Showing papers on "Mutation (genetic algorithm) published in 2013"

Heritable gene targeting in the mouse and rat using a CRISPR-Cas system

Abstract: To the Editor: CRISPR-Cas systems have been developed as an efficient gene editing technology in cells and model organisms. Here we use a CRISPR-Cas system to induce genomic DNA fragment deletion in mice by coinjecting two single-guide RNAs (sgRNAs) targeting the Uhrf2 locus with Cas9 mRNA. Furthermore, we report the generation of a Mc3R and Mc4R double-gene knockout rat by means of a single microinjection. High germline-transmission efficiency was observed in both mice and rats. The clustered, regularly interspaced, short palindromic repeats (CRISPR)associated protein (Cas) system has evolved in bacteria and archaea as an RNA-based adaptive immune system against viral and plasmid invasion1. Based on gene conservation and locus organization, three major types of CRISPR systems have been identified2,3. In the type II systems, the complex of a CRISPR RNA (crRNA) annealed to a trans-activating crRNA (tracrRNA) is sufficient to guide the Cas9 endonuclease to a specific genomic sequence to generate double-strand breaks in target DNA4. Previous studies established a strategy for multiplex genome engineering with the Cas9 RNA-guided endonuclease in mammalian cells5,6. Recently, efficient genome editing by the CRISPR-Cas system has been shown in multiple organisms, including zebrafish, mice and bacteria7–9. Several groups have demonstrated that compared with zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), CRISPR-Cas–mediated gene targeting has similar or greater efficiency in cells and zebrafish5–7,10. Although it has been demonstrated that multiple genes can be disrupted in individual mouse embryos using CRISPR-Cas–mediated systems9, germline transmission of Cas9-mediated mutations in animals has not yet been reported. In addition, whether long, specific, genomic DNA target fragments

GA: A Package for Genetic Algorithms in R

Abstract: Genetic algorithms (GAs) are stochastic search algorithms inspired by the basic principles of biological evolution and natural selection. GAs simulate the evolution of living organisms, where the fittest individuals dominate over the weaker ones, by mimicking the biological mechanisms of evolution, such as selection, crossover and mutation. GAs have been successfully applied to solve optimization problems, both for continuous (whether differentiable or not) and discrete functions. This paper describes the R package GA, a collection of general purpose functions that provide a flexible set of tools for applying a wide range of genetic algorithm methods. Several examples are discussed, ranging from mathematical functions in one and two dimensions known to be hard to optimize with standard derivative-based methods, to some selected statistical problems which require the optimization of user defined objective functions. (This paper contains animations that can be viewed using the Adobe Acrobat PDF viewer.)

Mutation research/fundamental and molecular mechanisms of mutagenesis: special issue: DNA repair and genetic instability.

Abstract: Ionizing radiation (IR) induces DNA strand breaks leading to cell death or deleterious genome rearrangements. In the present study, we examined the role of N-acetyl-L-cysteine (NAC), a clinically proven safe agent, for it’s ability to protect against -ray-induced DNA strand breaks and/or DNA deletions in yeast andmammals. In the yeast Saccharomyces cerevisiae, DNA deletions were scored by reversion to histidine prototrophy. Human lymphoblastoid cells were examined for the frequency of -H2AX foci formation, indicative of DNA double strand break formation. DNA strand breaks were also measured in mouse peripheral blood by the alkaline comet assay. In yeast, NAC reduced the frequency of IR-induced DNA deletions. However, NAC did not protect against cell death. NAC also reduced -H2AX foci formation in human lymphoblastoid cells but had no protective effect in the colony survival assay. NAC administration via drinking water fully protected against DNA strand breaks in mice whole-body irradiated with 1Gy but not with 4Gy. NAC treatment in the absence of irradiation was not genotoxic. These data suggest that, given the safety and efficacy of NAC in humans, NAC may be useful in radiation therapy to prevent radiation-mediated genotoxicity, but does not interfere with efficient cancer cell killing. © 2009 Published by Elsevier B.V.

