ESPE2019 Poster Category 1 Fat, Metabolism and Obesity (25 abstracts)
Pathogenic Mutations and Variants in KSR2 in a Cohort of Obese Children
Ingrid Körber 1 , Nadine Sowada 2 , Melanie Schirmer 1 , Gloria Herrmann 1 , Adriana Nunziata 1 , Martin Bald 3 , Stefan Ehehalt 4 , Ulrich Paetow 5 , Ute Ohlenschläger 5 , Hannah Rabenstein 2 , Reiner Siebert 2 , Julia von Schnurbein 1 & Martin Wabitsch 1
1Division of Paediatric Endocrinology and Diabetes, Department of Paediatric and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany. 2Institute of Human Genetics, University of Ulm, Ulm, Germany. 3Olga´s Children Hospital, Deparment of Paediatric Nephrology and Endocrinology, Klinikum Stuttgart, Stuttgart, Germany. 4Public Health Department, State Capital Stuttgart, Stuttgart, Germany. 5Division of Paediatric Endocrinology and Diabetology, Department of Paediatrics, University Hospital Frankfurt, Frankfurt, Germany
Background: Kinase suppressor of Ras 2 (KSR2) gene codes for a scaffold protein modulating intracellular pathways that involve MEK/BRAF cascade and AMPK signaling. KSR2 plays an important role in energy balance regulation, and KSR2 mutations were reported to be associated with obesity and insulin resistance in mice and humans. In transfected cells, several KSR2 mutations lead to impaired fatty acid oxidation, which improved under metformin treatment1.
Aim of the study: To report genotype and phenotype in obese children harboring KSR2 mutations in order to extend knowledge on clinical spectrum and therapeutic options in affected patients.
Patients and Methods: In n=88 children with suspected monogenic obesity, genetic panel analysis for known mutations in obesity-causing genes including the KSR2 gene (transcript ID ENST00000425217, NM0000173598.4) was performed. Three patients (Pat1-3) showing KSR2 mutations and seven patients showing KSR2 variants were identified. Genotype and phenotype were evaluated.
Results: In Pat1, who showed early-onset obesity (BMI>97th percentile (P) at 1 yr of age, >99.5th P from 7 yrs onward) compound heterozygosity for KSR2 missense mutations (p.Arg224Trp and p.Asp294Glu) was observed. Corresponding probably pathogenic mutations p.Arg253Trp*, p.Asp323Glu* have been previously reported1. Pat1 underwent bariatric surgery at age of 21 yrs, with postoperative impressive BMI improvement (preoperative BMI 50.8 kg/m2, postoperative BMI 34.8 kg/m2). Metformin therapy was interrupted after adverse gastrointestinal effects. Pat2 showed early-onset obesity (BMI> 97th P at 4 yrs of age, >99.5th P from 6 yrs onward). In Pat2, one heterozygous KSR2 missense mutation (p.Ala344Thr) was found. The corresponding pathogenic mutation p.Ala373Thr* was previously reported in one obese patient1. Pat2 started metformin treatment at age 17 yrs. Follow up is pending. In Pat3, aged 3 yrs, extreme weight increase despite diet restriction was observed. In this patient, one novel heterozygous KSR2 mutation (p.His536Tyr) was detected. Six patients showed the KSR2 variant p.Arg525Gln. One homozygous synonymous KSR2 variant p.Thr143Thr and one benigne heterozygous KSR2 variant p.Arg434Gln were observed in one additional patient.
Discussion: This is the first case study on KSR2 obesity patients since the initial report by Pearce et al. 20131. KSR2 mutations seem to be more frequent in obese children than previously suggested. Metformin treatment and bariatric surgery may be considered as therapeutic options in affected patients. For deeper understanding of pathogenic mechanisms in KSR2 related human obesity and evaluation of therapeutic approaches, further studies are needed.
Literature: Pearce et al., Cell. 2013;155(4):765-77, *transcript ID ENST00000339824
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