Eph and Ephrin Variants in Malaysian Neural Tube Defect Families

Abstract

Neural tube defects (NTDs) are common birth defects with a complex genetic etiology. Mouse genetic models have indicated a number of candidate genes, of which functional mutations in some have been found in human NTDs, usually in a heterozygous state. This study focuses on Ephs-ephrins as candidate genes of interest owing to growing evidence of the role of this gene family during neural tube closure in mouse models. Eph-ephrin genes were analyzed in 31 Malaysian individuals comprising seven individuals with sporadic spina bifida, 13 parents, one twin-sibling and 10 unrelated controls. Whole exome sequencing analysis and bioinformatic analysis were performed to identify variants in 22 known Eph-ephrin genes. We reported that three out of seven spina bifida probands and three out of thirteen family members carried a variant in either EPHA2 (rs147977279), EPHB6 (rs780569137) or EFNB1 (rs772228172). Analysis of public databases shows that these variants are rare. In exome datasets of the probands and parents of the probands with Eph-ephrin variants, the genotypes of spina bifida-related genes were compared to investigate the probability of the gene-gene interaction in relation to environmental risk factors. We report the presence of Eph-ephrin gene variants that are prevalent in a small cohort of spina bifida patients in Malaysian families.

Keywords: EFNB1; EPHA2; EPHB6; Eph; ephrins; neural tube defects; spina bifida.

Figure 1

The EPHA2, EPHB6 and EFNB1 variants in their protein form. The position of the non-synonymous variants (EPHA2:rs147977279, EPHB6:rs780569137 and EFNB1:rs772228172) were represented by red dashed bar (L = Leucine; V = Valine; Y = Tyrosine; C = Cysteine; R = Arginine; W = Tryptophan; EPH_lbd = Eph ligand binding domain; EGF like = epidermal growth factor-like; FN3 = fibronectin-3; Pfam EphA2_TM = protein family of EphA2 transmembrane; TyrKc = tyrosine kinase catalytic domain; SAM = sterile alpha domain; Pfam Ephrin_rec like = protein domain tyrosine-protein kinase ephrin type A/B receptor like; STYKc = Protein Ser/Thr/Tyr kinase or phosphotransferases; Pfam ephrin = protein family ephrin; red box = signal peptide; blue box = transmembrane region; pink box = low complexity region).