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J C Murray

Publications and source records attributed to J C Murray.

At least 37 records · Page 2Linked to original sources
PubMed2002

Genetic origins in a South American clefting population.

It has been proposed that susceptibility to clefting in South America is related to Amerindian ancestry, where clefting is present at a higher frequency than in the other admixed populations (Caucasian and African) that make up the diverse racial mix of current South Americans. To clarify the genetic origins and establish a method for genetic mapping, mitochondrial DNA variation and Y-chromosome markers were studied in a South American population affected with clefting. Two-hundred and seventeen subjects and matched controls were selected through the Latin-American Collaborative Study of Congenital Malformations (ECLAMC). The case group showed a higher frequency of Native American haplogroups and a lower frequency of African haplogroups (p < 0.00001). In addition, the case group showed a much higher frequency of the specific native American haplogroup D than the control group (p < 0.00001). For the Y-chromosome markers, the case group showed a lower frequency of the African-specific marker, YAP (p = 0.002), and a higher frequency of the Native American-specific marker, DYS199 (p < 0.00001). Even though differences were found in the frequencies of the markers studied, the contribution of each founder population was similar for both groups. Results suggest a strong Native American maternal contribution and a strong Caucasian (Spanish and Portuguese) paternal contribution to the population studied. The implications of this finding include the possibility of using admixture mapping approaches to this population.

Chromosomes, Human, Y↗
PubMed2002

Analysis of the p63 gene in classical EEC syndrome, related syndromes, and non-syndromic orofacial clefts.

EEC syndrome is an autosomal dominant disorder with the cardinal signs of ectrodactyly, ectodermal dysplasia, and orofacial clefts. EEC syndrome has been linked to chromosome 3q27 and heterozygous p63 mutations were detected in unrelated EEC families. In addition, homozygous p63 null mice exhibit craniofacial abnormalities, limb truncations, and absence of epidermal appendages, such as hair follicles and tooth primordia. In this study, we screened 39 syndromic patients, including four with EEC syndrome, five with syndromes closely related to EEC syndrome, and 30 with other syndromic orofacial clefts and/or limb anomalies. We identified heterozygous p63 mutations in three unrelated cases of EEC syndrome, two Iowa white families and one sporadic case in a Filipino boy. One family is atypical for EEC and has features consistent with Hay-Wells syndrome. In this family, the mutation ablates a splice acceptor site and, in the other two, mutations produce amino acid substitutions, R280C and R304Q, which alter conserved DNA binding sites. Germline mosaicism was detected in the founder of the mutation in one case. These three cases show significant interfamilial and intrafamilial variability in expressivity. We also screened p63 in 62 patients with non-syndromic orofacial clefts, identifying an intronic single nucleotide polymorphism but finding no evidence of mutations that would explain even a subset of non-syndromic orofacial clefts. This study supports a common role for p63 in classical EEC syndrome, both familial and sporadic, but not in other related or non-syndromic forms of orofacial clefts.

Abnormalities, Multiple↗
PubMed2001

Evaluation of two putative susceptibility loci for oral clefts in the Danish population.

Previous studies suggest that the risk of nonsyndromic cleft lip with or without cleft palate (CL+/-P) and isolated cleft palate (CP) is influenced by genetic variation at several loci and that the relation between specific genetic variants and disease risk may be modified by environmental factors. The present study evaluated potential associations between CL+/-P and CP and two putative clefting susceptibility loci, MSX1 and TGFB3, using data from a nationwide case-control study conducted in Denmark from 1991 to 1994. The potential effects of interactions between these genes and two common environmental exposures, first trimester exposure to maternal cigarette smoke and alcohol intake, were also examined. Analyses of these data provide evidence of an association between the risk of CP and variation at the TGFB3 locus. However, there is no evidence that the risk of CL+/-P or CP is influenced by gene-environment interactions involving MSX1 or TGFB3 and either first trimester exposure to maternal cigarette smoke or alcohol consumption.

Adult↗
PubMed2001

Identification of a dominant negative homeodomain mutation in Rieger syndrome.

