Search PubMed⌕ Search

Biomedical subjects

M Dean

Publications and source records attributed to M Dean.

At least 37 records · Page 2Linked to original sources
PubMed2001

Two new genes from the human ATP-binding cassette transporter superfamily, ABCC11 and ABCC12, tandemly duplicated on chromosome 16q12.

Several years ago, we initiated a long-term project of cloning new human ATP-binding cassette (ABC) transporters and linking them to various disease phenotypes. As one of the results of this project, we present two new members of the human ABCC subfamily, ABCC11 and ABCC12. These two new human ABC transporters were fully characterized and mapped to the human chromosome 16q12. With the addition of these two genes, the complete human ABCC subfamily has 12 identified members (ABCC1-12), nine from the multidrug resistance-like subgroup, two from the sulfonylurea receptor subgroup, and the CFTR gene. Phylogenetic analysis determined that ABCC11 and ABCC12 are derived by duplication, and are most closely related to the ABCC5 gene. Genetic variation in some ABCC subfamily members is associated with human inherited diseases, including cystic fibrosis (CFTR/ABCC7), Dubin-Johnson syndrome (ABCC2), pseudoxanthoma elasticum (ABCC6) and familial persistent hyperinsulinemic hypoglycemia of infancy (ABCC8). Since ABCC11 and ABCC12 were mapped to a region harboring gene(s) for paroxysmal kinesigenic choreoathetosis, the two genes represent positional candidates for this disorder.

ATP-Binding Cassette Transporters↗
PubMed2001

Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively.

Sitosterolemia is a rare autosomal recessive disorder characterized by (a) intestinal hyperabsorption of all sterols, including cholesterol and plant and shellfish sterols, and (b) impaired ability to excrete sterols into bile. Patients with this disease have expanded body pools of cholesterol and very elevated plasma plant-sterol species and frequently develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. In previous studies, we have mapped the STSL locus to human chromosome 2p21. Recently, we reported that a novel member of the ABC-transporter family, named "sterolin-1" and encoded by ABCG5, is mutated in 9 unrelated families with sitosterolemia; in the remaining 25 families, no mutations in sterolin-1 could be identified. We identified another ABC transporter, located <400 bp upstream of sterolin-1, in the opposite orientation. Mutational analyses revealed that this highly homologous protein, termed "sterolin-2" and encoded by ABCG8, is mutated in the remaining pedigrees. Thus, two highly homologous genes, located in a head-to-head configuration on chromosome 2p21, are involved as causes of sitosterolemia. These studies indicate that both sterolin-1 and sterolin-2 are indispensable for the regulation of sterol absorption and excretion. Identification of sterolin-1 and sterolin-2 as critical players in the regulation of dietary-sterol absorption and excretion identifies a new pathway of sterol transport.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2001

Statistical estimation and pedigree analysis of CCR2-CCR5 haplotypes.

As more SNP marker data becomes available, researchers have used haplotypes of markers, rather than individual polymorphisms, for association analysis of candidate genes. In order to perform haplotype analysis in a population-based case-control study, haplotypes must be determined by estimation in the absence of family information or laboratory methods for establishing phase. Here, we test the accuracy of the Expectation-Maximization (EM) algorithm for estimating haplotype state and frequency in the CCR2-CCR5 gene region by comparison with haplotype state and frequency determined by pedigree analysis. To do this, we have characterized haplotypes comprising alleles at seven biallelic loci in the CCR2-CCR5 chemokine receptor gene region, a span of 20 kb on chromosome 3p21. Three-generation CEPH families (n=40), totaling 489 individuals, were genotyped by the 5'nuclease assay (TaqMan). Haplotype states and frequencies were compared in 103 grandparents who were assumed to have mated at random. Both pedigree analysis and the EM algorithm yielded the same small number of haplotypes for which linkage disequilibrium was nearly maximal. The haplotype frequencies generated by the two methods were nearly identical. These results suggest that the EM algorithm estimation of haplotype states, frequency, and linkage disequilibrium analysis will be an effective strategy in the CCR2-CCR5 gene region. For genetic epidemiology studies, CCR2-CCR5 allele and haplotype frequencies were determined in African-American (n=30), Hispanic (n=24) and European-American (n=34) populations.

Alleles↗
PubMed2001

Mutational scanning of the ABCR gene with double-gradient denaturing-gradient gel electrophoresis (DG-DGGE) in Italian Stargardt disease patients.

