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J C Murray

Publications and source records attributed to J C Murray.

At least 73 records · Page 4Linked to original sources
PubMed1999

The many faces and factors of orofacial clefts.

Orofacial clefts are congenital structural anomalies of the lip and/or palate that affect approximately 1/1000 live births. Their frequent occurrence as well as their extensive psychological, surgical, speech and dental involvement emphasize the importance of understanding the underlying causes. The etiology of orofacial clefts is complex, including multiple genetic and environmental factors. Rare forms, where they occur as one component of multiple congenital anomaly syndromes, have Mendelian or teratogenic origins; the non-syndromic forms of orofacial clefts are more common and are likely due to secondary gene-environment interactions. Recent advances in both molecular and quantitative approaches have begun to identify the genes responsible for the rare syndromic forms of cleft and have also identified both candidate genes and loci for the more common and complex non-syndromic variants. Animal models, in particular the mouse, have also contributed greatly to an understanding of these disorders. This review describes genes that are involved in orofacial clefts in humans and animal models and explores genetic approaches to identifying additional genes and gene-environment interactions that constitute the many factors of orofacial clefts.

Animals↗
PubMed1998

Characterization of a novel gene disrupted by a balanced chromosomal translocation t(2;19)(q11.2;q13.3) in a family with cleft lip and palate.

Cleft lip with or without cleft palate is a common birth defect that is genetically complex. The nonsyndromic forms have been studied genetically using linkage and candidate-gene association studies with only partial success in defining the loci responsible for orofacial clefting. Loci for nonsyndromic cases have been suggested on 2p13, 4q31, 6p24, 17q21-q24, and 19q13.2. Recently, we identified a family in which cleft lip and palate segregated in two of three generations with a balanced chromosomal translocation t(2;19)(q11. 2;q13.3). We used a positional-cloning strategy to identify a novel gene disrupted by the translocation on chromosome 19. Eight rare (q < 0.01) and nine common (q > 0.01) variants of this gene were detected in the DNA of 74 unrelated cases of cleft lip and/or cleft palate; no variants associated significantly with clefting, suggesting that this gene is not a major contributor to abnormal craniofacial development. This gene, CLPTM1, was ubiquitously expressed on Northern blots containing RNA from adult tissues and in whole-mount in situ hybridization of day 10 to 12 mouse embryos. CLPTM1 encodes a transmembrane protein and has strong homology to two Caenorhabditis elegans genes, suggesting that CLPTM1 may belong to a new gene family.

Alleles↗
PubMed1998

Cloning and partial characterization of the human tie-2 receptor tyrosine kinase gene promoter.

The Tie-2 receptor plays a key role in vascular development, although little is known about the factors controlling its expression. Here we report the first cloning and characterisation of the 5' regulatory region of human tie-2. Multiple transcription start sites were identified between -414 and -265 bp upstream of the start codon using 5' RACE, fluorescent primer extension, and RNase protection assays. The human tie-2 promoter contains several transcription factor-binding sequences including ets, SP-1, AP-1, and GATA-1, but there are no canonical TATA or CCAAT initiation sequences proximal to the transcription start sites. Human tie-2 reporter constructs demonstrated approximately 10-fold greater activity in endothelial cells compared with fibroblasts. In endothelial cells the tie-2 promoter exhibited 5 and 16% of the activity of human tie-1 (830 bp) and KDR (1.1 kb) promoters, respectively. This promoter will be a useful tool for studying factors that regulate tie-2 expression and targeting the vasculature.

Animals↗
PubMed1998

Pitx2, a bicoid-type homeobox gene, is involved in a lefty-signaling pathway in determination of left-right asymmetry.

