Biomedical subjects

C W Richard

Publications and source records attributed to C W Richard.

At least 19 recordsLinked to original sources

PubMed2000

Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.

Hereditary paraganglioma (PGL) is characterized by the development of benign, vascularized tumors in the head and neck. The most common tumor site is the carotid body (CB), a chemoreceptive organ that senses oxygen levels in the blood. Analysis of families carrying the PGL1 gene, described here, revealed germ line mutations in the SDHD gene on chromosome 11q23. SDHD encodes a mitochondrial respiratory chain protein-the small subunit of cytochrome b in succinate-ubiquinone oxidoreductase (cybS). In contrast to expectations based on the inheritance pattern of PGL, the SDHD gene showed no evidence of imprinting. These findings indicate that mitochondria play an important role in the pathogenesis of certain tumors and that cybS plays a role in normal CB physiology.

Alleles↗

PubMed1999

Genomic structure of the human PLZF gene.

The human PLZF (promyelocytic leukaemia zinc finger) gene encodes a Krüppel-like zinc finger protein, which was identified via the reciprocal translocation t(11;17)(q23;q21) fusing it to the retinoic acid receptor alpha (RARalpha) gene in promyelocytic leukaemia. To determine its complete genomic organisation, we constructed a cosmid-map fully containing the hPLZF gene. The gene has seven exons, including a novel 5' untranslated exon, varying in size from 87 to 1358bp and spans at least 120kb. Flanking intronic sequences were identified and all splice acceptor and donor sites conformed to the gt/ag rule. Five polymorphic markers could be fine located in its vicinity. These data will facilitate mutation analysis of hPLZF in t(11;17) leukaemia cases, as well as assist mapping and loss-of-heterozygosity analysis. Here we have tested hPLZF as a possible candidate for the PGL1 locus involved in hereditary head and neck paragangliomas. However, mutation analysis revealed no aberration in 12 paraganglioma patients from different families.

Base Sequence↗

PubMed1999

Repositioning the hereditary paraganglioma critical region on chromosome band 11q23.

Hereditary paragangliomas (PGL, glomus tumors, MIM no.168000) are mostly benign, slow-growing tumors of the head and neck region. The gene (or genes) affecting risk to PGL are subject to genomic imprinting: children of affected fathers exhibit an autosomal dominant pattern of disease inheritance, whereas children of affected mothers rarely if ever develop the disease through maternal transmission. We previously confined the disease gene to an approximately 6 Mb critical region on chromosome band 11q23 (PGL1). Based on haplotype analysis of an extended Dutch pedigree, a 2 Mb sub-region between D11S938 and D11S1885 was proposed as the PGL1 critical interval. In this study, we excluded this interval by analysis of two new single tandem repeat polymorphisms (STRP) contained therein. Instead, we predicted a non-overlapping, more proximal 2 Mb critical interval between D11S1647 and D11S897, and evaluated this new region using nine STRP (D11S1986, five new, closely-linked STRP, D11S1347, D11S3178, and D11S1987). Consistent with our prediction, we observed substantial haplotype-sharing within the Dutch pedigree. We also analyzed four new American PGL families. A recombination event detected in one family further defined D11S1347 as the new telomeric border. We observed significant haplotype-sharing within this new interval among three unrelated American PGL families, strongly suggesting that they originated from a common ancestor. Thus, we confined PGL1 to an approximately 1.5 Mb region between D11S1986 and D11S1347, and showed identity-by-descent sharing for a group of American PGL families.

Chromosome Banding↗

PubMed1999

Fine mapping of the split-hand/split-foot locus (SHFM3) at 10q24: evidence for anticipation and segregation distortion.