Mutations in the retina-specific ABC transporter (ABCR) gene are responsible for autosomal recessive Stargardt disease (arSTGD). Mutation detection efficiency in ABCR in arSTGD patients ranges between 30% and 66% in previously published studies, because of high allelic heterogeneity and technical limitations of the employed methods. Conditions were developed to screen the ABCR gene by double-gradient denaturing-gradient gel electrophoresis. The efficacy of this method was evaluated by analysis of DNA samples with previously characterized ABCR mutations. This approach was applied to mutation detection in 44 Italian arSTGD patients corresponding to 36 independent genomes, in order to assess the nature and frequency of the ABCR mutations in this ethnic group. In 34 of 36 (94.4%) STGD patients, 37 sequence changes were identified, including 26 missense, six frameshift, three splicing, and two nonsense variations. Among these, 20 had not been previously described. Several polymorphisms were detected in affected individuals and in matched controls. Our findings extend the spectrum of mutations identified in STGD patients and suggest the existence of a subset of molecular defects specific to the Italian population. The identification of at least two disease-associated mutations in four healthy control individuals indicates a higher than expected carrier frequency of variant ABCR alleles in the general population. Genotype-phenotype analysis in our series showed a possible correlation between the nature and location of some mutations and specific ophthalmoscopic features of STGD disease.

ATP-Binding Cassette Transporters↗
PubMed2001

Complete characterization of the human ABC gene family.

The human ATP-binding cassette (ABC) transporters comprise a large family of membrane transport proteins and play a vital role in many cellular processes. The genes provide functions as diverse as peptide transport, cholesterol and sterol transport, bile acid, retinoid, and iron transport. In addition some ABC genes play a role as regulatory elements. Many ABC genes play a role in human genetic diseases, and several are critical drug transport proteins overexpressed in drug resistant cells. Analysis of the gene products allows the genes to be grouped into seven different subfamilies.

ATP-Binding Cassette Transporters↗
PubMed2001

Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption.

The molecular mechanisms regulating the amount of dietary cholesterol retained in the body, as well as the body's ability to exclude selectively other dietary sterols, are poorly understood. An average western diet will contain about 250-500 mg of dietary cholesterol and about 200-400 mg of non-cholesterol sterols. About 50-60% of the dietary cholesterol is absorbed and retained by the normal human body, but less than 1% of the non-cholesterol sterols are retained. Thus, there exists a subtle mechanism that allows the body to distinguish between cholesterol and non-cholesterol sterols. In sitosterolemia, a rare autosomal recessive disorder, affected individuals hyperabsorb not only cholesterol but also all other sterols, including plant and shellfish sterols from the intestine. The major plant sterol species is sitosterol; hence the name of the disorder. Consequently, patients with this disease have very high levels of plant sterols in the plasma and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. We previously mapped the STSL locus to human chromosome 2p21 and further localized it to a region of less than 2 cM bounded by markers D2S2294 and D2S2291 (M.-H.L. et al., manuscript submitted). We now report that a new member of the ABC transporter family, ABCG5, is mutant in nine unrelated sitosterolemia patients.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2001

Two rare confounding polymorphisms proximal to the factor V Leiden mutation.

BACKGROUND: Comprehensive assessment of thrombophilia risk includes characterization of the R506Q (Leiden) mutation in factor V in many patients. Although activated protein C resistance is often assessed by means of a coagulation test, molecular interrogation of the G1691A mutation provides confirmation and interpretive utility in patients undergoing anticoagulation. Many molecular methods are available to provide genotyping at this locus. Among these, PCR-restriction fragment length polymorphism (RFLP) is widely used. Unfortunately, because this common mutation is 11 bp from the 3' end of exon 10, one PCR primer often anneals within intron 10. As a consequence, polymorphism can confound test results. METHOD AND RESULTS: In the course of a clinical diagnostic test of 15,301 patients, two samples repeatedly showed two different unusual electrophoretic mobilities after PCR and restriction enzyme digestion. After stripping patient identifiers and entering a research protocol, the amplicons from these DNAs were sequenced in parallel with normal and heterozygous G1691A control genomic DNA samples. This sequencing showed two novel polymorphisms, each mapping to intron 10. CONCLUSION: PCR-RFLP-based methods rely on sequence conservation in the interrogated region. Amplification of mutated loci adjacent to introns present a special risk for confounding restriction patterns. Sequencing amplicons with reproducibly unusual restriction patterns resolved the paradoxical restriction pattern in this case.

Activated Protein C Resistance↗