Acquired Resistance to Crizotinib from a Mutation in CD74–ROS1

Abstract: Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), has also recently shown efficacy in the treatment of lung cancers with ROS1 translocations. Resistance to crizotinib developed in a patient with metastatic lung adenocarcinoma harboring a CD74– ROS1 rearrangement who had initially shown a dramatic response to treatment. We performed a biopsy of a resistant tumor and identified an acquired mutation leading to a glycine-to-arginine substitution at codon 2032 in the ROS1 kinase domain. Although this mutation does not lie at the gatekeeper residue, it confers resistance to ROS1 kinase inhibition through steric interference with drug binding. The same resistance mutation was observed at all the metastatic sites that were examined at autopsy, suggesting that this mutation was an early event in the clonal evolution of resistance. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.)

Differential Evolution With Ranking-Based Mutation Operators

Abstract: Differential evolution (DE) has been proven to be one of the most powerful global numerical optimization algorithms in the evolutionary algorithm family. The core operator of DE is the differential mutation operator. Generally, the parents in the mutation operator are randomly chosen from the current population. In nature, good species always contain good information, and hence, they have more chance to be utilized to guide other species. Inspired by this phenomenon, in this paper, we propose the ranking-based mutation operators for the DE algorithm, where some of the parents in the mutation operators are proportionally selected according to their rankings in the current population. The higher ranking a parent obtains, the more opportunity it will be selected. In order to evaluate the influence of our proposed ranking-based mutation operators on DE, our approach is compared with the jDE algorithm, which is a highly competitive DE variant with self-adaptive parameters, with different mutation operators. In addition, the proposed ranking-based mutation operators are also integrated into other advanced DE variants to verify the effect on them. Experimental results indicate that our proposed ranking-based mutation operators are able to enhance the performance of the original DE algorithm and the advanced DE algorithms.

Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits

Abstract: Analysis of whole-genome sequence data of Icelandic individuals has revealed a rare nonsense mutation within the LGR4 gene that is strongly associated with, among other things, low bone mineral density, late onset of menarche, and increased risk of biliary tract cancer. A search through whole-genome sequence data from thousands of Icelandic individuals for variants that may have a direct effect on the risk of pathologically low bone mineral density has identified a rare nonsense mutation that associates with a wide range of phenotypes in addition to those related to bone physiology. The mutation, found within the leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) gene, is strongly associated with osteoporotic fractures, and also with electrolyte imbalance, hormonal imbalance and an increased risk of squamous cell carcinoma of the skin and biliary tract cancer. The phenotype of carriers of this mutation overlaps with that of Lgr4 knockout mice. Low bone mineral density (BMD) is used as a parameter of osteoporosis. Genome-wide association studies of BMD have hitherto focused on BMD as a quantitative trait, yielding common variants of small effects that contribute to the population diversity in BMD1,2,3,4,5,6,7. Here we use BMD as a dichotomous trait, searching for variants that may have a direct effect on the risk of pathologically low BMD rather than on the regulation of BMD in the healthy population. Through whole-genome sequencing of Icelandic individuals, we found a rare nonsense mutation within the leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) gene (c.376C>T) that is strongly associated with low BMD, and with osteoporotic fractures. This mutation leads to termination of LGR4 at position 126 and fully disrupts its function. The c.376C>T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer. Interestingly, the phenotype of carriers of the c.376C>T mutation overlaps that of Lgr4 mutant mice.

Mutation rate dynamics in a bacterial population reflect tension between adaptation and genetic load.

Abstract: Mutations are the ultimate source of heritable variation for evolution. Understanding how mutation rates themselves evolve is thus essential for quantitatively understanding many evolutionary processes. According to theory, mutation rates should be minimized for well-adapted populations living in stable environments, whereas hypermutators may evolve if conditions change. However, the long-term fate of hypermutators is unknown. Using a phylogenomic approach, we found that an adapting Escherichia coli population that first evolved a mutT hypermutator phenotype was later invaded by two independent lineages with mutY mutations that reduced genome-wide mutation rates. Applying neutral theory to synonymous substitutions, we dated the emergence of these mutations and inferred that the mutT mutation increased the point-mutation rate by ∼150-fold, whereas the mutY mutations reduced the rate by ∼40-60%, with a corresponding decrease in the genetic load. Thus, the long-term fate of the hypermutators was governed by the selective advantage arising from a reduced mutation rate as the potential for further adaptation declined.

Capturing the mutational landscape of the beta-lactamase TEM-1.

