title: Functional and clinical relevance of novel and knownPCSK1variants for childhood obesity and glucose metabolism.
abstract: Variants inProprotein Convertase Subtilisin/Kexin Type 1(PCSK1) may be causative for obesity as suggested by monogenic cases and association studies. Here we assessed the functional relevance in experimental studies and the clinical relevance through detailed metabolic phenotyping of newly identified and knownPCSK1variants in children.
  
  
  
  In 52 obese children selected for elevated proinsulin levels and/or impaired glucose tolerance, we found eight known variants and two novel heterozygous variants (c.1095 + 1G > A and p.S24C) by sequencing thePCSK1gene. Patients with the new variants presented with extreme obesity, impaired glucose tolerance, and PCOS. Functionally, c.1095 + 1G > A caused skipping of exon8 translation and a complete loss of enzymatic activity. The protein was retained within the endoplasmic reticulum (ER) causing ER stress. The p.S24C variant had no functional effect on protein size, cell trafficking, or enzymatic activity. The known variants rs6230, rs35753085, and rs725522 in the 5' end did not affectPCSK1promoter activity. In clinical association studies in 1673 lean and obese children, we confirmed associations of rs6232 and rs6234 with BMI-SDS and of rs725522 with glucose stimulated insulin secretion and Matsuda index. We did not find the new variants in any other subjects.
  
  
  
  We identified and functionally characterized two rare novelPCSK1variants of which c.1095 + 1G > A caused complete loss of protein function. In addition to confirming rs6232 and rs6234 inPCSK1as polygenic risk variants for childhood obesity, we describe an association of rs725522 with insulin metabolism. Our results support the contribution ofPCSK1variants to obesity predisposition in children.
authors.affiliation: Center for Pediatric Research Leipzig, University Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany; Integrated Research and Treatment Center (IFB) Adiposity Diseases, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Löffler
authors.affiliation: Center for Pediatric Research Leipzig, University Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany; Integrated Research and Treatment Center (IFB) Adiposity Diseases, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Behrendt
authors.affiliation: Department of Human Genetics, University of Leuven, Leuven, Belgium.
authors.forename: John W M
authors.initials: JWM
authors.lastname: Creemers
authors.affiliation: Center for Pediatric Research Leipzig, University Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Klammt
authors.affiliation: Research Laboratories of the Department of Surgery, University of Leipzig, Leipzig, Germany.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Aust
authors.affiliation: Center for Pediatric Research Leipzig, University Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany; First Department of Pediatrics, Medical Faculty at Comenius University, Bratislava, Slovakia; DIABGENE Laboratory, Institute of Experimental Endocrinology, Biomedical Research Center SAS, Bratislava, Slovakia.
authors.forename: Juraj
authors.initials: J
authors.lastname: Stanik
authors.affiliation: Center for Pediatric Research Leipzig, University Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany.
authors.forename: Wieland
authors.initials: W
authors.lastname: Kiess
authors.affiliation: Integrated Research and Treatment Center (IFB) Adiposity Diseases, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kovacs
authors.affiliation: Center for Pediatric Research Leipzig, University Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany; Integrated Research and Treatment Center (IFB) Adiposity Diseases, Medical Faculty, University of Leipzig, Leipzig, Germany. Electronic address: antje.koerner@medizin.uni-leipzig.de.
authors.forename: Antje
authors.initials: A
authors.lastname: Körner
mesh_terms: D000293:Adolescent; D001786:Blood Glucose / Q000235:genetics; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance; D006801:Humans; D007328:Insulin / Q000235:genetics; D008297:Male; D063766:Pediatric Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D045664:Proprotein Convertase 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; C587576:PCSK1 protein, human; D045664:Proprotein Convertase 1; D005947:Glucose
keywords: Children; Obesity; PC1/3; PCSK1; Prohormone convertase 1/3