Heterozygous versus homozygous phenotype caused by the same MC4R mutation: novel mutation affecting a large consanguineous kindred
Abstract Background The hypothalamic G-protein-coupled-receptor melanocortin-4 receptor (MC4R) is a key player in the central circuit regulating energy expenditure and appetite. Heterozygous loss-of-function MC4R mutations are the most common known genetic cause of monogenic human obesity, with more...
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| Format: | Article |
| Language: | English |
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BMC
2018-08-01
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| Series: | BMC Medical Genetics |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12881-018-0654-1 |
| _version_ | 1818608137154854912 |
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| author | Max Drabkin Ohad S. Birk Ruth Birk |
| author_facet | Max Drabkin Ohad S. Birk Ruth Birk |
| author_sort | Max Drabkin |
| collection | DOAJ |
| description | Abstract Background The hypothalamic G-protein-coupled-receptor melanocortin-4 receptor (MC4R) is a key player in the central circuit regulating energy expenditure and appetite. Heterozygous loss-of-function MC4R mutations are the most common known genetic cause of monogenic human obesity, with more than 200 mutations described to date, affecting 2–3% of the population in various cohorts tested. Homozygous or compound heterozygous MC4R mutations are much less frequent, and only few families have been described in which heterozygotes and homozygotes of the same mutation are found. Methods We performed exome sequencing in a consanguineous Bedouin family with morbid obesity to identify the genetic cause of the disease. Clinical examination and biochemical assays were done to delineate the phenotype. Results We report the frequency of MC4R mutations in the large inbred Bedouin Israeli population. Furthermore, we describe consanguineous inbred Bedouin kindred with multiple individuals that are either homozygous or heterozygous carries of the same novel MC4R mutation (c.124G > T, p.E42*). All family members with the homozygous mutation exhibited morbid early-onset obesity, while heterozygote individuals had either a milder overweight phenotype or no discernable phenotype compared to wild type family members. While elder individuals homozygous or heterozygous for the MC4R mutation had abnormally high triglycerides, cholesterol, glucose and HbA1C levels, most did not. Conclusions MC4R mutation homozygotes exhibited morbid early-onset obesity, while heterozygotes had a significantly milder overweight phenotype. Whereas obesity due to MC4R mutations is evident as of early age – most notably in homozygotes, the metabolic consequences emerge only later in life. |
| first_indexed | 2024-12-16T14:37:51Z |
| format | Article |
| id | doaj.art-e8bdfa6e6ead4069bded4dd9b4b6bc7d |
| institution | Directory Open Access Journal |
| issn | 1471-2350 |
| language | English |
| last_indexed | 2024-12-16T14:37:51Z |
| publishDate | 2018-08-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medical Genetics |
| spelling | doaj.art-e8bdfa6e6ead4069bded4dd9b4b6bc7d2022-12-21T22:28:03ZengBMCBMC Medical Genetics1471-23502018-08-011911710.1186/s12881-018-0654-1Heterozygous versus homozygous phenotype caused by the same MC4R mutation: novel mutation affecting a large consanguineous kindredMax Drabkin0Ohad S. Birk1Ruth Birk2The Morris Kahn Laboratory of Human Genetics at the National Institute of Biotechnology in the Negev, Ben-Gurion University of the NegevThe Morris Kahn Laboratory of Human Genetics at the National Institute of Biotechnology in the Negev, Ben-Gurion University of the NegevDepartment of Nutrition, Faculty of Health Sciences, Ariel UniversityAbstract Background The hypothalamic G-protein-coupled-receptor melanocortin-4 receptor (MC4R) is a key player in the central circuit regulating energy expenditure and appetite. Heterozygous loss-of-function MC4R mutations are the most common known genetic cause of monogenic human obesity, with more than 200 mutations described to date, affecting 2–3% of the population in various cohorts tested. Homozygous or compound heterozygous MC4R mutations are much less frequent, and only few families have been described in which heterozygotes and homozygotes of the same mutation are found. Methods We performed exome sequencing in a consanguineous Bedouin family with morbid obesity to identify the genetic cause of the disease. Clinical examination and biochemical assays were done to delineate the phenotype. Results We report the frequency of MC4R mutations in the large inbred Bedouin Israeli population. Furthermore, we describe consanguineous inbred Bedouin kindred with multiple individuals that are either homozygous or heterozygous carries of the same novel MC4R mutation (c.124G > T, p.E42*). All family members with the homozygous mutation exhibited morbid early-onset obesity, while heterozygote individuals had either a milder overweight phenotype or no discernable phenotype compared to wild type family members. While elder individuals homozygous or heterozygous for the MC4R mutation had abnormally high triglycerides, cholesterol, glucose and HbA1C levels, most did not. Conclusions MC4R mutation homozygotes exhibited morbid early-onset obesity, while heterozygotes had a significantly milder overweight phenotype. Whereas obesity due to MC4R mutations is evident as of early age – most notably in homozygotes, the metabolic consequences emerge only later in life.http://link.springer.com/article/10.1186/s12881-018-0654-1MC4RObesityMutationHomozygousHeterozygous |
| spellingShingle | Max Drabkin Ohad S. Birk Ruth Birk Heterozygous versus homozygous phenotype caused by the same MC4R mutation: novel mutation affecting a large consanguineous kindred BMC Medical Genetics MC4R Obesity Mutation Homozygous Heterozygous |
| title | Heterozygous versus homozygous phenotype caused by the same MC4R mutation: novel mutation affecting a large consanguineous kindred |
| title_full | Heterozygous versus homozygous phenotype caused by the same MC4R mutation: novel mutation affecting a large consanguineous kindred |
| title_fullStr | Heterozygous versus homozygous phenotype caused by the same MC4R mutation: novel mutation affecting a large consanguineous kindred |
| title_full_unstemmed | Heterozygous versus homozygous phenotype caused by the same MC4R mutation: novel mutation affecting a large consanguineous kindred |
| title_short | Heterozygous versus homozygous phenotype caused by the same MC4R mutation: novel mutation affecting a large consanguineous kindred |
| title_sort | heterozygous versus homozygous phenotype caused by the same mc4r mutation novel mutation affecting a large consanguineous kindred |
| topic | MC4R Obesity Mutation Homozygous Heterozygous |
| url | http://link.springer.com/article/10.1186/s12881-018-0654-1 |
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