Abstract: Adaptation proceeds through the selection of mutations. The distribution of mutant fitness effect and the forces shaping this distribution are therefore keys to predict the evolutionary fate of organisms and their constituents such as enzymes. Here, by producing and sequencing a comprehensive collection of 10,000 mutants, we explore the mutational landscape of one enzyme involved in the spread of antibiotic resistance, the beta-lactamase TEM-1. We measured mutation impact on the enzyme activity through the estimation of amoxicillin minimum inhibitory concentration on a subset of 990 mutants carrying a unique missense mutation, representing 64% of possible amino acid changes in that protein reachable by point mutation. We established that mutation type, solvent accessibility of residues, and the predicted effect of mutations on protein stability primarily determined alone or in combination changes in minimum inhibitory concentration of mutants. Moreover, we were able to capture the drastic modification of the mutational landscape induced by a single stabilizing point mutation (M182T) by a simple model of protein stability. This work thereby provides an integrated framework to study mutation effects and a tool to understand/define better the epistatic interactions.

Tight Bounds on the Optimization Time of a Randomized Search Heuristic on Linear Functions

Abstract: The analysis of randomized search heuristics on classes of functions is fundamental to the understanding of the underlying stochastic process and the development of suitable proof techniques. Recently, remarkable progress has been made in bounding the expected optimization time of a simple evolutionary algorithm, called (1+1) EA, on the class of linear functions. We improve the previously best known bound in this setting from (1.39+o(1))en ln n to en ln n+O(n) in expectation and with high probability, which is tight up to lower-order terms. Moreover, upper and lower bounds for arbitrary mutation probabilities p are derived, which imply expected polynomial optimization time as long as p = O((ln n)/n) and p = Ω(n−C) for a constant C > 0, and which are tight if p = c/n for a constant c > 0. As a consequence, the standard mutation probability p = 1/n is optimal for all linear functions, and the (1+1) EA is found to be an optimal mutation-based algorithm. Furthermore, the algorithm turns out to be surprisingly robust since the large neighbourhood explored by the mutation operator does not disrupt the search.

DeNovoGear: de novo indel and point mutation discovery and phasing

Abstract: We present DeNovoGear software for analyzing de novo mutations from familial and somatic tissue sequencing data. DeNovoGear uses likelihood-based error modeling to reduce the false positive rate of mutation discovery in exome analysis and fragment information to identify the parental origin of germ-line mutations. We used DeNovoGear on human whole-genome sequencing data to produce a set of predicted de novo insertion and/or deletion (indel) mutations with a 95% validation rate.

Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing.

Abstract: Pheochromocytomas (PCC) and paragangliomas (PGL) are neuroendocrine tumors that, although rare, are an important cause of secondary hypertension because of the high morbidity and mortality. PCC/PGL are still thought of as the “tumor of tens,” with 10 % being hereditary; however, recent population based studies suggest that up to 32 % of patients have a germline mutation in one of the known common susceptibility genes (including NF1, VHL, RET, SDHB, SDHD, and SDHC). Despite this, most patients in the United States are not referred for clinical genetic testing by their physicians. We aimed to examine the mutation prevalence in a clinic-based population in the United States. We performed a retrospective chart review of 139 consecutive patients with PCC/PGL from the medical genetics clinic at the hospital of the University of Pennsylvania from January 2004 through February 2012. We found a 41 % overall mutation detection rate. Twenty-six percent of the cohort had a mutation in the SDHB or SDHD genes. Of patients with at least one PGL tumor outside the adrenal gland, 53 % had an identified mutation. Forty-one percent of the cohort had a heritable mutation. The most commonly mutated gene was SDHB, which carries the highest risk of malignancy. These data, together with American Society of Clinical Oncology guidelines suggesting that genetic testing be performed if the risk of a hereditable mutation is at least 10 % or if it will affect medical management, strongly suggest that all patients with PCC/PGL should undergo clinical genetic testing.

Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long‐QT syndrome

Abstract: Patient-specific induced pluripotent stem cells (iPSCs) will assist research on genetic cardiac maladies if the disease phenotype is recapitulated in vitro. However, genetic background variations may confound disease traits, especially for disorders with incomplete penetrance, such as long-QT syndromes (LQTS). To study the LQT2-associated c.A2987T (N996I) KCNH2 mutation under genetically defined conditions, we derived iPSCs from a patient carrying this mutation and corrected it. Furthermore, we introduced the same point mutation in human embryonic stem cells (hESCs), generating two genetically distinct isogenic pairs of LQTS and control lines. Correction of the mutation normalized the current (IKr) conducted by the HERG channel and the action potential (AP) duration in iPSC-derived cardiomyocytes (CMs). Introduction of the same mutation reduced IKr and prolonged the AP duration in hESC-derived CMs. Further characterization of N996I-HERG pathogenesis revealed a trafficking defect. Our results demonstrated that the c.A2987T KCNH2 mutation is the primary cause of the LQTS phenotype. Precise genetic modification of pluripotent stem cells provided a physiologically and functionally relevant human cellular context to reveal the pathogenic mechanism underlying this specific disease phenotype.

A New Method for Lower Bounds on the Running Time of Evolutionary Algorithms

Abstract: In this paper a new method for proving lower bounds on the expected running time of evolutionary algorithms (EAs) is presented. It is based on fitness-level partitions and an additional condition on transition probabilities between fitness levels. The method is versatile, intuitive, elegant, and very powerful. It yields exact or near-exact lower bounds for LO, OneMax, long k-paths, and all functions with a unique optimum. Most lower bounds are very general; they hold for all EAs that only use bit-flip mutation as variation operator, i.e., for all selection operators and population models. The lower bounds are stated with their dependence on the mutation rate. These results have very strong implications. They allow us to determine the optimal mutation-based algorithm for LO and OneMax, i.e., the algorithm that minimizes the expected number of fitness evaluations. This includes the choice of the optimal mutation rate.

A De Novo Mutation in the β-Tubulin Gene TUBB4A Results in the Leukoencephalopathy Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum

Abstract: Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare hereditary leukoencephalopathy that was originally identified by MRI pattern analysis, and it has thus far defied all attempts at identifying the causal mutation. Only 22 cases are published in the literature to date. We performed exome sequencing on five family trios, two family quartets, and three single probands, which revealed that all eleven H-ABC-diagnosed individuals carry the same de novo single-nucleotide TUBB4A mutation resulting in nonsynonymous change p.Asp249Asn. Detailed investigation of one of the family quartets with the singular finding of an H-ABC-affected sibling pair revealed maternal mosaicism for the mutation, suggesting that rare de novo mutations that are initially phenotypically neutral in a mosaic individual can be disease causing in the subsequent generation. Modeling of TUBB4A shows that the mutation creates a nonsynonymous change at a highly conserved asparagine that sits at the intradimer interface of α-tubulin and β-tubulin, and this change might affect tubulin dimerization, microtubule polymerization, or microtubule stability. Consistent with H-ABC's clinical presentation, TUBB4A is highly expressed in neurons, and a recent report has shown that an N-terminal alteration is associated with a heritable dystonia. Together, these data demonstrate that a single de novo mutation in TUBB4A results in H-ABC.

Evolutionary instability of zero-determinant strategies demonstrates that winning is not everything.

Abstract: In iterated Prisoner’s Dilemma games, zero-determinant strategies are able to define the opponent’s payoff regardless of the opponent’s strategy. Here the authors show that zero-determinant strategies are not evolutionary stable in adapting populations, and instead evolve into non-coercive strategies.

Direct detection of a BRAF mutation in total RNA from melanoma cells using cantilever arrays

Abstract: Malignant melanoma, the deadliest form of skin cancer, is characterized by a predominant mutation in the BRAF gene. Drugs that target tumours carrying this mutation have recently entered the clinic. Accordingly, patients are routinely screened for mutations in this gene to determine whether they can benefit from this type of treatment. The current gold standard for mutation screening uses real-time polymerase chain reaction and sequencing methods. Here we show that an assay based on microcantilever arrays can detect the mutation nanomechanically without amplification in total RNA samples isolated from melanoma cells. The assay is based on a BRAF-specific oligonucleotide probe. We detected mutant BRAF at a concentration of 500 pM in a 50-fold excess of the wild-type sequence. The method was able to distinguish melanoma cells carrying the mutation from wild-type cells using as little as 20 ng µl(-1) of RNA material, without prior PCR amplification and use of labels.