Mutations in the PITX2 bicoid-like homeobox gene cause Rieger syndrome. Rieger syndrome is an autosomal-dominant human disorder characterized by glaucoma as well as dental hypoplasia, mild craniofacial dysmorphism, and umbilical stump abnormalities. PITX2 has also been implicated in the development of multiple organs and left-right asymmetry in the body plan. The PITX2 homeodomain has a lysine at position 50, which has been shown to impart the bicoid-type (TAATCC) DNA binding specificity to other homeodomain proteins. A mutation (K88E), found in a Rieger syndrome patient, changes this lysine to glutamic acid. We were intrigued by the relatively pronounced phenotypic consequences of this K88E mutation. In the initial analyses, the mutant protein appeared to simply be inactive, with essentially no DNA binding and transactivation activities and, unlike the wild type protein, with an inability to synergize with another transcription factor, Pit-1. However, when the K88E DNA was cotransfected with wild type PITX2, analogous to the patient genotype, the K88E mutant suppressed the synergism of wild type PITX2 with Pit-1. In contrast, a different PITX2 homeodomain mutant, T68P, which is also defective in DNA binding, transactivation, and Pit-1 synergism activities, did not suppress the wild type synergism with Pit-1. These results describe the first dominant negative missense mutation in a homeodomain and support a model that may partially explain the phenotypic variation within Rieger syndrome.

Abnormalities, Multiple↗
PubMed2001

PITX2 regulates procollagen lysyl hydroxylase (PLOD) gene expression: implications for the pathology of Rieger syndrome.

The Rieger syndrome is an autosomal dominant disease characterized by ocular, craniofacial, and umbilical defects. Patients have mutations in PITX2, a paired-bicoid homeobox gene, also involved in left/right polarity determination. In this study we have identified a family of genes for enzymes responsible for hydroxylizing lysines in collagens as one group of likely cognate targets of PITX2 transcriptional regulation. The mouse procollagen lysyl hydroxylase (Plod)-2 gene was enriched for by chromatin precipitation using a PITX2/Pitx2-specific antibody. Plod-2, as well as the human PLOD-1 promoters, contains multiple bicoid (PITX2) binding elements. We show these elements to bind PITX2 specifically in vitro. The PLOD-1 promoter induces the expression of a luciferase reporter gene in the presence of PITX2 in cotransfection experiments. The Rieger syndrome causing PITX2 mutant T68P fails to induce PLOD-1-luciferase. Mutations and rearrangements in PLOD-1 are known to be prevalent in patients with Ehlers-Danlos syndrome, kyphoscoliosis type (type VI [EDVI]). Several of the same organ systems are involved in Rieger syndrome and EDVI.

Abnormalities, Multiple↗
PubMed2001

Mutations in the human forkhead transcription factor FOXE3 associated with anterior segment ocular dysgenesis and cataracts.

Dysgenesis of the anterior segment of the eye delineates a spectrum of human developmental disorders that show wide phenotypic and genetic heterogeneity. It is also frequently associated with cataracts and glaucoma resulting in visual disability in childhood. The recently described forkhead transcription factor gene Foxe3 was shown to be involved in the dysgenetic lens phenotype in mice, which is characterized by small cataractic lens and anterior segment anomalies. Here we report an identification and characterization of the human ortholog of this gene, FOXE3. The gene was found to be expressed in the anterior lens epithelium and to be mutated in patients with ocular disorders. An insertion of G in the coding region of the FOXE3 gene that occurred 15 nucleotides upstream of the stop codon was identified in a family with anterior segment ocular dysgenesis and cataracts. The mutation causes a frameshift that results in an abnormal sequence of five terminal amino acids and an addition of 111 amino acids to the predicted protein. The mutation was present in two affected individuals from this family and was not identified in 180 normal control chromosomes.

Amino Acid Sequence↗
PubMed2001

Matroshka and ectopic polymorphisms: Two new classes of DNA sequence variation identified at the Van der Woude syndrome locus on 1q32-q41.

