Functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B

Luoma, Leiah M.; Deeb, Taha; Macintyre, Georgina; Cox, Diane W.

doi:10.1002/humu.21228

Cited by 24 publications

(17 citation statements)

References 54 publications

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“…A number of studies have investigated whether these variants are really disease-causing mutations rather than rare normal variants, highlighting that ATP7B mutations in the same protein domain can have diverse functional effects. [29][30][31][32] Nevertheless, it is possible to evaluate the pathogenetic potential of our LD blocks using the Wilson Disease Mutation Database to calculate the density of For the descriptive characteristics p < 0.05 (*) and p < 0.01 (**) are considered significant, whereas for ATP7B genotypes p < 0.017 (*) and p < 0.003 (**) are significant according multiple test correction.…”

Section: Discussionmentioning

confidence: 99%

Linkage Disequilibrium and Haplotype Analysis of theATP7BGene in Alzheimer's Disease

Squitti

Polimanti

Bucossi

et al. 2013

Rejuvenation Research

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Copper dyshomeostasis leading to a labile Cu 2 + not bound to ceruloplasmin (''free'' copper) may influence Alzheimer's disease (AD) onset or progression. To investigate this hypothesis, we investigated ATP7B, the gene that controls copper excretion through the bile and concentrations of free copper in systemic circulation. Our study analyzed informative ATP7B single-nucleotide polymorphisms (SNPs) in a case-control population (n = 515). In particular, we evaluated the genetic structure of the ATP7B gene using the HapMap database and carried out a genetic association investigation. Linkage disequilibrium (LD) analysis highlighted that our informative SNPs and their LD SNPs covered 96% of the ATP7B gene sequence, distinguishing two ''strong LD'' blocks. The first LD block contains the gene region encoding for transmembrane and copper-binding, whereas the second LD block encodes for copper-binding domains. The genetic association analysis showed significant results after multiple testing correction for all investigated variants (rs1801243, odds ratio [OR] = 1.52, 95% confidence interval [CI] = 1.10-2.09, p = 0.010; rs2147363, OR = 1.58, 95% CI = 1.11-2.25, p = 0.010; rs1061472, OR = 1.73, 95% CI = 1.23-2.43, p = 0.002; rs732774, OR = 2.31, 95% CI = 1.41-3.77, p < 0.001), indicating that SNPs in transmembrane domains may have a stronger association with AD risk than variants in copper-binding domains. Our study provides novel insights that confirm the role of ATP7B as a potential genetic risk factor for AD. The analysis of ATP7B informative SNPs confirms our previous hypothesis about the absence of ATP7B in the significant loci of genome-wide association studies of AD and the genetic association study suggests that transmembrane and adenosine triphosphate (ATP) domains in the ATP7B gene may harbor variants/haplotypes associated with AD risk.

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Section: Discussionmentioning

confidence: 99%

Linkage Disequilibrium and Haplotype Analysis of theATP7BGene in Alzheimer's Disease

Squitti

Polimanti

Bucossi

et al. 2013

Rejuvenation Research

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“…A few metals like Ca 2+ and Mg 2+ which are similar in concentration in blood plasma and bile, may enter bile by a paracellular pathway by diffusion across the tight junctions (73). A P-type ATPase, ATP7B, is required for the biliary excretion of copper and is mutated in Wilson’s disease (98, 217, 345, 465, 544). This protein is localized to the trans -Golgi apparatus and nearby vesicles (241).…”

Section: Transport and Excretion Of Specific Substancesmentioning

confidence: 99%

Bile Formation and Secretion

Boyer

2013

Comprehensive Physiology

681

602

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Bile is a unique and vital aqueous secretion of the liver that is formed by the hepatocyte and modified down stream by absorptive and secretory properties of the bile duct epithelium. Approximately 5% of bile consists of organic and inorganic solutes of considerable complexity. The bile-secretory unit consists of a canalicular network which is formed by the apical membrane of adjacent hepatocytes and sealed by tight junctions. The bile canaliculi (~1 μm in diameter) conduct the flow of bile countercurrent to the direction of portal blood flow and connect with the canal of Hering and bile ducts which progressively increase in diameter and complexity prior to the entry of bile into the gallbladder, common bile duct, and intestine. Canalicular bile secretion is determined by both bile salt-dependent and independent transport systems which are localized at the apical membrane of the hepatocyte and largely consist of a series of adenosine triphosphate-binding cassette transport proteins that function as export pumps for bile salts and other organic solutes. These transporters create osmotic gradients within the bile canalicular lumen that provide the driving force for movement of fluid into the lumen via aquaporins. Species vary with respect to the relative amounts of bile salt-dependent and independent canalicular flow and cholangiocyte secretion which is highly regulated by hormones, second messengers, and signal transduction pathways. Most determinants of bile secretion are now characterized at the molecular level in animal models and in man. Genetic mutations serve to illuminate many of their functions.

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“…An increasing number of studies use the predicted impact in a variety of applications, and have reported that SNV impact predictions match experimental findings 130,132,133. Such applications include guiding mutagenesis,134,135 identifying disease associated genes in both Mendelian and common diseases,1,136–139 separating disease-causing variants from linkage disequilibrium variants,140 identifying somatic mutations that drive cancer,65,141,142 and predicting the overall phenotype of an organism 143.…”

Section: Applicationsmentioning

confidence: 99%

Single nucleotide variations: Biological impact and theoretical interpretation

Koire²,

et al. 2014

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Genome-wide association studies (GWAS) and whole-exome sequencing (WES) generate massive amounts of genomic variant information, and a major challenge is to identify which variations drive disease or contribute to phenotypic traits. Because the majority of known disease-causing mutations are exonic non-synonymous single nucleotide variations (nsSNVs), most studies focus on whether these nsSNVs affect protein function. Computational studies show that the impact of nsSNVs on protein function reflects sequence homology and structural information and predict the impact through statistical methods, machine learning techniques, or models of protein evolution. Here, we review impact prediction methods and discuss their underlying principles, their advantages and limitations, and how they compare to and complement one another. Finally, we present current applications and future directions for these methods in biological research and medical genetics.

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Functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B

Cited by 24 publications

References 54 publications

Linkage Disequilibrium and Haplotype Analysis of theATP7BGene in Alzheimer's Disease

Linkage Disequilibrium and Haplotype Analysis of theATP7BGene in Alzheimer's Disease

Bile Formation and Secretion

Single nucleotide variations: Biological impact and theoretical interpretation

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