Relevance of polymorphisms in MC4R and BDNF in short normal stature

Abstract

BackgroundVariation 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.MethodsWe 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 χ2-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.ResultsWe 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.ConclusionTaken 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.Electronic supplementary materialThe online version of this article (10.1186/s12887-018-1245-1) contains supplementary material, which is available to authorized users.

Mouse models for V103I and I251L gain of function variants of the human MC4R display reduced adiposity and are not protected from a hypercaloric diet

“…Homozygous mutant females carrying V103I or I251L Mc4r alleles display shorter longitudinal growth, a phenotype also found in a recent association study performed in children carrying V103I MC4R variants [32]. Animal longitudinal length and human height are highly heritable polygenic traits, and although many genes contribute with a small percentage to the overall variation of human height there are some monogenic examples that produce relatively large effects, including MC4R.…”

Identification of p.Met215Ile mutation of the MC4R gene in a Moroccan woman with obesity

“…In addition, the p. Met215Ile has been cited in subjects with obesity and underweight. This mutation has already been described in a boy with underweight and short normal stature in Germany 33 and in a 14‐year‐old girl with morbid obesity of Latino ancestry (BMI = 57.50 kg/m 2 ). This girl developed obesity in the first months of her life and had hypertension, dyslipidemia, pre‐diabetes, hyperinsulinemia, and extensive acanthosis.…”

“… 36 According to Herrfurth et al, the methionine at position 215 is located in a critical region of the helix arrangements, which is modified during the receptor activation and is needed for binding G‐protein or arrestin. 33 Indeed, two major signaling conformations are adopted by the receptor, one of which couples almost exclusively to arrestin, while the other also couples effectively to G proteins. 37 A study reported that the TMs5/6 bundle could interact with arrestin through hydrogen bond contacts.…”

“…Some functional assays were performed to analyze the surface expression of the receptor, the response of cAMP to agonist binding, and the activation of ERK/MAPK signaling. 33 , 34 , 35 Herrfurth et al reported that this variant reduced cell surface expression by 80% compared to the wild‐type receptor. 33 The ligand‐activated cAMP accumulation was reduced following binding to NDP‐α‐MSH (a synthetic analog of α‐MSH) and required a 10‐fold higher concentration of α‐MSH compared to the wild‐type receptor.…”

“… 33 , 34 , 35 Herrfurth et al reported that this variant reduced cell surface expression by 80% compared to the wild‐type receptor. 33 The ligand‐activated cAMP accumulation was reduced following binding to NDP‐α‐MSH (a synthetic analog of α‐MSH) and required a 10‐fold higher concentration of α‐MSH compared to the wild‐type receptor. 33 , 34 , 35 In fact, the mutation resulted in reduced MC4R activity.…”