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M Dean

Publications and source records attributed to M Dean.

At least 73 records · Page 4Linked to original sources
PubMed2000

Configural information in facial expression perception.

Composite facial expressions were prepared by aligning the top half of one expression (e.g., anger) with the bottom half of another (e.g., happiness). Experiment 1 shows that participants are slower to identify the expression in either half of these composite images relative to a "noncomposite" control condition in which the 2 halves are misaligned. This parallels the composite effect for facial identity (A. W. Young, D. Hellawell, & D. C. Hay, 1987), and like its identity counterpart, the effect is disrupted by inverting the stimuli (Experiment 2). Experiment 3 shows that no composite effect is found when the top and bottom sections contain different models' faces posing the same expression; this serves to exclude many nonconfigural interpretations of the composite effect (e.g., that composites are more "attention-grabbing" than noncomposites). Finally, Experiment 4 demonstrates that the composite effects for identity and expression operate independently of one another.

Adult↗
PubMed2000

Use of denaturing HPLC to map human and murine genes and to validate single-nucleotide polymorphisms.

Linkage mapping has been extensively applied in the murine and human genomes. It remains a powerful approach to mapping genes and identifying genetic variants. As genome efforts identify large numbers of single-nucleotide polymorphisms, it will be critical to validate these polymorphisms and confirm their gene assignment and chromosomal location. The presence of pseudogenes can confuse such efforts. We have used denaturing HPLC to identify polymorphisms in human genes and to genotype individuals in selected CEPH pedigrees. The same approach has been applied to the mapping of murine genes in interspecies backcross animals. This strategy is rapid, accurate and superior in several respects to other technologies.

5'-Nucleotidase↗
PubMed2000

Amplification of 4q21-q22 and the MXR gene in independently derived mitoxantrone-resistant cell lines.

Molecular cytogenetic studies were conducted on three multidrug-resistant cancer sublines which are highly resistant to the chemotherapeutic agent mitoxantrone, an anthracenedione. The three independently selected sublines were derived by exposure to mitoxantrone or Adriamycin and do not overexpress MDR1 or MRP. Two sublines, MCF-7 AdVp3000 and MCF-7 MX, showed an amplification peak at 4q21-q22, as demonstrated by comparative genomic hybridization (CGH), while the third, S1-M1-80, did not. FISH using a whole chromosome 4 paint demonstrated multiple rearrangements involving chromosome 4 in MCF-7 AdVp3000 and MCF-7 MX, while S1-M1-80 contained only a simple reciprocal translocation. The parental cell lines had no chromosome 4 rearrangements and no copy number gain or amplification of chromosome 4. Spectral karyotyping (SKY) analysis revealed a balanced translocation, t(4;17)(q21-q22;p13) in S1-M1-80 and multiple clonal translocations involving chromosome 4 in MCF-7 AdVp3000 and MCF-7 MX. A novel cDNA, designated MXR, which encodes an ABC half-transporter and is highly overexpressed in the three sublines, was localized to chromosome 4 by somatic cell hybrid analysis. Southern blot analysis demonstrated amplification of the MXR gene in MCF-7 AdVp3000 and MCF-7 MX, but not in S1-M1-80. FISH studies with a BAC probe for MXR localized the gene to 4q21-22 in the normal chromosome 4 and revealed in both MCF-7 AdVp3000 and MCF-7 MX amplification of MXR at one translocation juncture, shown by SKY to be t(4;5)(4qter-->4cen-->4q21-22::5q13-->5qter++ +) in MCF-7 AdVp3000 and t(6;4;6;3)(6pter-->6q15::4q21-q22::hsr::6q?::3q?27-->+ ++3qter) in MCF MX; neither of the breakpoints in the partner chromosomes showed amplification by CGH. The data are consistent with the hypothesis of a transporter, presumably that encoded by the MXR gene, mediating mitoxantrone resistance. The MXR gene encodes a half-transporter and the absence of cytogenetic evidence of coamplification of other regions suggests that a partner may not be overexpressed, and instead the MXR half-transporter homodimerizes to mediate drug transport. Genes Chromosomes Cancer 27:110-116, 2000. Published 2000 Wiley-Liss, Inc.

Antineoplastic Agents↗
PubMed2000

Screening methods for cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in non-human primates.

We report here a comparison of isotopic and non-isotopic conformation analysis approach, for screening genomic DNA for coding variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. A large pool of non-human primates was tested in order to detect naturally occuring CFTR carriers, for future testing of gene therapy of cystic fibrosis. We screened 25 of 27 CFTR exons in over 1,000 animals. We have detected numerous missense mutations and single nucleotide polymorphisms. We found that both methods are highly efficient for detection of variations in DNA sequence, but the non-radioactive approach is faster, less expensive and in some cases more sensitive.

