University of Oulu

Loid P, Mustila T, Mäkitie RE, Viljakainen H, Kämpe A, Tossavainen P, Lipsanen-Nyman M, Pekkinen M and Mäkitie O (2020) Rare Variants in Genes Linked to Appetite Control and Hypothalamic Development in Early-Onset Severe Obesity. Front. Endocrinol. 11:81. doi: 10.3389/fendo.2020.00081

Rare variants in genes linked to appetite control and hypothalamic development in early-onset severe obesity

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Author: Loid, Petra1,2,3; Mustila, Taina4,5; Mäkitie, Riikka E.2,3,6;
Organizations: 1Children's Hospital, Helsinki University Hospital, Helsinki, Finland
2Folkhälsan Research Center, Genetics Research Program, Helsinki, Finland
3Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
4Department of Pediatrics, Seinäjoki Central Hospital, Seinäjoki, Finland
5City of Turku, Welfare Division, Preventive Healthcare, Turku, Finland
6Molecular Endocrinology Laboratory, Department of Medicine, Hammersmith Campus, Imperial College London, London, United Kingdom
7The Department of Food and Nutrition, University of Helsinki, Helsinki, Finland
8Department of Molecular Medicine and Surgery, Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
9Department of Children and Adolescents, PEDEGO Research Unit, University of Oulu, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.5 MB)
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Language: English
Published: Frontiers Media, 2020
Publish Date: 2020-05-08


Context: The hypothalamic circuit has an essential role in the regulation of appetite and energy expenditure. Pathogenic variants in genes involved in the hypothalamic leptin–melanocortin pathway, including melanocortin-4-receptor (MC4R), have been associated with monogenic obesity.

Objective: To determine the rate and spectrum of rare variants in genes involved in melanocortin pathway or hypothalamic development in patients with severe early-onset obesity (height-adjusted weight >60% before age 10 years).

Methods: We used a custom-made targeted exome sequencing panel to assess peripheral blood DNA samples for rare (minor allele frequency <0.5%), pathogenic/likely pathogenic variants in 24 genes related to the hypothalamic circuit in 92 subjects (51% males, median age 13.7 years) with early-onset severe obesity (median body mass index (BMI) Z-score + 4.0).

Results: We identified a novel frameshift deletion in MC4R (p.V103Afs5*) in two unrelated patients and a previously reported MC4R variant (p.T112M) in one patient. In addition, we identified rare heterozygous missense variants in ADCY3 (p.G1110R), MYT1L (p.R807Q), ISL1 (p.I347F), LRP2 (p.R2479I, and p.N3315S) and a hemizygous missense variant in GRPR (p.L87M) (each in one patient), possibly contributing to the obesity phenotype in these patients. Altogether 8% (7/92) of the subjects had rare pathogenic/likely pathogenic variants in the studied genes.

Conclusions:: Rare genetic variants within the hypothalamic circuit are prevalent and contribute to the development of severe early-onset obesity. Targeted exome sequencing is useful in identifying affected subjects. Further studies are needed to evaluate the variants’ clinical significance and to define optimal treatment.

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Series: Frontiers in endocrinology
ISSN: 1664-2392
ISSN-E: 1664-2392
ISSN-L: 1664-2392
Volume: 11
Article number: 81
DOI: 10.3389/fendo.2020.00081
Type of Publication: A1 Journal article – refereed
Field of Science: 3123 Gynaecology and paediatrics
3121 General medicine, internal medicine and other clinical medicine
Funding: This study was financially supported by the Academy of Finland; Sigrid Jusélius Foundation; Foundation for Pediatric Research; Folkhälsan Research Foundation; Päivikki ja Sakari Sohlberg Foundation; Stiftelsen Dorothea Olivia, Karl Walter och Jarl Walter Perkléns minne; Emil Aaltonen Foundation; Swedish Research Council; Novo Nordisk Foundation; University of Helsinki through the Doctoral Program in Clinical Research; Helsinki University Hospital research funds.
Copyright information: © 2020 Loid, Mustila, Mäkitie, Viljakainen, Kämpe, Tossavainen, Lipsanen-Nyman, Pekkinen and Mäkitie. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.