Split-hand/split-foot malformation (SHFM, ectrodactyly, or lobster-claw deformity) is a human limb malformation characterized by aberrant development of central digital rays with absence of fingers and toes, a deep median cleft, and fusion of remaining digits. SHFM is clinically heterogeneous, presenting both in an isolated form and in combination with additional abnormalities affecting the tibia and/or other organ systems, including the genitourinary, craniofacial, and ectodermal structures. Three SHFM disease loci have been genetically mapped to chromosomes 7q21 (SHFM1), Xq26 (SHFM2), and 10q24 (SHFM3). We mapped data from a large Turkish family with isolated SHFM to chromosome 10q24 and have narrowed the SHFM3 region from 9 cM to an approximately 2-cM critical interval between genetic markers D10S1147 and D10S1240. In several instances we found evidence for a more severe phenotype in offspring of a mildly affected parent, suggesting anticipation. Finally, data from this family, combined with those from six other pedigrees, mapped to 10q24, demonstrate biased transmission of SHFM3 alleles from affected fathers to offspring. The degree of this segregation distortion is obvious in male offspring and is possibly of the same magnitude for female offspring.

Chromosome Mapping↗

PubMed1998

Genomic organization and precise physical location of protein phosphatase 2A regulatory subunit A beta isoform gene on chromosome band 11q23.

Protein phosphatase 2A (PP2A) holoenzyme plays a critical role in cell-cycle control and growth-factor signaling, and is implicated in tumorigenesis. Because the protein phosphatase 2 regulatory subunit A beta isoform gene (PPP2R1B) maps within the critical region of hereditary paraganglioma (PGL1) on chromosomal band 11q23, we characterized its genomic structure and evaluated it as a candidate gene for PGL1. PPP2R1B has 15 exons spanning approx. 27kb genomic distance. We placed the exons on genomic EcoRI fragments and identified their flanking intronic sequences. The gene was oriented from telomere to centromere. Splice acceptor and donor sites of all introns conformed to the GT/AG rule. Northern analysis with a cDNA probe identified 2.5kb and 5.0kb transcript sizes. We identified an ATG initiation codon in a favorable context and mapped two transcription start sites 15bp and 66bp upstream of it. We also mapped a 3'-polyadenylation site 504bp downstream of the TGA stop codon, consistent with the 2.5kb transcript size. We did not detect germ-line mutations by single-stranded conformational polymorphism (SSCP) analysis or major rearrangements by Southern analysis in a set of PGL1 patients. In conclusion, we precisely mapped and characterized the structure of PPP2R1B and evaluated it as a candidate gene for PGL1.

Base Sequence↗

PubMed1998

Bipolar affective disorder partially cosegregates with a balanced t(9;11)(p24;q23.1) chromosomal translocation in a small pedigree.

Analysis of an extended pedigree in which a balanced t(9;11)(p24;q23.1) translocation was found to cosegregate with bipolar affective disorder revealed that five of 11 translocation carriers had bipolar affective disorder and one carrier had unipolar depression. There were no affected individuals in the pedigree without the balanced translocation. We hypothesized that gene(s) or gene regulatory regions disrupted by the translocation might be contributing to the bipolar affective disorder in a dominant fashion. To test this hypothesis, we isolated the derivative chromosome 9 and derivative chromosome 11 in somatic cell hybrids and identified the nearest flanking markers on chromosome 9 (D9S230 and D9S2011E/HRFX3) and chromosome 11 (EST00652 and CRYA2). YAC contigs were constructed in the region of flanking markers for both chromosomes 9 and 11. Chromosome 11 breakpoint was localized within an 8-kb region in a small insert (100 kb) YAC. Chromosome 9 breakpoint was localized within approximately 2 Mb region. Several genes and ESTs including EST00652, CRYA2, DRD2, 5HTR3 on chromosome 11 and VLDLR and SLC1A1 on chromosome 9 were mapped within the vicinity of the breakpoint but were shown not to be disrupted by the translocation breakpoint. Although several possibilities exist regarding the role of the balanced translocation in developing bipolar affective disorder in this pedigree, including a chance cosegregation, identification of a disrupted gene or gene regulatory region with the help of physical mapping resources described in this study may help to identify the presence of a susceptibility gene for this disorder.

Bipolar Disorder↗

PubMed1997

A high-resolution STS, EST, and gene-based physical map of the hereditary paraganglioma region on chromosome 11q23.