NF1 Molecular Characterization and Neurofibromatosis Type I Genotype–Phenotype Correlation: The French Experience

Abstract: Neurofibromatosis type 1 (NF1) affects about one in 3,500 people in all ethnic groups. Most NF1 patients have private loss-of-function mutations scattered along the NF1 gene. Here, we present an original NF1 investigation strategy and report a comprehensive mutation analysis of 565 unrelated patients from the NF-France Network. A NF1 mutation was identified in 546 of the 565 patients, giving a mutation detection rate of 97%. The combined cDNA/DNA approach showed that a significant proportion of NF1 missense mutations (30%) were deleterious by affecting pre-mRNA splicing. Multiplex ligation-dependent probe amplification allowed the identification of restricted rearrangements that would have been missed if only sequencing or microsatellite analysis had been performed. In four unrelated families, we identified two distinct NF1 mutations within the same family. This fortuitous association points out the need to perform an exhaustive NF1 screening in the case of molecular discordant-related patients. A genotype-phenotype study was performed in patients harboring a truncating (N = 368), in-frame splicing (N = 36), or missense (N = 35) mutation. The association analysis of these mutation types with 12 common NF1 clinical features confirmed a weak contribution of the allelic heterogeneity of the NF1 mutation to the NF1 variable expressivity.

Genetic Diversity and the Structure of Genealogies in Rapidly Adapting Populations

Abstract: Positive selection distorts the structure of genealogies and hence alters patterns of genetic variation within a population. Most analyses of these distortions focus on the signatures of hitchhiking due to hard or soft selective sweeps at a single genetic locus. However, in linked regions of rapidly adapting genomes, multiple beneficial mutations at different loci can segregate simultaneously within the population, an effect known as clonal interference. This leads to a subtle interplay between hitchhiking and interference effects, which leads to a unique signature of rapid adaptation on genetic variation both at the selected sites and at linked neutral loci. Here, we introduce an effective coalescent theory (a “fitness-class coalescent”) that describes how positive selection at many perfectly linked sites alters the structure of genealogies. We use this theory to calculate several simple statistics describing genetic variation within a rapidly adapting population and to implement efficient backward-time coalescent simulations, which can be used to predict how clonal interference alters the expected patterns of molecular evolution.

Static and adaptive mutation techniques for genetic algorithm: a systematic comparative analysis

Abstract: In this paper, a systematic comparative analysis is presented on various static and adaptive mutation techniques to understand their nature on genetic algorithm. Three most popular random mutation techniques such as uniform mutation, Gaussian mutation and boundary mutation, two recently introduced individual adaptive mutation techniques, a self-adaptive mutation technique and a deterministic mutation technique are taken to carry out the analysis. A common experimental bench of benchmark test functions is used to test the techniques and the results are analysed. The analysis intends to identify a best mutation technique for every benchmark problem and to understand the dependency behaviour of mutation techniques with other genetic algorithm parameters such as population sizes, crossover rates and number of generations. Based on the analytical results, interesting findings are obtained that would improve the performance of genetic algorithm.

Genetic Correction of Tauopathy Phenotypes in Neurons Derived from Human Induced Pluripotent Stem Cells

Abstract: Tauopathies represent a group of neurodegenerative disorders characterized by the accumulation of pathological TAU protein in brains. We report a human neuronal model of tauopathy derived from induced pluripotent stem cells (iPSCs) carrying a TAU-A152T mutation. Using zinc-finger nuclease-mediated gene editing, we generated two isogenic iPSC lines: one with the mutation corrected, and another with the homozygous mutation engineered. The A152T mutation increased TAU fragmentation and phosphorylation, leading to neurodegeneration and especially axonal degeneration. These cellular phenotypes were consistent with those observed in a patient with TAU-A152T. Upon mutation correction, normal neuronal and axonal morphologies were restored, accompanied by decreases in TAU fragmentation and phosphorylation, whereas the severity of tauopathy was intensified in neurons with the homozygous mutation. These isogenic TAU-iPSC lines represent a critical advancement toward the accurate modeling and mechanistic study of tauopathies with human neurons and will be invaluable for drug-screening efforts and future cell-based therapies.