Van der Woude syndrome (VWS) is an orofacial clefting disorder with an autosomal dominant pattern of inheritance. In our efforts to clone the VWS gene, 900 kb of genomic sequence from the VWS candidate region at chromosome 1q32-q41 was analyzed for new DNA sequence variants. We observed that in clone CTA-321i20 a 7922 bp sequence is absent relative to the sequence present in PAC clone RP4-782d21 at positions 1669-9590, suggesting the presence of a deletion/insertion (del/ins) polymorphism. Embedded in this 7922 bp region was a TTCC short tandem repeat (STR). Genotype analysis showed that both the internal STR and the (del/ins) mutation were true polymorphisms. This is a novel example of intraallelic variation, a polymorphism within a polymorphism, and we suggest that it be termed a "Matroshka" polymorphism. Further genetic and DNA sequence analysis indicated that the ancestral state of the 1669-9590 del/ins polymorphism was the insertion allele and that the original deletion mutation probably occurred only once. A second class of novel DNA sequence variation was discovered on chromosome 5 that shared a 328 bp identical sequence with this region on chromosome 1. A single nucleotide polymorphism (SNP) was detected by SSCP using a pair of primers derived from the chromosome 1 sequence. Surprisingly, these primers also amplified the identical locus on chromosome 5, and the SNP was only located on chromosome 5. Since the probe unexpectedly detected alleles from another locus, we suggest that this type of sequence variant be termed an "ectopic" polymorphism. These two novel classes of DNA sequence polymorphisms have the potential to confound genetic and DNA sequence analysis and may also contribute to variation in disease phenotypes.

Alleles↗
PubMed2001

Time for T.

Genetic defects responsible for cleft lip and cleft palate are only now beginning to be uncovered. Mutations in the gene encoding a T-box transcription factor have been identified as the cause of the rare X-linked syndrome cleft palate with tongue-tie. And in another study, heterozygotes for a defective allele for a cell adhesion molecule, which is responsible for a rare clefting syndrome when homozygous, have been found at higher than expected incidence in sporadic forms of clefting.

Cleft Lip↗
PubMed2001

Genetic susceptibility to preeclampsia: roles of cytosineto-thymine substitution at nucleotide 677 of the gene for methylenetetrahydrofolate reductase, 68-base pair insertion at nucleotide 844 of the gene for cystathionine beta-synthase, and factor V Leiden mutation.

OBJECTIVE: The purpose of this study was to evaluate the association between preeclampsia and 3 relatively common mutations that are important in the development of vascular disease and thrombosis; these are similar to conditions observed in pregnancies complicated by preeclampsia. STUDY DESIGN: Deoxyribonucleic acid was extracted from whole blood or cheek swabs of 281 patients with preeclampsia and 360 control subjects (all white). Control subjects consisted of women who had undergone at least 2 term pregnancies unaffected by preeclampsia. Mutation frequencies among patients with preeclampsia and control subjects were compared by standard chi2 analysis, with P <.05 considered significant. RESULTS: Thirty-three of 281 women with preeclampsia (11.7%) and 22 of 193 women with severe preeclampsia (11.4%) were homozygous for cytosine-to-thymine substitution at nucleotide 677 in the gene for methyltetrahydrofolate reductase (MTHFR), versus 41 of 360 control subjects (11.4%; difference not significant). Forty of 258 women with preeclampsia (15.5%) and 22 of 175 women with severe preeclampsia (12.6%) were heterozygous for the insertion of 68 bases at position 844 in the gene for cystathionine beta-synthase (CBS), versus 58 of 332 control subjects (17.5%). Fifteen of 250 women with preeclampsia (6.0%) and 11 of 169 with severe preeclampsia (6.5%) were heterozygous for the Leiden mutation (glycine-to-alanine substitution at nucleotide 1691) in the gene for factor V (F5), versus 12 of 253 control subjects (4.7%; difference not significant). CONCLUSION: In this white population a missense mutation of MTHFR, an insertion mutation of CBS, and a missense mutation of F5 were not found to be associated with an increased risk for preeclampsia, either independently or in combination.

Amino Acid Substitution↗
PubMed2001

Lipoprotein lipase gene mutations and the genetic susceptibility of preeclampsia.

