Melanocortin-3 receptor gene variants in a Maori kindred with obesity and early onset type 2 diabetes

Wong, Jencia; Love, Donald R.; Kyle, Campbell; Daniels, A.; White, Marie; Stewart, Alistair; Schnell, Audrey H.; Elston, Robert C.; Holdaway, I. M.; Mountjoy, Kathleen G.

doi:10.1016/s0168-8227(02)00126-2

Cited by 31 publications

(23 citation statements)

References 36 publications

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“…In this report we provide evidence that not ATG1 but ATG2 is the preferred start ATG for the human MC3R, resulting in a 37 amino acid shorter protein at least in COS-7 cells. This finding is of importance since the association of single nucleotide polymorphisms (SNP) in the coding region of the MC3R with obesity is discussed [10,11,12,13,14]. One of these SNPs, T6K, is located between these two ATGs.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we showed that a common variant C17A (T6K) does not influence the translation initiation in vitro; however, we cannot rule out that C17A influences mRNA stability. This underlines the lack of association of this variant with obesity and related diseases in humans in most studies [10], [12], [13]. …”

Section: Discussionmentioning

confidence: 99%

“…So far, only few MC3R mutations with functional relevance were identified [6,7,8,9]. However, numerous studies investigated the association of two frequent MC3R variants with obesity or diabetes in various collectives [10,11,12,13,14]. These variants are located in the coding region and lead to amino acid exchanges T6K (nt C17A) and V81I (nt G241A) and the double mutant T6K/V81I.…”

Section: Introductionmentioning

confidence: 99%

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Identification of the Translation Start Site of the Human Melanocortin 3 Receptor

Tarnow

Rediger²,

Schulz³

et al. 2012

Obes Facts

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Background: The melanocortin-3-receptor (MC3R) is a G-protein coupled receptor participating in hypothalamic energy metabolism. So far, it was assumed that the translation of the human MC3R starts at the non-conserved first ATG, however, a second evolutionary conserved ATG is located 37 amino acids downstream. One frequent polymorphism, T6K, is located between these two ATGs. Methods: For characterization of the two potential start ATGs, COS-7 cells were transfected with plasmids encoding the longer and the shorter form of the human MC3R. For signal transduction properties, cAMP was measured. Cell surface expression was determined by using an ELISA method. The translational start point of the MC3R was investigated by a GFP-based method. Results: Signal transduction was comparable for the long and the short receptor form. Cell surface expression via aminoterminal hemagglutinin tag could only be detected in the shorter form, but not in the longer one. In our study we show that the translation of the human MC3R protein starts at the evolutionary conserved ATG codon which results in a shorter protein than previously assumed. Conclusion: The polymorphism T6K is not located in the coding region of the human MC3R and has no influence on translation initiation which makes an impact on body weight unlikely.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of the Translation Start Site of the Human Melanocortin 3 Receptor

Tarnow

Rediger²,

Schulz³

et al. 2012

Obes Facts

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“…N-terminal FLAG tagged receptor activity modifying protein 1 (RAMP1) in pcDNA 3.1 was a gift. hMC1R, hMC2R, hMC3R, hMC4R and hMC5R in pcDNA Neo, hMRAPa-FLAG in pcDNA 3.1, mMRAPa-FLAG in pcDNA 3.1 and HA-tagged hCL in pcDNA 3.1 have previously been described (Mountjoy et al 1992, 1994, McLatchie et al 1998, Wong et al 2002, Xu et al 2002, Kay et al 2013.…”

Section: Construction Of Recombinant Dnasmentioning

confidence: 97%

hMRAPa increases αMSH-induced hMC1R and hMC3R functional coupling and hMC4R constitutive activity

Kay

Botha

Montgomery

et al. 2013

Journal of Molecular Endocrinology

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Human melanocortin 2 receptor accessory protein (hMRAPa) is hypothesised to have functions beyond promoting human melanocortin 2 receptor (hMC2R) functional expression. To understand these potential functions, we exogenously co-expressed hMRAPa-FLAG with each of the five hMCR subtypes in HEK293 cells and assessed hMCR subtype coupling to adenylyl cyclase. We also co-expressed each HA-hMCR subtype with hMRAPa-FLAG to investigate their subcellular localisation. hMRAPa-FLAG enhanced a-melanocyte stimulating hormone (a-MSH)-stimulated hMC1R and hMC3R but reduced NDP-a-MSH-stimulated hMC5R, maximum coupling to adenylyl cyclase. hMRAPa-FLAG specifically increased hMC4R constitutive coupling to adenylyl cyclase despite not co-localising with the HA-hMC4R in the cell membrane. hMRAPa-FLAG co-localised with HA-hMC1R or HA-hMC3R in the perinuclear region, in cytoplasmic vesicles and at the plasma membrane, while it co-localised with HA-hMC2R, HA-hMC4R and HA-hMC5R predominantly in cytoplasmic vesicles. These diverse effects of hMRAPa indicate that hMRAPa could be an important modulator of the central and peripheral melanocortin systems if hMRAPa and any hMCR subtype co-express in the same cell. Key Words" GPCR accessory protein " constitutive activity " subcellular localisation " melanocortin 4 receptor

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“…If as Jackson suggests, Māori health needs arise as a consequence of their indigenous rights being breached, will Māori health improve with the reinstatement of such rights? Likewise it is naïve to argue that genetic differences are not likely to be part of the complex contributory factors for racial inequities in New Zealand when, for example, this is clearly untrue in the light of research that shows melanocortin-3 receptor gene variants in Māori are linked to obesity and the early onset of type 2 diabetes [28][29][30][31][32]. When seeking the reason why health inequity exists in New Zealand today it is not helpful to pound the colonisation drum.…”

Section: Racial Inequities In Cardiovascular Disease In New Zealandmentioning

confidence: 99%

Racial Inequities in Cardiovascular Disease in New Zealand

Miner-Williams¹

2017

Divers Equal Health Care

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The literature is replete with studies pertaining to ethnic inequities in healthcare. A thorny subject that has been described for decades and yet has few remedial solutions. The pattern of ethnic inequities in healthcare is a global phenomenon that is not confined to any specific race or culture. Worldwide, cardiovascular disease (CVD) is the topmost cause of death and a substantial burden on healthcare resources. In New Zealand CVD is the leading cause of death, accounting for 40% of all deaths annually. Diminished life expectancy is one example of racial inequity in healthcare between Māori and Pākehā (the non-indigenous population). This review attempts to clarify the muddy waters of 175 years of post-colonial healthcare inequity in New Zealand and in particular the causes of inequity in the incidence of CVD and mortality in Māori. Such dialogue will hopefully stimulate discussion among policy makers and clinicians to redress the ethnic inequities in healthcare.

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Melanocortin-3 receptor gene variants in a Maori kindred with obesity and early onset type 2 diabetes

Cited by 31 publications

References 36 publications

Identification of the Translation Start Site of the Human Melanocortin 3 Receptor

Identification of the Translation Start Site of the Human Melanocortin 3 Receptor

hMRAPa increases αMSH-induced hMC1R and hMC3R functional coupling and hMC4R constitutive activity

Racial Inequities in Cardiovascular Disease in New Zealand

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