TY  - GEN
A1  - Volckmar, Anna-Lena
A1  - Han, Chung-Ting
A1  - Pütter, Carolin
A1  - Haas, Stefan
A1  - Vogel, Carla I. G.
A1  - Knoll, Nadja
A1  - Struve, Christoph
A1  - Göbel, Maria
A1  - Haas, Katharina
A1  - Herrfurth, Nikolas
A1  - Jarick, Ivonne
A1  - Grallert, Harald
A1  - Schürmann, Annette
A1  - Al- Hasani, Hadi
A1  - Hebebrand, Johannes
A1  - Sauer, Sascha
A1  - Hinney, Anke
T1  - Analysis of genes involved in body weight regulation by targeted re-sequencing
T2  - PLoS ONE
N2  - Introduction

Genes involved in body weight regulation that were previously investigated in genome-wide association studies (GWAS) and in animal models were target-enriched followed by massive parallel next generation sequencing.

Methods

We enriched and re-sequenced continuous genomic regions comprising FTO, MC4R, TMEM18, SDCCAG8, TKNS, MSRA and TBC1D1 in a screening sample of 196 extremely obese children and adolescents with age and sex specific body mass index (BMI) >= 99th percentile and 176 lean adults (BMI <= 15th percentile). 22 variants were confirmed by Sanger sequencing. Genotyping was performed in up to 705 independent obesity trios (extremely obese child and both parents), 243 extremely obese cases and 261 lean adults.

Results and Conclusion

We detected 20 different non-synonymous variants, one frame shift and one nonsense mutation in the 7 continuous genomic regions in study groups of different weight extremes. For SNP Arg695Cys (rs58983546) in TBC1D1 we detected nominal association with obesity (p(TDT) = 0.03 in 705 trios). Eleven of the variants were rare, thus were only detected heterozygously in up to ten individual(s) of the complete screening sample of 372 individuals. Two of them (in FTO and MSRA) were found in lean individuals, nine in extremely obese. In silico analyses of the 11 variants did not reveal functional implications for the mutations. Concordant with our hypothesis we detected a rare variant that potentially leads to loss of FTO function in a lean individual. For TBC1D1, in contrary to our hypothesis, the loss of function variant (Arg443Stop) was found in an obese individual. Functional in vitro studies are warranted.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 423 
KW  - melanocortin-4 receptor gene
KW  - stimulated glucose-uptake
KW  - life-style intervention
KW  - onset extreme obesity
KW  - genome-wide analysis
KW  - mass index
KW  - FTO gene
KW  - fat mass
KW  - overweight children
KW  - diabetes-melllitus
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-410289
ER  - 
TY  - JOUR
A1  - Cui, Huanhuan
A1  - Schlesinger, Jenny
A1  - Schoenhals, Sophia
A1  - Toenjes, Martje
A1  - Dunkel, Ilona
A1  - Meierhofer, David
A1  - Cano, Elena
A1  - Schulz, Kerstin
A1  - Berger, Michael F.
A1  - Haack, Timm
A1  - Abdelilah-Seyfried, Salim
A1  - Bulyk, Martha L.
A1  - Sauer, Sascha
A1  - Sperling, Silke R.
T1  - Phosphorylation of the chromatin remodeling factor DPF3a induces cardiac hypertrophy through releasing HEY repressors from DNA
JF  - Nucleic acids research
N2  - DPF3 (BAF45c) is a member of the BAF chromatin remodeling complex. Two isoforms have been described, namely DPF3a and DPF3b. The latter binds to acetylated and methylated lysine residues of histones. Here, we elaborate on the role of DPF3a and describe a novel pathway of cardiac gene transcription leading to pathological cardiac hypertrophy. Upon hypertrophic stimuli, casein kinase 2 phosphorylates DPF3a at serine 348. This initiates the interaction of DPF3a with the transcriptional repressors HEY, followed by the release of HEY from the DNA. Moreover, BRG1 is bound by DPF3a, and is thus recruited to HEY genomic targets upon interaction of the two components. Consequently, the transcription of downstream targets such as NPPA and GATA4 is initiated and pathological cardiac hypertrophy is established. In human, DPF3a is significantly up-regulated in hypertrophic hearts of patients with hypertrophic cardiomyopathy or aortic stenosis. Taken together, we show that activation of DPF3a upon hypertrophic stimuli switches cardiac fetal gene expression from being silenced by HEY to being activated by BRG1. Thus, we present a novel pathway for pathological cardiac hypertrophy, whose inhibition is a long-term therapeutic goal for the treatment of the course of heart failure.
Y1  - 2016
U6  - https://doi.org/10.1093/nar/gkv1244
SN  - 0305-1048
SN  - 1362-4962
VL  - 44
SP  - 2538
EP  - 2553
PB  - Oxford Univ. Press
CY  - Oxford
ER  -