The genes responsible for hereditary paragangliomas (glomus tumors, MIM No. 168000) have been mapped to two distinct loci on the long arm of chromosome 11. Most of the informative families appear to be linked to the distal locus on chromosome 11q23 (PGL1), which has been previously confined to a 2-cM interval by haplotype analysis in an extended Dutch pedigree. To facilitate the identification of the PGL1 disease gene, we constructed an approximately 4-Mb ordered clone contig map of Sequence tagged sites, expressed sequence tags (ESTs), and known genes that spans the PGL1 critical region on chromosome 11q23. Among 29 new positional candidate ESTs, only two (EST100999 and EST241777) mapped within the PGL1 critical region. We further characterized the genomic organization of the promyelocytic leukemia zinc finger (PLZF) gene that maps within the PGL1 critical region and physically excluded the serotonin receptor type 3 (5HT3R) gene. Finally, we identified a common, silent, single-base substitution polymorphism in the 5HT3R gene and characterized the allele sets of two new highly polymorphic microsatellite repeats within the PGL1 critical region.

Alleles↗

PubMed1997

Fine mapping of an imprinted gene for familial nonchromaffin paragangliomas, on chromosome 11q23.

Hereditary nonchromaffin paragangliomas (PGL; glomus tumors; MIM 168000) are mostly benign, slow-growing tumors of the head and neck region, inherited from carrier fathers in an autosomal dominant fashion subject to genomic imprinting. Genetic linkage analysis in two large, unrelated Dutch families assigned PGL loci to two regions of chromosome 11, at 11q23 (PGL1) and 11q13.1 (PGL2). We ascertained a total of 11 North American PGL families and confirmed maternal imprinting (inactivation). In three of six families, linkage analysis provided evidence of linkage to the PGL1 locus at 11q23. Recombinants narrowed the critical region to an approximately 4.5-Mb interval flanked by markers D11S1647 and D11S622. Partial allelic loss of strictly maternal origin was detected in 5 of 19 tumors. The greatest degree of imbalance was detected at 11q23, distal to D11S1327 and proximal to CD3D. Age at onset of symptoms was significantly different between fathers and children (Wilcoxon rank-sum test, P < .002). Affected children had an earlier age at onset of symptoms in 39 of 57 father-child pairs (chi2 = 7.74, P < .006). However, a more conservative comparison of the number of pairs in which a child had > or = 5 years earlier age at onset (n = 33) vis-a-vis that of complementary pairs (n = 24) revealed no significant difference (chi2 = 1.42, P > .2). Whether these data represent genetic anticipation or ascertainment bias can be addressed only by analysis of a larger number of father-child pairs.

Adolescent↗

PubMed1996

Cloning of human RTEF-1, a transcriptional enhancer factor-1-related gene preferentially expressed in skeletal muscle: evidence for an ancient multigene family.

Transcriptional Enhancer Factor-1 (TEF-1) is a transcription factor required for cardiac muscle gene activation. Since ablation of TEF-1 does not abolish cardiac gene expression, we sought to identify a human gene related to TEF-1 (RTEF-1) that might also participate in cardiac gene regulation. A human heart cDNA library was screened to obtain a full-length RTEF-1 cDNA. Fluorescence in situ hybridization assigned the RTEF-1 gene to chromosome 12p13.2-p13.3. In contrast, PCR screening of human/rodent cell hybrid panels identified TEF-1 on chromosome 11p15.2, between D11S1315 and D11S1334, extending a region of known synteny between human chromosomes 11 and 12 and arguing for an ancient divergence between these two closely related genes. Northern blot analysis revealed a striking similarity in the tissue distribution of RTEF-1 and TEF-1 mRNAs; skeletal muscle showed the highest abundance of both mRNAs, with lower levels detected in pancreas, placenta, and heart. Phylogenetic analysis of all known TEF-1-related proteins identified human RTEF-1 as one of four vertebrate members of this multigene family and further suggests that these genes diverged in the earliest metazoan ancestors.

Amino Acid Sequence↗

PubMed1995

A radiation hybrid map of 95 STSs spanning human chromosome 13q.