Alleles↗
PubMed2000

Evidence that hereditary pancreatitis is genetically heterogeneous disorder.

Hereditary pancreatitis (HP) is an autosomal dominant disorder characterized by recurrent acute attacks of severe abdominal pain with an onset in early childhood. Many HP patients progress to complicated chronic pancreatitis and/or pancreatic cancer. Initially, a single mutation R117H in the cationic trypsinogen gene was detected in all affected members of five unrelated HP families. Further studies identified a second mutation (N21L) in two HP families without the R117H mutation. Before the association between cationic trypsinogen and HP was found, we detected a cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation (L327R) in all affected individuals of a family with HP. We therefore performed a mutational analysis for R117H and N21L in cationic trypsinogen in this and three additional unrelated families with HP. The R117H mutation was detected in all 9 affected members of three HP families and in 3 asymptomatic but at-risk relatives. However, neither the R117H nor the N21L mutation in the cationic trypsinogen were found in the HP family with the L327R alteration in CFTR. The L327R allele segregates with the disease within this HP family and was not detected on 360 unrelated Caucasian non-CF chromosomes. Although close to 800 different mutations have been detected in the CF gene of cystic fibrosis patients, L327R is a new alteration, not yet reported in connection with CF. The results of this study indicate that the CFTR gene may play a role in the etiology of minority of cases with HP and suggest that hereditary pancreatitis is genetically heterogeneous disease.

Chromosome Mapping↗
PubMed2000

Study of mutant and polyvariant mutant CFTR genes in patients with congenital absence of the vas deferens.

Congenital bilateral absence of the vas deferens (CBAVD) is a form of male infertility in which mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been identified. Cystic fibrosis patients have mutations in both alleles of the gene while most CBAVD patients have mutations in only one allele. Frequently, the second CFTR allele is not mutant but polyvariant. We have studied CFTR gene mutations and polyvariant allele (TG)m(T)n in intron 8 in 37 patients with CBAVD. Ten (27%) compound heterozygotes and 16 (43.3%) heterozygotes have been detected, while no alteration have been found in the coding and intronic bounderies regions in 11 (29.7%) patients. DeltaF508 was the most frequent mutation present in 15/74 (20.3%) alleles. Additional mutant alleles include: R117H (6.8%), R75Q (5.4%), D1270N (2.7%) and G576A (2.7%). We identified in total 14 different mutations and mutant variants, of which one E804V has not been reported previously. Of 37 alleles with not detectable alteration in the coding or splice site regions the (TG)12(T)5 allele has been found in 14 (37.8%) genes. If we consider that (TG)12(T)5 is believed per se to be a highly penetrant pathogenic allele connected with CBAVD, we have detected a disease causing alterations in 49/74 (66.2%) CFTR alleles of CBAVD patients. These results are extremely important for genetic counseling of couples indicated for in vitro fertilization.

Alleles↗
PubMed2000

New ABCR mutations and clinical phenotype in Italian patients with Stargardt disease.

PURPOSE: To assess the mutation spectrum in the ABCR gene and clinical phenotypes in Italian families with autosomal recessive Stargardt disease (STGD1) and fundus flavimaculatus (FFM). METHODS: Eleven families from southern Italy, including 18 patients with diagnoses of STGD1, were clinically examined. Ophthalmologic examination included kinetic perimetry, electrophysiological studies, and fluorescein angiography. DNA samples of the affected individuals and their family members were analyzed for variants in all 50 exons of the ABCR gene by a combination of single-strand conformation polymorphism analysis and direct sequencing techniques. RESULTS: TenABCR variants were identified in 16 (73%) of 22 mutant alleles of patients with STGD1. Five mutations of 10 that were found had not been previously described. The majority of variants represent missense amino acid substitutions, and all mutant alleles cosegregate with the disease in the respective families. These ABCR variants were not detected in 170 unaffected control individuals (340 chromosomes) of Italian origin. Clinical evaluation of these families affected by STGD1 showed an unusually high frequency of early age-related macular degeneration (AMD) in parents of patients with STGD1 (8/22; 36%), consistent with the hypothesis that some heterozygous ABCR mutations enhance susceptibility to AMD. CONCLUSIONS: Patients from southern Italy with Stargardt disease show extensive allelic heterogeneity of the ABCR gene, concordant with previous observations in patients with STGD1 from different ethnic groups. Half the mutations identified in this study had not been previously described in patients with STGD1. Screening of increasingly large numbers of patients would help to determine whether this can be explained by ethnic differences, or is an indicator of extensive allelic heterogeneity of ABCR in STGD1 and other eye diseases. In 6 (55%) of 11 families, the first-degree relatives of patients with STGD1 were diagnosed with early AMD, supporting the previous observation that some STGD1 alleles are also associated with AMD.

