replication in larger sample size would significantly strengthen these findings.