Signaling molecules such as Activin, Sonic hedgehog, Nodal, Lefty, and Vg1 have been found to be involved in determination of left-right (L-R) asymmetry in the chick, mouse, or frog. However, a common signaling pathway has not yet been identified in vertebrates. We report that Pitx2, a bicoid-type homeobox gene expressed asymmetrically in the left lateral plate mesoderm, may be involved in determination of L-R asymmetry in both mouse and chick. Since Pitx2 appears to be downstream of lefty-1 in the mouse pathway, we examined whether mouse Lefty proteins could affect the expression of Pitx2 in the chick. Our results indicate that a common pathway from lefty-1 to Pitx2 likely exists for determination of L-R asymmetry in vertebrates.

Animals↗
PubMed1998

Cloning, characterization, and mapping of the mouse homeobox gene Hmx1.

Homeobox-containing genes play an important role in development, including positional specification of the body plan and organogenesis. We previously isolated the human HMX1 (H6) gene, a novel homeobox-containing gene of the HMX family, from a human embryonic craniofacial cDNA library. The closely related mouse genes Hmx3 (Nkx5.1) and Hmx2 (Nkx5.2) are in the same class as the HMX1 gene and are expressed in the craniofacial region of the developing embryo. To provide a resource for further characterization of the human HMX1 gene, we isolated the mouse Hmx1 genomic clone. We show here the mouse Hmx1 genomic sequence, its gene mapping, and its expression pattern in the developing mouse embryo. Evidence is presented showing that the three known Hmx genes in the mouse likely play complementary roles in the development of the second arch, retina, sympathetic nerve ganglia, and cranial neural ganglia. Hmx1 may play an important role in the development of craniofacial structures and may interact with Hoxa-2 and Dlx-2 in the second branchial arch.

Amino Acid Sequence↗
PubMed1998

Autosomal dominant iris hypoplasia is caused by a mutation in the Rieger syndrome (RIEG/PITX2) gene.

PURPOSE: To determine whether autosomal dominant iris hypoplasia is caused by mutations in the newly described gene for Rieger syndrome (RIEG/PITX2). METHOD: Mutation screening and sequence analysis was performed in a single family. RESULTS: A novel mutation in the RIEG/PITX2 gene was found in all affected but no unaffected individuals. This mutation would be expected to result in an arginine to tryptophan amino acid change in the homeodomain of solurshin, the RIEG/ITX2 gene product. CONCLUSION: Autosomal dominant iris hypoplasia is caused by a defect in the same gene that is defective in many cases of Rieger syndrome.

Anterior Chamber↗
PubMed1998

Detection of double minute chromosomes in a child with acute lymphoblastic leukemia.

A child with acute lymphoblastic leukemia (ALL) whose predominant leukemic clone demonstrated double minute chromosomes (dmin) is presented. The patient had no history of mutagen or carcinogen exposure and responded well to combination chemotherapy. Although dmin have been described in acute myelogenous leukemia and various solid tumors in adults, their presence in childhood neoplasms is less frequent and limited primarily to neurogenic tumors. This is the first documentation of dmin in childhood ALL, suggesting that there may be an unrecognized subgroup of ALL patients with gene amplification.

Child↗
PubMed1998

The effect of follow-up on limiting non-participation bias in genetic epidemiologic investigations.

The use of a comprehensive follow-up strategy to limit non-participation bias was evaluated in a population-based case-control study of orofacial clefts. Birth parents were requested to provide exposure data, and index children and parents were asked to provide blood specimens. Follow-up included telephone or postal reminders every two weeks for up to three months. Consent to participate was received from 281 (76.6%) case mothers and 246 (72.4%) case fathers. The corresponding totals for controls were 279 (54.7%) and 245 (49.8%). Evaluation of participation rates by intensity of follow-up showed that 23% of case and 18% of control families consented without reminders (first stage); 81% of cases and 83% of controls agreed following one or two reminders (second stage); and the remainder of participants consented following three or more reminders (final stage). Cumulative distributions of sociodemographic characteristics differed little between second and final stage participants. Odds ratios for maternal multivitamin use were similar between second and final stage participants, whereas those for maternal and paternal smoking tended to decline. Although follow-up measures were necessary to enroll most families, use of more than two reminders did not appear to increase the representativeness of the sample; however, termination of recruitment after only two reminders would have led to different conclusions. Future studies require data collection protocols that encourage participation from all population subgroups, and one alternative is presented.