In the pathogenesis of preeclampsia, endothelial cell activation or dysfunction is a central theme, and marked dyslipidemia may contribute to endothelial cell dysfunction. The objective of this study was to evaluate the association between preeclampsia and mutations within the lipoprotein lipase (LPL) gene. DNA was extracted from whole blood or cheek swabs of 250 preeclamptic patients, 265 control subjects, and 106 offspring of preeclamptic patients (all white). Control subjects were women who had undergone >/=2 term pregnancies unaffected by preeclampsia. All samples were genotyped for 3 LPL polymorphisms with the use of polymerase chain reaction of known allelic variants. The 3 mutations studied were the following: (1) Asp9Asn substitution in exon 2, (2) T-to-G substitution at position -93 of the proximal promotor region (-93T/G), and (3) Asn291Ser substitution in exon 6. Results were analyzed with an chi(2) contingency table. The prevalences of the Asp9Asn mutation, -93T/G promotor mutation, and Asn291Ser mutation were not significantly different among the preeclamptic patients and control subjects (Asp9Asn: patients, 2.8%; control subjects, 4.0%; -93T/G: patients, 4.5%; control subjects, 5.5%; Asn291Ser: patients, 4.0%; control subject, 3.0%). In addition, there was no difference in the frequency of any of the mutations in the offspring of preeclamptic women compared with that observed in the control population. Between a small group of patients with nulliparous HELLP syndrome (a variant of severe preeclampsia: hemolysis, elevated liver enzyme, low platelets) patients (n=12) and control subjects, there was a significant difference in the prevalence of the Asn291Ser mutation (16.7% versus 3.0%, P=0.01). In this large white population, the Asp9Asn mutation, -93T/G promotor mutation, and Asn291Ser mutation were not associated with an increased risk for preeclampsia. In a small subgroup of patients, the Asn291Ser mutation was associated with an increased risk for nulliparous HELLP syndrome.

Female↗
PubMed2001

Antagonistic regulation of Dlx2 expression by PITX2 and Msx2: implications for tooth development.

The transcriptional mechanisms underlying tooth development are only beginning to be understood. Pitx2, a bicoid-like homeodomain transcription factor, is the first transcriptional marker observed during tooth development. Because Pitx2, Msx2, and Dlx2 are expressed in the dental epithelium, we examined the transcriptional activity of PITX2 in concert with Msx2 and the Dlx2 promoter. PITX2 activated while Msx2 unexpectedly repressed transcription of a TK-Bicoid luciferase reporter in a tooth epithelial cell line (LS-8) and CHO cell line. Surprisingly, Msx2 binds to the bicoid element (5'-TAATCC-3') with a high specificity and competes with PITX2 for binding to this element. PITX2 binds to bicoid and bicoid-like elements in the Dlx2 promoter and activates this promoter 45-fold in CHO cells. However, it is only modestly activated in the LS-8 tooth epithelial cell line that endogenously expresses Msx2 and Pitx2. RT-PCR and Western blot assays reveal that two Pitx2 isoforms are expressed in the LS-8 cells. We further demonstrate that PITX2 dimerization can occur through the C-terminus of PITX2. Msx2 represses the Dlx2 promoter in CHO cells and coexpression of both PITX2 and Msx2 resulted in transcriptional antagonism of the Dlx2 promoter. Electrophoretic mobility shift assays demonstrate that factors in the LS-8 cell line specifically interact with PITX2. Thus, Dlx2 gene transcription is regulated by antagonistic effects between PITX2, Msx2, and factors expressed in the tooth epithelia.

Animals↗
PubMed2001

Long-circulating and target-specific nanoparticles: theory to practice.

The rapid recognition of intravenously injected colloidal carriers, such as liposomes and polymeric nanospheres from the blood by Kupffer cells, has initiated a surge of development for "Kupffer cell-evading" or long-circulating particles. Such carriers have applications in vascular drug delivery and release, site-specific targeting (passive as well as active targeting), as well as transfusion medicine. In this article we have critically reviewed and assessed the rational approaches in the design as well as the biological performance of such constructs. For engineering and design of long-circulating carriers, we have taken a lead from nature. Here, we have explored the surface mechanisms, which affords red blood cells long-circulatory lives and the ability of specific microorganisms to evade macrophage recognition. Our analysis is then centered where such strategies have been translated and fabricated to design a wide range of particulate carriers (e.g., nanospheres, liposomes, micelles, oil-in-water emulsions) with prolonged circulation and/or target specificity. With regard to the targeting issues, attention is particularly focused on the importance of physiological barriers and disease states.

Animals↗
PubMed2000

Deletion in the promoter region and altered expression of Pitx3 homeobox gene in aphakia mice.