We have constructed a high-resolution physical map of the long arm of human chromosome 13 using a panel of 94 radiation hybrids. A comprehensive map of 95 chromosome 13-specific sequence tagged sites (STSs) spanning 13q from the presumed centromere at D13Z1 to the known telomere was obtained by multipoint maximum likelihood statistical methods. The 95 markers have an average retention frequency of 10%, with markers closer to the centromere having much greater retention frequencies (22-49%) than distal 13q markers (2-12%). The most likely radiation hybrid map localized the 95 STSs into 54 unique map positions, 34 with odds of 1000:1 or greater; the comprehensive map localized all but 17 STSs with odds exceeding 10:1. The total map length of 13q was 1302 cR9000 (range 6.4-94.4 cR9000) and a physical distance of 98 Mb, so that 1% breakage in the RH panel corresponds to 75 kb. A comparison of the comprehensive RH map to genetic maps of chromosome 13q shows identical locus orders for the common markers, with two exceptions over 1-cM distances. We discuss the possible relationships between the genetic and the radiation hybrid maps.

Animals↗

PubMed1995

A high-density microsatellite map of the ataxia-telangiectasia locus.

The locus of the autosomal recessive disorder ataxia-telangiectasia (A-T) has been assigned by linkage analysis with biallelic markers to a 4-Mb interval on chromosome 11q22-23, between GRIA4 and D11S1897. We have undertaken to saturate the A-T region with highly polymorphic microsatellite markers. To this end, we have identified seven new polymorphic CA-repeats in this region, and have mapped to it five new markers generated by Genethon and the Cooperative Human Linkage Center. These markers are in addition to 12 others that we have previously mapped or generated at the A-T locus. All 24 markers have been integrated into a high-density microsatellite map spanning some 6 Mb DNA. This map, which contains the A-T locus and flanking sequences, allows the construction of extensive, highly informative haplotypes.

Ataxia Telangiectasia↗

PubMed1995

Physical mapping of 3 candidate tumor suppressor genes relative to Beckwith-Wiedemann syndrome associated chromosomal breakpoints at 11p15.3.

A physical map encompassing the 3 Mb region containing the breakpoints of two Beckwith-Wiedemann Syndrome patients at chromosome band 11p15.3 is presented. The candidate tumor suppressor genes WEE1, ST5, and rhombotin, are positioned on this map relative to these Beckwith-Wiedemann syndrome translocation and inversion breakpoints.

Beckwith-Wiedemann Syndrome↗

PubMed1994

An ordered NotI fragment map of human chromosome band 11p15.

An ordered NotI fragment map containing over 60 loci and encompassing approximately 17 Mb has been constructed for human chromosome band 11p15. Forty-two probes, including 11 NotI-linking cosmids, were subregionally mapped to 11p15 using a subset of the J1-deletion hybrids. These and 23 other probes defining loci previously mapped to 11p15 were hybridized to genomic DNA digested with NotI and 5 other infrequently cleaving restriction enzymes and separated by pulsed-field gel electrophoresis. Thirty-nine distinct NotI fragments were detected encompassing approximately 85% of the estimated length of 11p15. The predicted order of the gene loci used is cen-MYOD1-PTH-CALCA-ST5-RBTN1-HPX-HBB-RRM1 -TH/INS/IGF2-H19-CTSD-MUC2-DRD4-HRAS - RNH-tel. This map will allow higher resolution mapping of new 11p15 markers, facilitate positional cloning of disease genes, and provide a framework for the physical mapping of 11p15 in clone contigs.

Cells, Cultured↗

PubMed1994

Physical localization of microsatellite markers at the ataxia-telangiectasia locus at 11q22-q23.

The autosomal recessive disorder ataxia-telangiectasia (A-T) is genetically heterogeneous, with four complementation groups. The genes for the two major groups (ATA and ATC) have been mapped to 11q22-q23. Genetic analysis of the disease has been conducted to date using biallelic polymorphisms. We have physically mapped to this region eight new microsatellite markers that were generated by three laboratories that construct whole-genome linkage maps. These markers should be valuable for refined localization and positional cloning of the A-T genes and for diagnostic purposes. The results demonstrate the value of integrating genetic and physical maps generated by different laboratories.