ATP-Binding Cassette Transporters↗
PubMed1999

Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity.

PTEN/MMAC1 (phosphatase, tensin homologue/mutated in multiple advanced cancers) is a tumor suppressor protein that has sequence homology with dual-specificity phosphatases, which are capable of dephosphorylating both tyrosine phosphate and serine/threonine phosphate residues on proteins. The in vivo function of PTEN/MMAC1 appears to be dephosphorylation of phosphotidylinositol 3,4, 5-triphosphate. The PTEN/MMAC1 gene is mutated in the germline of patients with rare autosomal dominant cancer syndromes and in subsets of specific cancers. Here we review the mutational spectra of the PTEN/MMAC1 gene in tumors from various tissues, especially endometrium, brain, prostate, and ovary, in which the gene is inactivated very frequently. Germline and somatic mutations in the PTEN/MMAC1 gene occur mostly in the protein coding region and involve the phosphatase domain and poly(A)(6) stretches. Compared with germline alterations found in the PTEN/MMAC1 gene, there is a substantially increased frequency of frameshift mutations in tumors. Glioblastomas and endometrial carcinomas appear to have distinct mutational spectra, probably reflecting differences in the underlying mechanisms of inactivation of the PTEN/MMAC1 gene in the two tissue types. Also, depending on the tissue type, the gene appears to be involved in the initiation or the progression of cancers. Further understanding of PTEN/MMAC1 gene mutations in different tumors and the physiologic consequences of these mutations is likely to open up new therapeutic opportunities for targeting this critical gene.

Brain Neoplasms↗
PubMed1999

What can we learn about age-related macular degeneration from other retinal diseases?

Age-related macular degeneration (AMD) is increasingly recognized as a complex genetic disorder in which one or more genes contribute to an individual's susceptibility for developing the condition. Twin and family studies as well as population-based genetic epidemiologic methods have convincingly demonstrated the importance of genetics in AMD, though the extent of heritability, the number of genes involved, and the phenotypic and genetic heterogeneity of the condition remain unresolved. The extent to which other hereditary macular dystrophies such as Stargardts disease, familial radial drusen (malattia leventinese), Best's disease, and peripherin/RDS-related dystrophy are related to AMD remains unclear. Alzheimer's disease, another late onset, heterogeneous degenerative disorder of the central nervous system, offers a valuable model for identifying the issues that confront AMD genetics.

ATP-Binding Cassette Transporters↗
PubMed1999

Human ATP-binding cassette transporter 1 (ABC1): genomic organization and identification of the genetic defect in the original Tangier disease kindred.

Tangier disease is characterized by low serum high density lipoproteins and a biochemical defect in the cellular efflux of lipids to high density lipoproteins. ABC1, a member of the ATP-binding cassette family, recently has been identified as the defective gene in Tangier disease. We report here the organization of the human ABC1 gene and the identification of a mutation in the ABC1 gene from the original Tangier disease kindred. The organization of the human ABC1 gene is similar to that of the mouse ABC1 gene and other related ABC genes. The ABC1 gene contains 49 exons that range in size from 33 to 249 bp and is over 70 kb in length. Sequence analysis of the ABC1 gene revealed that the proband for Tangier disease was homozygous for a deletion of nucleotides 3283 and 3284 (TC) in exon 22. The deletion results in a frameshift mutation and a premature stop codon starting at nucleotide 3375. The product is predicted to encode a nonfunctional protein of 1,084 aa, which is approximately half the size of the full-length ABC1 protein. The loss of a Mnl1 restriction site, which results from the deletion, was used to establish the genotype of the rest of the kindred. In summary, we report on the genomic organization of the human ABC1 gene and identify a frameshift mutation in the ABC1 gene of the index case of Tangier disease. These results will be useful in the future characterization of the structure and function of the ABC1 gene and the analysis of additional ABC1 mutations in patients with Tangier disease.

ATP Binding Cassette Transporter 1↗
PubMed1999

The ABCR gene in recessive and dominant Stargardt diseases: a genetic pathway in macular degeneration.

