Genetic variants help define the role of the MC4R C-terminus in signaling and cell surface stability

Abstract Screening 92,445 subjects in the Geisinger-Regeneron DiscovEHR cohort, we identified 5 patients heterozygous for nonsense mutations causing early terminations at Glu307 or Leu328 on the C-terminus of melanocortin 4 receptor (MC4R). Two Q307Ter carriers are severely obese (BMI > 40), whil...

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Autores principales:	Bryn S. Moore, Tooraj Mirshahi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/496ef38961674a63aa1c9134ecbad95c
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spelling	oai:doaj.org-article:496ef38961674a63aa1c9134ecbad95c2021-12-02T15:07:44ZGenetic variants help define the role of the MC4R C-terminus in signaling and cell surface stability10.1038/s41598-018-28758-32045-2322https://doaj.org/article/496ef38961674a63aa1c9134ecbad95c2018-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-28758-3https://doaj.org/toc/2045-2322Abstract Screening 92,445 subjects in the Geisinger-Regeneron DiscovEHR cohort, we identified 5 patients heterozygous for nonsense mutations causing early terminations at Glu307 or Leu328 on the C-terminus of melanocortin 4 receptor (MC4R). Two Q307Ter carriers are severely obese (BMI > 40), while one is overweight (BMI > 25). One L328Ter carrier is overweight and the other is lean. Pedigree analysis for two Q307Ter carriers shows segregation of the variant with higher BMI. Functionally, MC4R(Q307Ter) eliminated receptor surface expression and signaling, while MC4R(L328Ter) functioned like the wild-type receptor. MC4R(Q307Ter) is therefore a loss of function (LOF) variant and the region between the two truncation sites identified in our patients is critical to MC4R function. Truncating MC4R at various C-terminal positions between these two variant sites, we find that cysteine318 sits at a critical junction for receptor trafficking and function. We show that MC4R is lipid modified at cysteine318 and cysteine319. Therefore, truncation early in the MC4R C-terminus results in haploinsufficiency in humans while truncation after the first lipid-modification site is well tolerated. MC4R haploinsufficiency clearly segregates with higher BMI; however, severe obesity is not fully penetrant even in MC4R LOF carriers, suggesting critical roles for environmental and lifestyle factors in MC4R monogenic obesity.Bryn S. MooreTooraj MirshahiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-8 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Bryn S. Moore Tooraj Mirshahi Genetic variants help define the role of the MC4R C-terminus in signaling and cell surface stability
description	Abstract Screening 92,445 subjects in the Geisinger-Regeneron DiscovEHR cohort, we identified 5 patients heterozygous for nonsense mutations causing early terminations at Glu307 or Leu328 on the C-terminus of melanocortin 4 receptor (MC4R). Two Q307Ter carriers are severely obese (BMI > 40), while one is overweight (BMI > 25). One L328Ter carrier is overweight and the other is lean. Pedigree analysis for two Q307Ter carriers shows segregation of the variant with higher BMI. Functionally, MC4R(Q307Ter) eliminated receptor surface expression and signaling, while MC4R(L328Ter) functioned like the wild-type receptor. MC4R(Q307Ter) is therefore a loss of function (LOF) variant and the region between the two truncation sites identified in our patients is critical to MC4R function. Truncating MC4R at various C-terminal positions between these two variant sites, we find that cysteine318 sits at a critical junction for receptor trafficking and function. We show that MC4R is lipid modified at cysteine318 and cysteine319. Therefore, truncation early in the MC4R C-terminus results in haploinsufficiency in humans while truncation after the first lipid-modification site is well tolerated. MC4R haploinsufficiency clearly segregates with higher BMI; however, severe obesity is not fully penetrant even in MC4R LOF carriers, suggesting critical roles for environmental and lifestyle factors in MC4R monogenic obesity.
format	article
author	Bryn S. Moore Tooraj Mirshahi
author_facet	Bryn S. Moore Tooraj Mirshahi
author_sort	Bryn S. Moore
title	Genetic variants help define the role of the MC4R C-terminus in signaling and cell surface stability
title_short	Genetic variants help define the role of the MC4R C-terminus in signaling and cell surface stability
title_full	Genetic variants help define the role of the MC4R C-terminus in signaling and cell surface stability
title_fullStr	Genetic variants help define the role of the MC4R C-terminus in signaling and cell surface stability
title_full_unstemmed	Genetic variants help define the role of the MC4R C-terminus in signaling and cell surface stability
title_sort	genetic variants help define the role of the mc4r c-terminus in signaling and cell surface stability
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/496ef38961674a63aa1c9134ecbad95c
work_keys_str_mv	AT brynsmoore geneticvariantshelpdefinetheroleofthemc4rcterminusinsignalingandcellsurfacestability AT toorajmirshahi geneticvariantshelpdefinetheroleofthemc4rcterminusinsignalingandcellsurfacestability
_version_	1718388445930323968

Genetic variants help define the role of the MC4R C-terminus in signaling and cell surface stability

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