Journal
MOLECULAR GENETICS AND METABOLISM
Volume 106, Issue 3, Pages 345-350Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymgme.2012.04.026
Keywords
Leptin receptor; OB-RGRP/endospanin-1; Epilepsy; Obesity; Auxilin-1
Funding
- FP7 EUROCHIP
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Centre National de la Recherche Scientifique (CNRS)
- Direction de l'Hospitalisation et de l'Organisation des Soins (DHOS)
- Fondation pour la Recherche Medicale
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Context: The genomic organization of the LEPR gene is complex and generates three independent transcripts whose respective functions are still poorly understood. Methods/results: We describe here a 7-year old patient with a homozygous 80 kb deletion in the chromosomal 1p31.3 region with early onset obesity, mental retardation and epilepsy. The deleted region comprises the proximal promoter and exons 1 and 2 of the LEPR gene and exons 5 to 19 of the DNAJC6 gene. The deletion leads to the deficiency of all canonical OB-R isoforms but maintains the B219 OB-R short isoforms controlled by the preserved second LEPR promoter. The DNAJC6 gene encodes auxilin-1, a protein required for clathrin-dependent recycling of synaptic vesicles in neurons that is possibly at the origin of the mental retardation and epilepsy phenotype. The obese phenotype and the absence of signaling-competent OB-R are consistent with previously reported individuals with OB-R deficiency. The deletion eliminates an additional transcript of the LEPR gene that encodes endospanin-1, a protein that has been genetically and biochemically linked to OB-R function. Conclusions: Our study confirms the phenotype of individuals with OB-R deficiency and postulates the effects of auxilin-1 deficiency (mental retardation/epilepsy) and endospanin-1 deficiency (OB-R specific functions) in humans. (C) 2012 Elsevier Inc. All rights reserved.
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