Single-Nucleotide Variants in Trace Amine-Associated Receptor 1 May Predispose for Disturbed Glucose Homeostasis

Presentation Number: SUN 268
Date of Presentation: April 2nd, 2017

Heike Biebermann*1, Jessica Mühlhaus2, Alexander Teumer3, Georg Homuth4, Peter Kühnen2, Susanna Wiegand5, Annette Grüters6, Klemens Raile7, Henry Völzke8, Gunnar Kleinau2 and Heiko Krude2
1Charité Universitätsmedizin Berl, 13353 Berlin, Germany, 2Charité - Universitätsmedizin Berlin Campus Virchow, Berlin, Germany, 33Interfaculty Institute for Genetics and Functional Genomics, Greifswald, Germany, 4Interfaculty Institute for Genetics and Functional Genomics, Greifswald, Germany, 5Charite University Medicine, Berlin, Germany, 6Department for Pediatric Endocrinology and Diabetes, 7Department of endocrinology and Diabetes, Berlin, Germany, 8Institute for Community Medicine, University Medicine Greifswald, Germany

Abstract

3-iodothyronamine is a thyroid hormone derivative that can act via activation of trace amine-associated receptor 1 (TAAR1). So far in humans no physiological function of the 3-T1AM/TAAR1 system was described. Activation of TAAR1 in endocrine pancreas is involved in weight regulation and glucose homeostasis. The purpose of this study was the identification and characterization of TAAR1 variants in patients with overweight/obesity and disturbed glucose homeostasis. Screening for TAAR1 variants was performed in 314 obese or overweight patients with impaired insulin secretion. The detected variants were functionally characterized in regards to TAAR1 cell surface expression and signaling properties and their allele frequencies were determined in the population-based Study of Health in Pomerania (SHIP).

Three heterozygous carriers of the single nucleotide missense variants p.Arg23Cys (R23C, rs8192618), p.Ser49Leu (S49L, rs140960896), and p.Ille171Leu (I171L, rs20079534) were detected in the patient cohort. While S49L and I171L were found in obese/overweight patients with slightly impaired glucose homeostasis, R23C was identified in a patient with complete loss of insulin production. Functional in vitro characterization revealed a partial loss-of-function for S49L and a complete loss-of-function for R23C. The frequency of the R23C mutation in 2018 non-diabetic control individuals aged 60 years and older in the general population-based SHIP cohort was lower than in the analyzed patient sample. Both variants are rare in the general population indicating a recent origin in the general gene pool and/ or the consequence of pronounced purifying selection, in line with the obvious detrimental effect of the mutations. Our study provides first evidence for the existence of naturally-occurring TAAR1 variants with potential relevance for weight regulation and glucose homeostasis.

 

Nothing to Disclose: HB, JM, AT, GH, PK, SW, AG, KR, HV, GK, HK