Herrfurth Nikolas, Volckmar Anna-Lena, Peters Triinu, Kleinau Gunnar, Müller Anne, Cetindag Cigdem, Schonnop Laura, Föcker Manuel, Dempfle Astrid, Wudy Stefan A, Grant Struan F A, Reinehr Thomas, Cousminer Diana L, Hebebrand Johannes, Biebermann Heike, Hinney Anke
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Institute of Experimental Pediatric Endocrinology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
BMC Pediatr. 2018 Aug 22;18(1):278. doi: 10.1186/s12887-018-1245-1.
Variation in genes of the leptinergic-melanocortinergic system influence both body weight and height. Because short normal stature (SNS) is characterized by reduced body height, delayed maturation and leanness, allelic variation of genes in this pathway are hypothesized to affect this common condition.
We analyzed the coding regions of LEP, MC4R, MRAP2 and BDNF in 185 children with SNS (height < 5th percentile) to search for non-synonymous and frameshift variants. For association studies (two-sided χ-tests) population-based data sets (ExAC, EVS and KORA) were used. Cyclic AMP accumulation, cell surface expression, central expression and MAP kinase activation were assayed in vitro to determine the functional implications of identified variants.
We detected eleven variants predicted to be protein-altering, four in MC4R, four in BDNF, and three in MRAP2. No variants were found in LEP. In vitro analysis implied reduced function for the MC4R variant p.Met215Ile. Loss-of-function is contrary to expectations based on obesity studies, and thus does not support that this variant is relevant for SNS. The minor SNP alleles at MC4R p.Val103Ile and BDNF p.Val66Met were nominally associated with SNS.
Taken together, although genes of the leptinergic-melanocortinergic system are important for normal growth, our data do not support the involvement of rare mutations in LEP, MC4R, MRAP2 or BDNF in short normal stature.
瘦素-促黑素系统基因的变异会影响体重和身高。由于正常身材矮小（SNS）的特征是身高降低、成熟延迟和体型偏瘦，因此推测该途径中基因的等位基因变异会影响这种常见情况。
我们分析了185名SNS儿童（身高<第5百分位数）的LEP、MC4R、MRAP2和BDNF的编码区，以寻找非同义变异和移码变异。对于关联研究（双侧χ检验），使用了基于人群的数据集（ExAC、EVS和KORA）。在体外测定环磷酸腺苷积累、细胞表面表达、中枢表达和丝裂原活化蛋白激酶激活，以确定所鉴定变异的功能影响。
我们检测到11个预计会改变蛋白质的变异，其中4个在MC4R中，4个在BDNF中，3个在MRAP2中。在LEP中未发现变异。体外分析表明MC4R变异p.Met215Ile功能降低。功能丧失与基于肥胖研究的预期相反，因此不支持该变异与SNS相关。MC4R p.Val103Ile和BDNF p.Val66Met的次要SNP等位基因与SNS名义上相关。
综上所述，尽管瘦素-促黑素系统基因对正常生长很重要，但我们的数据不支持LEP、MC4R、MRAP2或BDNF中的罕见突变参与正常身材矮小的发生。