Mouse aphakia (ak) is a recessive phenotype that spontaneously occurs in the 129/Sv-SlJ strain and is characterized by small eyes that lack a lens. We have recently identified a homeobox-containing gene, Pitx3, and have shown that it is expressed in the developing lens and maps to chromosome 19 close to ak in mouse. Human PITX3 gene was found to underlie anterior segment dysgenesis and cataracts. We have now obtained the entire sequence of the mouse Pitx3 gene including 10 kb of the 5' region and 5 kb of the 3' region. Of several microsatellite repeat regions identified within the Pitx3 sequence, one was informative for linkage analysis. No recombination was observed between ak and the Pitx3 marker, indicating that these two loci are closely linked (0.2 +/- 0.2 cM). Additionally, Pitx3 transcripts were not detected in the ak/ak mice either in the lens placode or at later developmental stages of the lens by in situ hybridization. Since no differences were previously found between ak/ak and wild-type sequences in the Pitx3 coding region, we hypothesized that an etiologic mutation is located in the promoter or other regulatory regions. To test this hypothesis we studied the 5' flanking region of the Pitx3 gene. This analysis revealed a deletion of 652 bp located 2.5 kb upstream from the start point of the Pitx3 5' UTR sequence in ak/ak mice. The deletion co-segregated with the ak mutation and was not detected in 16 samples from 10 different mouse strains including the founder strains. Analysis of the 652 bp region identified sequences similar to consensus binding sites for transcription factors AP-2 and Maf that were shown to play a critical role in lens determination. These lines of evidence suggest that the abnormal ocular development in the aphakia mouse is due to the deletion upstream of the Pitx3 gene.

Acetyltransferases↗
PubMed2000

Prostate adenocarcinoma cells release the novel proinflammatory polypeptide EMAP-II in response to stress.

The proinflammatory protein endothelial monocyte-activating polypeptide II (EMAP-II) was first detected in supernatants of murine tumor cells by virtue of its ability to stimulate endothelial-dependent coagulation in vitro. The purified protein has pleiotropic effects on endothelial cells, monocytes, and neutrophils; however, its function in vivo is unknown, and the mechanism whereby it is released from cells is poorly understood. We investigated the expression of EMAP-II in human prostate adenocarcinoma specimens by immunohistochemistry and in LNCaP and DU-145 human prostate adenocarcinoma cells by reverse transcription-PCR, flow cytometry, and Western blotting. We then examined the effects of chemical and physiological stress on release and processing of EMAP-II by LNCaP and DU-145 cells. These cells constitutively express a Mr 34,000 form of EMAP-II that is retained intracellularly. Exposure to agents that induce apoptosis or, in some cases, necrosis induces the release of the Mr 34,000 form and further processing to the Mr 27,000 and Mr 22,000 forms. Hypoxia, but not heat shock, is a potent inducer of release and processing of biologically active EMAP-II by LNCaP and DU-145 cells. We suggest that release of EMAP-II by prostate adenocarcinoma cells as a consequence of treatment with anticancer agents or as a result of constitutive hypoxia may potentiate the effects of those agents through the localized activation of host effector mechanisms.

Adenocarcinoma↗
PubMed2000

Exclusion of the branchio-oto-renal syndrome locus (EYA1) from patients with branchio-oculo-facial syndrome.

In addition to craniofacial, auricular, ophthalmologic, and oral anomalies, the distinctive phenotype of the branchio-oculo-facial (BOF) syndrome (MIM 113620) includes skin defects in the neck or infra/supra-auricular region. These unusual areas of thin, erythematous wrinkled skin differ from the discrete cervical pits, cysts, and fistulas of the branchio-oto-renal (BOR) syndrome (MIM 113650). Although the BOF and BOR syndromes are sufficiently distinctive that they should not be confused, both can be associated with nasolacrimal duct stenosis, deafness, prehelical pits, malformed pinna, and renal anomalies. Furthermore, a reported father and son [Legius et al., 1990, Clin Genet 37:347-500] had features of both conditions. It was not clear whether they had an atypical presentation of either BOR or BOF syndrome, or represented a private syndrome. In light of these issues, we selected the BOR locus (EYA1) as a possible gene mutation for the BOF syndrome. In five BOF patients, there were no mutations detected in the EYA1 gene, suggesting that it is not allelic to the BOR syndrome.

Branchio-Oto-Renal Syndrome↗
PubMed2000

Gene-transfer systems for human endothelial cells. stewart.martin@nottingham.ac.uk.

By virtue of its location and importance in a number of pathophysiological processes the endothelium represents an attractive target tissue for gene-transfer and gene-therapy strategies. Although it is important to maximise gene-transfer to endothelial cells in such strategies primary human endothelial cells have proven to be rather intransigent to a variety of transfection techniques both in vitro and in vivo. We report on the variety of techniques in current use, revealing their strengths and weaknesses, indicate the steps that should ideally be taken to optimise expression and discuss the usefulness and future directions for viral mediated transduction.

Endothelium, Vascular↗