Ataxia Telangiectasia↗

PubMed1994

A radiation hybrid map of 506 STS markers spanning human chromosome 11.

We present a high resolution radiation hybrid map of human chromosome 11 using 506 sequence tagged sites (STSs) scored on a panel of 86 radiation hybrids. The 506 STSs fall into 299 unique positions (average resolution of about 480 kilobases (kb)) that span the whole chromosome. A subset of 260 STSs (143 positions) form a framework map that has a resolution of approximately 1 megabase between adjacent positions and is ordered with odds of at least 1,000:1. The centromere was clearly defined with pericentric markers unambiguously assigned to the short or long arm. The map contains most genes (125) and expressed sequence tags (26) currently assigned to chromosome 11 and more than half of the STSs are polymorphic microsatellite loci. These markers and the map can be used for high resolution physical and genetic mapping.

Animals↗

PubMed1994

The gene encoding myeloid alpha-3-fucosyl-transferase (FUT4) is located between D1 1S388 and D11S919 on 11q21.

The last step in the biosynthesis of Le(x) antigen, the addition of a fucose to precursor polysaccharides, can be catalyzed by different alpha-3-fucosyltransferases. We localized the gene (FUT4) encoding myeloid alpha-3-fucosyltransferase by PCR assay using panels of somatic cell and radiation hybrids which retain different rearrangements of chromosome 11. FUT4 was assigned to chromosome band 11q21 between D11S388 and D11S919.

Animals↗

PubMed1993

A radiation hybrid map of human chromosome 11q22-q23 containing the ataxia-telangiectasia disease locus.

We describe a high-resolution radiation hybrid map of human chromosome 11q22-q23 containing the ataxia-telangiectasia (AT) disease gene loci. The order and intermarker distances of 32 chromosome 11q22-q23 markers were determined by a multipoint maximum likelihood method of analysis of the cosegregation of markers in 100 radiation hybrids. The radiation hybrid map of polymorphic loci was consistent with genetic linkage maps of common markers. Several genes, including alpha B-crystallin, adrenal ferrodoxin, CBL2, collagenase, dopamine receptor type 2, neural cell adhesion molecule, progesterone receptor, and stromelysins 1 and 2, were placed in relation to previously ordered, genetically mapped polymorphic loci. Five new markers (alpha B-crystallin, adrenal ferrodoxin, CJ52.114, CJ52.3, and D11S535) were ordered within the current published flanking markers for the AT group A and group C disease loci. A candidate AT group D gene (ATDC) identified by Kapp et al. (1992, Am. J. Hum. Genet. 51: 45-54) was mapped telomeric to THY1, outside the flanking markers identified by multipoint linkage analysis for the major AT locus.

Animals↗

PubMed1993

A radiation hybrid map of the distal short arm of human chromosome 11, containing the Beckwith-Wiedemann and associated embryonal tumor disease loci.

We describe a high-resolution radiation hybrid (RH) map of the distal short arm of human chromosome 11 containing the Beckwith-Wiedemann gene and the associated embryonal tumor disease loci. Thirteen human 11p15 genes and 17 new anonymous probes were mapped by a statistical analysis of the cosegregation of markers in 102 rodent-human radiation hybrids retaining fragments of human chromosome 11. The 17 anonymous probes were generated from lambda phage containing human 11p15.5 inserts, by using ALU-PCR. A comprehensive map of all 30 loci and a framework map of nine clusters of loci ordered at odds of 1,000:1 were constructed by a multipoint maximum-likelihood approach by using the computer program RHMAP. This RH map localizes one new gene to chromosome 11p15 (WEE1), provides more precise order information for several 11p15 genes (CTSD, H19, HPX, ST5, RNH, and SMPD1), confirms previous map orders for other 11p15 genes (CALCA, PTH, HBBC, TH, HRAS, and DRD4), and maps 17 new anonymous probes within the 11p15.5 region. This RH map should prove useful in better defining the positions of the Beckwith-Wiedemann and associated embryonal tumor disease-gene loci.

Animals↗