Genetic association analysis of inositol polyphosphate phosphatase-like 1 (INPPL1, SHIP2) variants with essential hypertension

Marçano, Ana Carolina B.; Burke, Beverley; Gungadoo, Johannie; Wallace, Chris; Kaisaki, Pamela J.; Woon, Peng Yeong; Farrall, Martin; Clayton, David; Dominiczak, Anna F.; Connell, John; Webster, J; Lathrop, Mark; Caulfield, Mark; Samani, Nilesh J.; Guyader, Dominique; Munroe, Patricia B.

doi:10.1136/jmg.2007.049718

Cited by 16 publications

(9 citation statements)

References 15 publications

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“…For example, evidence from QTL mapping and analyses of knockouts implicates Tnfsf4 in diet-induced atherosclerosis in mice (Wang et al 2005b); however, genetic association studies have not provided consistent evidence for its involvement in humans (Koch et al 2008). Similar difficulties are found for the involvement of type II SH2 domain-containing inositol 5-phosphatase in the metabolic syndrome (Kaisaki et al 2004;Marcano et al 2007) and regulators of G protein signaling in anxiety (Fullerton et al 2008).…”

Section: How Much Does Genetic Architecture Vary Between Phenotypes?mentioning

confidence: 75%

Genetic architecture of quantitative traits in mice, flies, and humans

Flint¹,

Mackay²

2009

Genome Res.

404

364

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We compare and contrast the genetic architecture of quantitative phenotypes in two genetically well-characterized model organisms, the laboratory mouse, Mus musculus, and the fruit fly, Drosophila melanogaster, with that found in our own species from recent successes in genome-wide association studies. We show that the current model of large numbers of loci, each of small effect, is true for all species examined, and that discrepancies can be largely explained by differences in the experimental designs used. We argue that the distribution of effect size of common variants is the same for all phenotypes regardless of species, and we discuss the importance of epistasis, pleiotropy, and gene by environment interactions. Despite substantial advances in mapping quantitative trait loci, the identification of the quantitative trait genes and ultimately the sequence variants has proved more difficult, so that our information on the molecular basis of quantitative variation remains limited. Nevertheless, available data indicate that many variants lie outside genes, presumably in regulatory regions of the genome, where they act by altering gene expression. As yet there are very few instances where homologous quantitative trait loci, or quantitative trait genes, have been identified in multiple species, but the availability of high-resolution mapping data will soon make it possible to test the degree of overlap between species.Recent successes in mapping quantitative trait loci (QTLs) that contribute to phenotypic variation in humans and model organisms make it possible to address important questions about the genetic architecture of quantitative phenotypes, such as the likely number of loci, their mode of genetic action, and interaction with each other and with the environment. An understanding of the genetic architecture of quantitative traits is not only important in its own right, it will also inform studies that seek to proceed to the identification of the quantitative trait genes (QTGs) and the quantitative trait nucleotide (QTN) variants, the functional changes in DNA sequence that contribute to trait variation.In this work we use examples from two genetically wellcharacterized model organisms, the laboratory mouse, Mus musculus, and the fruit fly, Drosophila melanogaster, to discuss how an understanding of the genetic architecture of quantitative phenotypes in model organisms informs mapping experiments in human genetics. In our discussion of the latter, we draw upon the recent successful application of genome-wide association studies (GWAS) to both quantitative phenotypes (such as height and weight) and disease phenotypes (assuming that the genetic architecture of common disease is similar, if not identical, to that of quantitative phenotypes).Genetic architecture has been the subject of a number of recent reviews, most of which deal with information from a single model organism (Mackay 2004) or review a small number of phenotypes (Kendler and Greenspan 2006). Here, our purpose is different. We tackle three relate...

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Section: How Much Does Genetic Architecture Vary Between Phenotypes?mentioning

confidence: 75%

Genetic architecture of quantitative traits in mice, flies, and humans

Flint¹,

Mackay²

2009

Genome Res.