Stargardt disease (STGD) is a juvenile-onset macular dystrophy and can be inherited in an autosomal recessive or in an autosomal dominant manner. Genes involved in dominant STDG have been mapped to human chromosomes 13q (STGD2) and 6q (STGD3). Here, we identify a new kindred with dominant STGD and demonstrate genetic linkage to the STGD3 locus. Because of a more severe macular degeneration phenotype of one of the patients in this family, the gene responsible for the recessive STGD1, ABCR, was analyzed for sequence variants in all family members. One allele of the ABCR gene was shown to carry a stop codon-generating mutation (R152X) in three family members, including the one patient who had inherited also the dominant gene. A grandparent of that patient with the same ABCR mutation developed age-related macular degeneration (AMD), consistent with our earlier observation that some variants in the ABCR gene may increase susceptibility to AMD in the heterozygous state. Based on these results, we propose that there is a common genetic pathway in macular degeneration that includes genes for both recessive and dominant STGD.

ATP-Binding Cassette Transporters↗
PubMed1999

Phenotypic expressions of CCR5-delta32/delta32 homozygosity.

OBJECTIVE: As blockade of CC-chemokine receptor 5 (CCR5) has been proposed as therapy for HIV-1, we examined whether the CCR5-delta32/delta32 homozygous genotype has phenotypic expressions other than those related to HIV-1. DESIGN: Study subjects were white homosexual men or men with hemophilia who were not infected with HIV-1. In this study, 15 CCR5-delta32/delta32 homozygotes were compared with 201 CCR5 wild-type (+/+) subjects for a wide range of clinical conditions and laboratory assay results ascertained during prospective cohort studies and routine clinical care. CCR5-delta32 genotype was determined by polymerase chain reaction, followed by single-stranded conformational polymorphism analysis. RESULTS: Hypertension and conditions attributable to hemophilia were the only diagnoses frequently found in clinical records of CCR5-delta32/delta32 study subjects. Based on blood pressure measurement and treatment history, CCR5-delta32/delta32 homozygotes had a 2.8-fold higher prevalence of hypertension than age-matched CCR5-+/+ study subjects (95% confidence interval [CI], 1.2-6.4; p = .01); none of the homozygotes had severe hypertension. Hematologic measures were generally similar across the genotypes, but total lymphocyte counts were approximately 20% higher in CCR5-delta32/delta32 study subjects than in CCR5-+/+ study subjects (p < .05). Among patients with hemophilia who were infected with hepatitis C virus (HCV), mean alanine aminotransferase levels were 117% higher among CCR5-delta32/delta32 homozygotes (p < .05), but serum HCV levels did not differ by CCR5-delta32 genotype. CCR5-delta32/delta32 homozygous study subjects had a lower prevalence of antibodies to measles virus than those with other genotypes, but this association was not confirmed in a group of blood donors. The prevalence of antibodies to nine other common viruses, HBV, and HCV was not related to CCR5 genotype. CONCLUSIONS: CCR5-delta32/delta32 homozygotes are generally similar to wild-type persons. Confirmatory investigations are required to determine whether hypertension, increased lymphocyte counts, and higher hepatic enzyme levels in the presence of HCV infection represent true phenotypic expressions of this genotype. CCR5-delta32/delta32 homozygosity does not provide broad protection against viral infections.

Adult↗
PubMed1999

Reduced risk of AIDS lymphoma in individuals heterozygous for the CCR5-delta32 mutation.

Non-Hodgkin's lymphoma (NHL) has been increasing in frequency in the industrialized world, but the environmental and genetic factors that contribute to susceptibility are not known. B-cell lymphomas represent a major cause of morbidity and mortality in HIV-infected individuals. The identification of a deletion in the CCR5 chemokine receptor gene that alters the risk for infection and progression to AIDS led us to examine a potential role of this gene in AIDS lymphoma. A matched case-control analysis was performed using all eligible NHL cases in the Multicenter AIDS Cohort Study. Patients were matched for age, study center, time AIDS-free, and slope of the CD4+ T-cell decline. The CCR5-delta32 allele was found to be associated with a 3-fold lower risk of NHL among individuals after controlling for time of infection and progression toward AIDS. The CCR5 gene was not associated with a difference in risk for Kaposi's sarcoma, another common malignancy in AIDS patients, or opportunistic infections. Costimulation of normal phorbol 12-myristate 13-acetate-treated B cells with the CCR5 ligand RANTES induced a proliferative response, indicating that RANTES is a mitogen for B cells. Taken together, these findings suggest that the CCR5 gene plays a role in the risk of NHL in HIV-infected patients, perhaps through a mechanism involving a decreased response of B cells to the mitogenic activity of RANTES.

AIDS-Related Opportunistic Infections↗