ESPE Abstracts (2018) 89 RFC6.4

Functionality and Phenotypic Characteristics of Mutations in the Human Leptin Receptor

Adriana Nunziataa, Jan-Bernd Funckea, Guntram Borckb, Julia von Schnurbeina, Belinda Lennerzc, Barbara Moeppsd, Peter Gierschikd, Pamela Fischer-Posovszkya & Martin Wabitscha


aDivision of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany; bInstitute of Human Genetics, University of Ulm, Ulm, Germany; cBoston Children’s Hospital, Division of Endocrinology & Harvard Medical School, Boston, Massachusetts, USA; dInstitute of Pharmacology and Toxicology, University of Ulm, Ulm, Germany


Objective: Merge and standardize the scarce data on molecular and phenotypic findings of mutations in the human leptin receptor (LEPR) gene causing a rare form of severe early-onset obesity.

Methods: We summarized functional and phenotypic traits of LEPR mutations reported in the literature in a structured and comprehensive manner. Additional data was obtained from 6 subjects of our outpatient clinic not reported so far. Functionality of mutations was assessed by reported in vitro-, in silico- and own analysis considering the type of mutation and clinical manifestations.

Results: In total 57 subjects with 38 distinct mutations in the LEPR were identified. Thirteen mutations led to a single amino acid change. Twenty-five deletions, duplications, insertions or nonsense mutations result in truncated LEPR proteins. Most mutations occurred in the Fibronectin(FN)-III and FN-III like subdomain of cytokine receptor homology(CRH) 2, none were located in the intracellular or transmembrane domain. In silico analysis were reported for 23 mutations. Functional data from in vitro experiments were available for four mutations, showing residual function in one. Considering clinical phenotype and character of respective mutations, we suspect residual function in five additional mutations. Summarizing clinical data, we found severe early-onset obesity, hyperphagia and hypogonadotropic hypogonadism to be cardinal features of a complete loss of LEPR function. In contrast, symptoms like recurring infections, altered growth, developmental delay and metabolic disorders were variable in manifestation but without obvious genotype-phenotype relationship. Only two subjects managed to regulate their weight due to an extremely restrictive and controlled lifestyle. Bariatric surgery was performed in six subjects and yield in weight loss below expectations. However, bariatric surgery seemed to support pubertal development and fertility.

Conclusion: Our results represent the first structured and comprehensive analysis of 57 subjects with 38 distinct LEPR gene mutations. Complete losses of LEPR function result in severe early-onset obesity, hyperphagia, and hypogonadotropic hypogonadism. Symptoms like recurring infections and metabolic disorders were variable in manifestation, but without obvious genotype-phenotype relationship. Considering clinical phenotype, available functional data and character of respective mutations we assume residual LEPR activity for 6 mutations.

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