Adult↗
PubMed1998

A novel homeobox gene PITX3 is mutated in families with autosomal-dominant cataracts and ASMD.

We report here the identification of a new human homeobox gene, PITX3, and its involvement in anterior segment mesenchymal dysgenesis (ASMD) and congenital cataracts in humans. The PITX3 gene is the human homologue of the mouse Pitx3 gene and is a member of the RIEG/PITX homeobox gene family. The protein encoded by PITX3 shows 99% amino-acid identity to the mouse protein, with 100% identity in the homeodomain and approximately 70% overall identity to other members of this family. We mapped the human PITX3 gene to 10q25 using a radiation-hybrid panel. A collection of 80 DNA samples from individuals with various eye anomalies was screened for mutations in the PITX3 gene. We identified two mutations in independent patients. A 17-bp insertion in the 3'-end of the coding sequence, resulting in a frame shift, occurred in a patient with ASMD and cataracts, and a G-->A substitution, changing a codon for serine into a codon for asparagine, in the 5'-end of the gene occurred in a patient with congenital cataracts. Both mutations cosegregate with the disease phenotype in families, and neither were found in up to 300 control individuals studied. Further expression analysis of Pitx3 in the mouse supports a unique role in early ocular development, with later expression extending to the midbrain, tongue, incisors, sternum, vertebrae and limbs. These data strongly suggest a role for PITX3 in ASMD and cataracts and provide new evidence of the contribution of the RIEG/PITX gene family to the developmental program underpinning normal eye formation.

Amino Acid Sequence↗
PubMed1998

Association of MSX1 and TGFB3 with nonsyndromic clefting in humans.

Nonsyndromic cleft lip with or without cleft palate (CL/P) and nonsyndromic cleft palate only (CPO) are common congenital anomalies with significant medical, psychological, social, and economic ramifications. Both CL/P and CPO are examples of complex genetic traits. There exists sufficient evidence to hypothesize that disease loci for CL/P and CPO can be identified by a candidate-gene linkage-disequilibrium (LD) strategy. Candidate genes for clefting, including TGFA, BCL3, DLX2, MSX1, and TGFB3, were screened for LD with either CL/P or CPO in a predominantly Caucasian population, with both case-control- and nuclear-family-based approaches. Previously reported LD for TGFA with both CL/P and CPO could not be confirmed, except in CL/P patients with a positive family history. Also, in contrast to previous studies, no LD was found between BCL3 and either CL/P or CPO. Significant LD was found between CL/P and both MSX1 and TGFB3 and between CPO and MSX1, suggesting that these genes are involved in the pathogenesis of clefting. In addition, a mutation search in the genes DLX2, MSX1, and TGFB3 was performed in 69 CPO patients and in a subset of the CL/P patients. No common mutations were found in the coding regions of these genes; however, several rare variants of MSX1 and TGFB3 were found that may alter the latters' normal function. These results form the basis for future research, including (a) mutation searches in the MSX1 and TGFB3 genes in Caucasian CL/P patients and (b) extension of the search for MSX1 mutations in CPO patients to the noncoding regions.

Amino Acid Substitution↗
PubMed1998

Comprehensive human genetic maps: individual and sex-specific variation in recombination.

Comprehensive human genetic maps were constructed on the basis of nearly 1 million genotypes from eight CEPH families; they incorporated >8,000 short tandem-repeat polymorphisms (STRPs), primarily from Généthon, the Cooperative Human Linkage Center, the Utah Marker Development Group, and the Marshfield Medical Research Foundation. As part of the map building process, 0.08% of the genotypes that resulted in tight double recombinants and that largely, if not entirely, represent genotyping errors, mutations, or gene-conversion events were removed. The total female, male, and sex-averaged lengths of the final maps were 44, 27, and 35 morgans, respectively. Numerous (267) sets of STRPs were identified that represented the exact same loci yet were developed independently and had different primer pairs. The distributions of the total number of recombination events per gamete, among the eight mothers of the CEPH families, were significantly different, and this variation was not due to maternal age. The female:male ratio of genetic distance varied across individual chromosomes in a remarkably consistent fashion, with peaks at the centromeres of all metacentric chromosomes. The new linkage maps plus much additional information, including a query system for use in the construction of reliably ordered maps for selected subsets of markers, are available from the Marshfield Website.