PIK3CA and PTEN Gene and Exon Mutation-Specific Clinicopathologic and Molecular Associations in Colorectal Cancer

Abstract: Purpose: PIK3CA and PTEN mutations are prevalent in colorectal cancer and potential markers of response to mitogen-activated protein/extracellular signal–regulated kinase inhibitors and anti-EGF receptor antibody therapy. Relationships between phosphoinositide 3-kinase (PI3K) pathway mutation, clinicopathologic characteristics, molecular features, and prognosis remain controversial. Experimental Design: A total of 1,093 stage I–IV colorectal cancers were screened for PIK3CA (exons 9 and 20), KRAS (codons 12–13), BRAF (codon 600) mutations, and microsatellite instability (MSI). PTEN (exons 3–8) and CpG island methylator phenotype (CIMP) status were determined in 744 and 489 cases. PIK3CA data were integrated with 17 previous reports ( n = 5,594). Results: PIK3CA and PTEN mutations were identified in 11.9% and 5.8% of colorectal cancers. PTEN mutation was associated with proximal tumors, mucinous histology, MSI-high (MSI-H), CIMP-high (CIMP-H), and BRAF mutation ( P PIK3CA mutation was related to older age, proximal tumors, mucinous histology, and KRAS mutation ( P PIK3CA exon 9 and 20 mutations were overrepresented in proximal, CIMP-low (CIMP-L), and KRAS -mutated cancers ( P ≤ 0.011). Comparing PIK3CA exonic mutants, exon 20 mutation was associated with MSI-H, CIMP-H, and BRAF mutation, and exon 9 mutation was associated with KRAS mutation ( P ≤ 0.027). Disease-free survival for stage II/III colorectal cancers did not differ by PI3K pathway status. Conclusion: PI3K pathway mutation is prominent in proximal colon cancers, with PIK3CA exon 20 and PTEN mutations associated with features of the sessile-serrated pathway (MSI-H/CIMP-H/ BRAF mut ), and PIK3CA exon 9 (and to a lesser extent exon 20) mutation associated with features of the traditional serrated pathway (CIMP-L/ KRAS mut ) of tumorigenesis. Our data highlight the PI3K pathway as a therapeutic target in distinct colorectal cancer subtypes. Clin Cancer Res; 19(12); 3285–96. ©2013 AACR .

β-Catenin Mutation Status and Outcomes in Sporadic Desmoid Tumors

Abstract: Background. Mutations in the gene-encoding β-catenin, CTNNB1, are highly prevalent in sporadic desmoid tumors and may predict the risk for recurrence. We sought to determine the prevalence of CTNNB1 mutations in a large cohort of sporadic desmoid tumors and to determine whether CTNNB1 mutation status correlates with disease outcome.

Genetics. Mysterious ribosomopathies.

Abstract: Ribosomes are essential in all cell types, yet mutations to ribosomal proteins or assembly factors cause tissue-specific disease. Ribosomes are absolutely essential for life, generating all cellular proteins required for growth. The prevailing thought for many years was that mutations in ribosomal proteins or ribosome assembly factors would be lethal to developing embryos. Complete loss of any single ribosomal protein often leads to embryonic lethality in mice (1). Yet, mutations in ribosomal proteins or ribosome assembly factors result in a puzzling phenomenon—a specific mutation can affect a specific cell type and cause a tissue-specific human disease. What accounts for this tissue proclivity has been a mystery. Why do defects in a macromolecule as ubiquitous and essential as the ribosome cause diseases—ribosomopathies—only in select tissues?

Gout-causing Q141K mutation in ABCG2 leads to instability of the nucleotide-binding domain and can be corrected with small molecules

Abstract: The multidrug ATP-binding cassette, subfamily G, 2 (ABCG2) transporter was recently identified as an important human urate transporter, and a common mutation, a Gln to Lys substitution at position 141 (Q141K), was shown to cause hyperuricemia and gout. The nature of the Q141K defect, however, remains undefined. Here we explore the Q141K ABCG2 mutation using a comparative approach, contrasting it with another disease-causing mutation in an ABC transporter, the deletion of Phe-508 (ΔF508) in the cystic fibrosis transmembrane conductance regulator (CFTR). We found, much like in ΔF508 CFTR, that the Q141K mutation leads to instability in the nucleotide-binding domain (NBD), a defect that translates to significantly decreased protein expression. However, unlike the CFTR mutant, the Q141K mutation does not interfere with the nucleotide-binding domain/intracellular loop interactions. This investigation has also led to the identification of critical residues involved in the protein–protein interactions necessary for the dimerization of ABCG2: Lys-473 (K473) and Phe-142 (F142). Finally, we have demonstrated the utility of using small molecules to correct the Q141K defect in expression and function as a possible therapeutic approach for hyperuricemia and gout.