404

364

View full text Add to dashboard Cite

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“…Ship1−/− mice develop myeloproliferative syndrome (Helgason et al , 1998), a fact that has implications for immunity and leukemias (Kerr, 2011; Kerr et al , 2011). In contrast, studies of SHIP2 have linked its polymorphism to metabolic syndromes such as insulin resistance and hypertension (Kaisaki et al , 2004; Marcano et al , 2007; Marion et al , 2002). Taken together, diverse functions are expected from these 5’-phosphate enzymes.…”

Section: Diverse Functions Of Pi35p2 Kinases and Phosphatasesmentioning

confidence: 99%

Fig4 deficiency: A newly emerged lysosomal storage disorder?

Martyn

2013

Progress in Neurobiology

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FIG4 (Sac3 in mammals) is a 5’-phosphoinositide phosphatase that coordinates the turnover of phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2), a very low abundance phosphoinositide. Deficiency of FIG4 severely affects the human and mouse nervous systems by causing two distinct forms of abnormal lysosomal storage. The first form occurs in spinal sensory neurons, where vacuolated endolysosomes accumulate in perinuclear regions. A second form occurs in cortical/spinal motor neurons and glia, in which enlarged endolysosomes become filled with electron dense materials in a manner indistinguishable from other lysosomal storage disorders. Humans with a deficiency of FIG4 (known as Charcot-Marie-Tooth disease type 4J or CMT4J) present with clinical and pathophysiological phenotypes indicative of spinal motor neuron degeneration and segmental demyelination. These findings reveal a signaling pathway involving FIG4 that appears to be important for lysosomal function. In this review, we discuss the biology of FIG4 and describe how the deficiency of FIG4 results in lysosomal phenotypes. We also discuss the implications of FIG4/PI(3,5)P2 signaling in understanding other lysosomal storage diseases, neuropathies, and acquired demyelinating diseases.

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“…Additionally, transgenic mouse, overexpressing SHIP2, showed signs of mild insulin resistance (744). Higher levels of SHIP2 expression were found in the cerebral cortex of the db/db obese mice (1429), and SHIP2 gene polymorphisms have been linked to metabolic syndrome (746,991). A mouse strain lacking Ship2 (and the neighboring Phox2a gene) shows insulin hypersensitivity and severe hypoglycemia and has early neonatal mortality (271).…”

Section: Type III 5-phosphatasesmentioning

confidence: 99%

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Balla

2013

Physiological Reviews

1,329

1,655

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Phosphoinositides (PIs) make up only a small fraction of cellular phospholipids, yet they control almost all aspects of a cell's life and death. These lipids gained tremendous research interest as plasma membrane signaling molecules when discovered in the 1970s and 1980s. Research in the last 15 years has added a wide range of biological processes regulated by PIs, turning these lipids into one of the most universal signaling entities in eukaryotic cells. PIs control organelle biology by regulating vesicular trafficking, but they also modulate lipid distribution and metabolism via their close relationship with lipid transfer proteins. PIs regulate ion channels, pumps, and transporters and control both endocytic and exocytic processes. The nuclear phosphoinositides have grown from being an epiphenomenon to a research area of its own. As expected from such pleiotropic regulators, derangements of phosphoinositide metabolism are responsible for a number of human diseases ranging from rare genetic disorders to the most common ones such as cancer, obesity, and diabetes. Moreover, it is increasingly evident that a number of infectious agents hijack the PI regulatory systems of host cells for their intracellular movements, replication, and assembly. As a result, PI converting enzymes began to be noticed by pharmaceutical companies as potential therapeutic targets. This review is an attempt to give an overview of this enormous research field focusing on major developments in diverse areas of basic science linked to cellular physiology and disease.

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Genetic association analysis of inositol polyphosphate phosphatase-like 1 (INPPL1, SHIP2) variants with essential hypertension

Cited by 16 publications

References 15 publications

Genetic architecture of quantitative traits in mice, flies, and humans

Genetic architecture of quantitative traits in mice, flies, and humans

Fig4 deficiency: A newly emerged lysosomal storage disorder?

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

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