Chromosome Mapping↗
PubMed1998

A new human homeobox gene OGI2X is a member of the most conserved homeobox gene family and is expressed during heart development in mouse.

Homeodomain (HD) proteins are transcription regulators controlling a variety of cell fates. The HD region characterizing this protein family is a domain of 60 amino acid residues that recognizes and binds a site in the regulatory region of the target gene. It has been suggested that regions outside the HD may determine the specific functions of the various HD proteins by forming additional contacts with DNA sequences or by interactions with other proteins. We have identified a 14 amino acid motif within the C-terminal region of the protein encoded by the RIEG1 gene that is conserved among several HD proteins. Overlapping expression of the genes encoding these proteins during craniofacial development suggested that they might interact with a common factor. In order to identify additional genes possessing this motif we screened a human craniofacial cDNA library with oligoprobes. A novel gene was identified, exhibiting the most homology to murine Og12x (formerly OG12) and the recently reported human SHOX gene. Human OG12X and murine Og12x are highly homologous and the OG12X and Og12x proteins are 100% identical. In situ hybridization on mouse embryos ranging from 9 to 16 days post-coitum localized murine Og12x mRNA in the heart, otic region, maxillary and mandibular components of the first branchial arch, nasal processes, eyelid, midbrain, medulla oblongata, limbs, dorsal root ganglia and genital tubercle. OG12X was mapped to human chromosome 3q22-26 and murine Og12x to the syntenic region on mouse chromosome 3. Based upon the expression pattern of its mouse cognate, OG12X represents a candidate for the blepharophimosis (BPES) and Cornelia de Lange syndromes previously mapped to this region.

Amino Acid Sequence↗
PubMed1998

Infant TGF-alpha genotype, orofacial clefts, and maternal periconceptional multivitamin use.

OBJECTIVE: We previously demonstrated a strong association between periconceptional maternal cigarette smoking, infant transforming growth factor-alpha (TGFa) genotype, and risk of orofacial clefts. Because serum folate may be decreased by cigarette smoking and because maternal periconceptional use of multivitamins containing folic acid has been associated with a reduced risk of clefting, we explored whether a potential relation existed between infant TGFa genotype, maternal multivitamin use, and risk of orofacial cleft phenotypes. DESIGN: Data were derived from a population-based case-control study of fetuses and live-born infants among a cohort of 1987 to 1989 California births (n = 548,844). Information concerning periconceptional multivitamin use was obtained via telephone interviews with mothers of 731 (84.7% of eligible) orofacial cleft case infants, and of 734 (78.2%) nonmalformed control infants. DNA was obtained from newborn screening bloodspots and genotyped for the Taql polymorphism of TGFa. Among infants of interviewed mothers, genotypes were available for 571 (78.1%) case infants and 640 (87.2%) control infants. SETTING: The study encompassed all hospitals in selected California counties. MAIN OUTCOME MEASURE: The main outcome measures were the risks of specific cleft phenotypes among infants with uncommon TGFa genotypes and whose mothers did not use multivitamins periconceptionally. RESULTS: Compared with infants homozygous for the common TGFa genotype and whose mothers used multivitamins, increased clefting risks were observed for infants with the A2 genotype (homozygous or heterozygous) and whose mothers did not use multivitamins. Risk estimates were 3.0 (1.4-6.6 [95% confidence interval]) for isolated cleft lip with or without cleft palate (CLP), 2.4 (0.69-11.6) for multiple CLP, 2.6 (0.97-7.7) for isolated cleft palate (CP), 4.2 (1.3-16.2) for multiple CP, and 8.1 (2.6-27.7) for "known-syndrome" clefts. Clefting risks for infants with the A2 genotype and whose mothers used multivitamins were substantially smaller, as were the risks for infants with the A1 genotype whose mothers did not use multivitamins. CONCLUSION: These data provide preliminary evidence for a gene-nutrient interaction in risk of clefting.

