Implication of Chromosome 18 in Hypertension by Sibling Pair and Association Analyses

Guzmán, Blanca; Cormand, Bru; Ribasés, Marta; González-Núñez, Daniel; Botey, A; Poch, Esteban

doi:10.1161/01.hyp.0000244085.52918.a0

Cited by 23 publications

(21 citation statements)

References 37 publications

(52 reference statements)

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“…However, the molecular mechanisms of MEX-3 and PEM-3 functions remain to be elucidated. In humans, MEX3D (also known as TINO or RKHD1) has been shown to destabilize BCL2 mRNA by binding to its ARE (Donnini et al, 2004), and MEX3C (also known as RKHD2) is putatively involved in the congenital human disease 'essential hypertension' (Guzman et al, 2006). However, the developmental role of mex3 genes in vertebrate embryos has not yet been investigated, and the existence of the 3ЈLCU has not been reported.…”

Section: Introductionmentioning

confidence: 99%

The RNA-binding protein Mex3b has a fine-tuning system for mRNA regulation in earlyXenopusdevelopment

et al. 2009

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Post-transcriptional control by RNA-binding proteins is a precise way to assure appropriate levels of gene expression. Here, we identify a novel mRNA regulatory system involving Mex3b (RKHD3) and demonstrate its role in FGF signaling. mex3b mRNA has a 3Ј long conserved UTR, named 3ЈLCU, which contains multiple elements for both mRNA destabilization and translational enhancement. Notably, Mex3b promotes destabilization of its own mRNA by binding to the 3ЈLCU, thereby forming a negative autoregulatory loop. The combination of positive regulation and negative autoregulation constitutes a fine-tuning system for posttranscriptional control. In early embryogenesis, Mex3b is involved in anteroposterior patterning of the neural plate. Consistent with this, Mex3b can attenuate FGF signaling and destabilize mRNAs for the FGF signaling components Syndecan 2 and Ets1b through their 3Ј UTRs. These data suggest that the 3ЈLCU-mediated fine-tuning system determines the appropriate level of mex3b expression, which in turn contributes to neural patterning through regulating FGF signaling.

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Section: Introductionmentioning

confidence: 99%

The RNA-binding protein Mex3b has a fine-tuning system for mRNA regulation in earlyXenopusdevelopment

et al. 2009

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“…Linkage analysis and association studies suggest that MEX3C contributes to genetic susceptibility of hypertension (21), although the mechanism is unknown. Recently, we reported that Mex3c mutation in mice causes growth retardation due to IGF1 deficiency in developing bone (26).…”

mentioning

confidence: 99%

Mex3c Mutation Reduces Adiposity and Increases Energy Expenditure

Jiao

George

Zhao

et al. 2012

Molecular and Cellular Biology

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bThe function of MEX3C, the mammalian homolog of Caenorhabditis elegans RNA-binding protein muscle excess 3 (MEX-3), was unknown until our recent report that MEX3C is necessary for normal postnatal growth and enhances the expression of local bone Igf1 expression. Here we report the pivotal role of Mex3c in energy balance regulation. Mex3c mutation caused leanness in both heterozygous and homozygous transgenic mice, as well as a more beneficial blood glucose and lipid profile in homozygous transgenic mice, in both sexes. Although transgenic mice showed normal food intake and fecal lipid excretion, they had increased energy expenditure independent of physical activity. Mutant mice had normal body temperature, Ucp1 expression in brown adipose tissue, and muscle and liver fatty acid oxidation. Mex3c is expressed in neurons and is detectable in the arcuate nucleus, the ventromedial nucleus, and the dorsomedial nucleus of the hypothalamus. Mex3c was not detected in NPY or POMC neurons but was detected in leptin-responsive neurons in the ventromedial nucleus. Mex3c and Leptin double mutant mice were growth retarded and obese and had blood profiles similar to those of ob/ob mice but showed none of the steatosis observed in ob/ob mice. Our data show that Mex3c is involved in energy balance regulation. Caenorhabditis elegans MEX-3 is an hnRNP K homology (KH) domain-containing RNA-binding protein regulating RNA targets such as pal-1 (13, 22, 23), rme-2 (6), and nos-2 (25). It is involved in the cell fate specification process in C. elegans and in totipotency maintenance of the germ line in adult worms (7,13,23,40). Human and mouse genomes encode four MEX-3 homologues: MEX3A, MEX3B, MEX3C, and MEX3D (3). They all have two KH RNA-binding domains at the N terminus which are also present in the C. elegans homolog and a zinc finger (ZNF) domain at the C terminus which is absent in MEX-3 in C. elegans. MEX3A and MEX3B colocalize with decapping factor DCP1a and Argonaute proteins in processing bodies (3), and the localization of MEX3B is regulated by 14-3-3 protein (9). MEX3D, once called TINO, is a BCL2 mRNA AU-rich element-binding protein that negatively regulates the stability of BCL2 mRNA (12).Mouse MEX3C is 99% identical to human, chimpanzee, and bovine MEX3Cs. Linkage analysis and association studies suggest that MEX3C contributes to genetic susceptibility of hypertension (21), although the mechanism is unknown. Recently, we reported that Mex3c mutation in mice causes growth retardation due to IGF1 deficiency in developing bone (26). Mex3c is highly expressed in resting and proliferating chondrocytes, and IGF1 protein expression in these cells of mutant mice is significantly reduced, although Igf1 mRNA expression in bones from mutant mice is not changed. In the C57BL/6 background, 85% of homozygous mutant pups die soon after birth, whereas in the FVB/N background, about 80% of the pups survive to adulthood, although they are still growth retarded. Mutant male and female mice are fertile, although Mex3c is highly expressed i...

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“…The mechanistic involvement of RKHD1 with hypertension is not understood. 15 In a study of 2142 sibling pairs with evidence of linkage for hypertension on 5q13, the subsequent TDT (transmission disequilibrium test; association test controlling for family background) analysis revealed only borderline-significant evidence (PϽ0.07) for linkage and association at marker D5S2019 on 5q13, suggesting that this region may harbor a susceptibility gene with modest effects on hypertension. 16 In the FBPP, linkage and subsequent positional candidate-based association studies demonstrated that chromosome 1q contains at least 3 genes associated with BP: ATP1B1, RGS5, and SELE.…”

Section: Genome-wide Linkage Studies: From Chromosomal Regions To Susmentioning

confidence: 99%

“…In the case of candidate genetic locus studies, the rationale for involvement of a specific gene product in hypertension may be apparent, whereas in hypothesis-free, genome-wide linkage or association studies, establishing the responsible variant in the associated chromosomal interval may be challenging. 15 Particular problems in the linkage or association studies of the hereditary basis of complex traits (including hypertension) include likely phenotypic and genetic heterogeneity, complicated by problematic statistical power, sometimes resulting in inconsistent results or lack of replication.…”

Section: Human Genetic Study Designsmentioning

confidence: 99%