Molecular genetics and expression analyses of CtBP2/RIBEYE : a gene derived from genome wide association studies in anorexia nervosa and in body weight regulation

Anorexia nervosa (AN) is a serious eating disorder that affects majorly female adolescents from western industrialized countries. The lifetime prevalence for women with AN oscillates between 1.2-2.2 %. Genetic factors play a significant role in the etiology of AN and body weight regulation. So, a former look-up analysis reported three intronic variants in the CtBP2 gene to be associated with decreased BMI (Hinney et al., 2017). To our knowledge, mutations in the CtBP2 gene have not been described in patients with AN or in individuals with obesity. Due to alternative splicing, CtBP2 encodes two proteins, a transcriptional co-repressor and a major component of synaptic ribbons found mainly in sensory cells of the retina. Studies have already demonstrated that CtBP2 has an impact on weight regulation, while it is not known yet, if RIBEYE could also be involved. In this thesis, we performed a mutation screen of the CtBP2 / RIBEYE gene in 95 patients with AN and 92 obese controls, in order to find mutations for AN and / or body weight regulation. The obese group was chosen, as loci associated with body weight regulation may also play a role in the manifestation of AN and vice versa. A total of 41 sequence variants were detected. All 24 coding variants are located in the specific first exon of RIBEYE. After genotyping of all 9 rare variants (Arg72Trp [rs146900874], Val289Met [rs375685611], and Gly362Arg [rs202010294] only in patients with AN; as well as Pro53Ser [rs150867595], Val132AlafsTer35 [rs1379972000], Gln175ArgfsTer45 [rs141864737], Leu310Val [rs769811964], Pro397Ala [rs76134089] and Pro402Ser [rs113477585] only in obese individuals) via RFLP or TaqMan SNP genotyping assays, only the missense SNP Val289Met [rs375685611] was identified only once in a total of 469 patients with AN. In contrast, two missense (Leu310Val [rs769811964] and Pro402Ser [rs113477585], as well as one frameshift (Val132AlafsTer35 [rs1379972000]) variants were only once detected in a total of 484 obese subjects. One coding non-synonymous variant (Val234Met [rs3781409]) was in strong LD with one of the previously detected intronic SNPs (rs1561589; Hinney et al., 2017). The intronic SNP was also in high LD with Tyr455His (rs3012075) and Gln539Glu (rs2946994). Look-up analysis in both, the currently largest published GWAS for AN (Watson et al., 2019) and BMI variation (Yengo et al., 2018), revealed genome-wide significance in the present GWAS for BMI (Yengo et al., 2018). The effect for all variants was more pronounced in females than in males. Family-based analysis of Val234Met (rs3781409) via TDT showed that the BMI-increasing allele T was nominally more frequently transmitted from biological parents in the group of patients with AN than non-transmitted (transmission rate (AN) = 60 %; p = 0.06). This result was not expected, since all other analyses showed association of the weight lowering allele and AN. However, the small sample size and thus power could lead to a spurious finding. No transmission distortion was detected in the obesity trios (transmission rate = 49 %; p = 0.61). Finally, we observed the presence of Ribeye-mRNA in the hypothalamus of wild-type mice, but not the presence of RIBEYE protein. That does not necessarily mean that RIBEYE is not expressed in the hypothalamus, as further factors could influence its expression. Further functional in vitro analyses are necessary to confirm the relevance of RIBEYE in body weight regulation.


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