Adult↗
PubMed1997

Maternal interview reports of family history of birth defects: evaluation from a population-based case-control study of orofacial clefts.

Accurate family histories of birth defects are critical for risk assessment and etiologic investigations. Typically, information about family history of birth defects is ascertained from interviews with birth mothers of index children; however, the quality of these interviews is rarely assessed. We evaluated family history information provided by case (n = 28) and control (n = 29) mothers who participated in a population-based, case-control study of orofacial clefts. Interview responses from mothers were compared to questionnaire reports collected by mail from first- and second-degree parental relatives. A total of 345 case and 380 control adult relatives completed questionnaires. These relatives also provided reports for 130 case and 169 control offspring. To examine the quality of birth defect reports, the sensitivity and specificity of birth mother responses were calculated. Sensitivity for presence (yes/no) of a birth defect was 31% for case mothers and 9% for control mothers. Specificity for case and control mothers was 98% and 97%, respectively. Interview responses from mothers who participate in family genealogy were more likely to be concordant with relative reports than were responses from mothers who do not participate in family genealogy. Case mother responses were more likely to be concordant than control mother responses. These results suggest that reliance on interview reports from birth mothers may lead to an underestimation of the occurrence of birth defects in relatives. Future investigations should explore methods to improve the quality of informant reports about family histories of birth defects. One alternative approach is discussed.

Case-Control Studies↗
PubMed1997

Genomic structure, sequence, and mapping of human FGF8 with no evidence for its role in craniosynostosis/limb defect syndromes.

Fibroblast growth factor-8 (Fgf8) is a recently identified growth factor that stimulates the androgen-dependent growth of mouse mammary carcinoma cells. Evidence from mouse development also shows that Fgf8 may play an important role in growth and patterning of limbs, face, and the central nervous system. We describe here the human FGF8 genomic sequence and demonstrate conservation between the human and mouse sequences, including alternatively spliced exons in the mouse. Mapping of FGF8 by FISH using an FGF8-containing bacterial artificial chromosome and by genetic linkage using a SSCP variant identified in this study is also reported and refines the FGF8 map location to 10q24. Since FGF8 maps to the same chromosomal region as FGFR2, has indeed been shown to be a ligand for FGFR2, and has an expression pattern consistent with limb and craniofacial anomalies, we have screened two kindreds with Pfeiffer syndrome that were previously linked to markers from 10q24-25 and a large number of individuals with craniosynostosis and limb anomalies for mutations in the coding sequence of FGF8. While no such mutations were identified, a rare polymorphic variant, consisting of an 18-base-pair (six-amino-acid) duplication in exon 1c, is reported that apparently has no clinical effect. Our exclusionary data suggest that mutations in FGF8 would be, at best, an infrequent cause of such disorders.

Amino Acid Sequence↗
PubMed1997

Sequence and chromosomal assignment of human BAPX1, a bagpipe-related gene, to 4p16.1: a candidate gene for skeletal dysplasia.

Homeobox-containing genes play an important role in both body axis determination and specific organ development. They have increasingly been found to be mutated in human birth defect disorders. Sequences of two bagpipe-related genes in the mouse, Nkx-3.1 and Nkx-3.2, have already been reported. Nkx-3.1 was isolated from the prostate, and its human homolog NKX-3.1 has also been described. Mouse Nkx-3.2, or bapx1, has also been isolated, and its expression in the visceral mesoderm and embryonic skeleton in the mouse has been described. We report here the human BAPX1 sequence and its localization to chromosome region 4p16.1 and suggest BAPX1 as a candidate for disorders of skeletal development that might map to 4p16.1.

Amino Acid Sequence↗