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Biomedical subjects

S W Scherer

Publications and source records attributed to S W Scherer.

At least 127 records · Page 7Linked to original sources
PubMed1996

Gene structure and chromosome localization to 7q21.3 of the human rod photoreceptor transducin gamma-subunit gene (GNGT1).

The transducin gamma-subunit gene (GNGT1) encodes a member (gamma1) of the family of heterotrimeric G-protein gamma-subunits that is specific to rod photoreceptors. In this report we have determined the complete structure of the GNGT1 gene and have localized it to human chromosome 7q21.3 using somatic cell hybrid and yeast artificial chromosome analysis.

Amino Acid Sequence↗
PubMed1996

A panel of radiation hybrids defining the 7q31-q32 region of human chromosome 7.

Mouse A9 cells containing human chromosome 7 tagged with pSV2neo were irradiated with X-rays and fused to A9 cells to isolate G418-resistant clones. From these clones, we selected radiation hybrids that contained 10-40 Mb of human DNA apparently at a single site of their genome by FISH analysis using human repetitive sequences as a probe. Then we made a panel of hybrids that contained various fragments of the 7q31-q32 region and cover its entire region altogether by PCR with STS markers of human chromosome 7. This panel is useful in chromosome transfer experiments since the dominant selective marker neo gene is attached to human DNA.

Animals↗
PubMed1996

Molecular definition of a narrow interval at 7q22.1 associated with myelodysplasia.

Chromosome 7 translocations, deletions, or monosomy are associated with myelodysplasia (MDS) and acute myeloid leukemia both in children and adults. These chromosomal anomalies represent one of the most common cytogenetic abnormalities associated with these diseases and usually herald a poor prognosis. In this study two cosmid DNA probes that mapped to 7q22.1 and were known to be separated by approximately 500 kb were identified to flank the proximal inversion breakpoint in a patient carrying a constitutional inversion (7q22.1-34) associated with MDS. A yeast artificial chromosome (YAC) clone that encompassed the two cosmids was identified and shown to span the breakpoint. Fluorescence in situ hybridization was then used to analyze six additional patients with myelodysplasia and chromosomal rearrangements of the 7q22 region (three patients had translocations and three carried deletions). The breakpoint in one of the patients was found to be contained within the same YAC clone that spanned the inversion breakpoint. Moreover, this same interval was determined to be absent in all three patients with chromosomal deletions. These results suggest that this segment of DNA on chromosome 7q22.1 may contain specific gene(s) that have a significant role in myeloid malignancies.

Cell Line, Transformed↗
PubMed1996

Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q.

Metabotropic glutamate receptors (GRMs) are neurotransmitter receptors that respond to glutamate stimulations by activating GTP-binding proteins and modulating second-messenger cascades. Eight related GRMs have been identified to date. In this study, we have mapped GRM3 and GRM8 to human chromosome 7q21.1-q21.2 and 7q31.3-q32.1, respectively, using somatic cell hybrid and fluorescence in situ hybridization analysis. A yeast artificial chromosome contig was constructed surrounding the genes, allowing their location to be integrated into the genetic and physical map of chromosome 7.

Animals↗
PubMed1996

Fine mapping of the human and mouse genes for the type I procollagen COOH-terminal proteinase enhancer protein.

The human gene (PCOLCE) for the C-proteinase enhancer, a glycoprotein that enhances the enzymatic activity that cleaves the type I procollagen C-propeptide, was previously mapped to the same cytogenetic region (7q21.3-q22) as COL1A2, the type I collagen pro-alpha 2 chain gene. The apparent proximity of these two genes, whose products interact, might have reflected some mechanism for coregulation of expression. We have employed somatic cell hybrids, cosmid contigs, and interspecific backcross mice to investigate further the apparent proximity of the two genes. Our data show that PCOLCE and COL1A2 are separated by at least 6 Mb on human chromosome 7q and that Pcolce and Col1a2 are located on two separate chromosomes in mouse. These data also indicate that PCOLCE is located within a 10- to 15-cM region of conserved synteny between human chromosome 7 and mouse chromosome 5.

Animals↗
PubMed1996

Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly.

Holoprosencephaly (HPE) is a genetically and phenotypically heterogenous disorder involving the development of forebrain and midface, with an incidence of 1:16,000 live born and 1:250 induced abortions. This disorder is associated with several distinct facies and phenotypic variability: in the most extreme cases, anophthalmia or cyclopia is evident along with a congenital absence of the mature nose. The less severe form features facial dysmorphia characterized by ocular hypertelorism, defects of the upper lip and/or nose, and absence of the olfactory nerves or corpus callosum. Several intermediate phenotypes involving both the brain and face have been described. One of the gene loci, HPE3, maps to the terminal band of chromosome 7. We have performed extensive physical mapping studies and established a critical interval for HPE3, and subsequently identified the sonic hedgehog (SHH) gene as the prime candidate for the disorder. SHH lies within 15-250 kilobases (kb) of chromosomal rearrangements associated with HPE, suggesting that a 'position effect' has an important role in the aetiology of HPE. As detailed in the accompanying report, this role for SHH is confirmed by the detection of point mutations in hereditary HPE patients.

Amino Acid Sequence↗
PubMed1996

Mutations in the human Sonic Hedgehog gene cause holoprosencephaly.

Holoprosencephaly (HPE) is a common developmental defect of the forebrain and frequently the midface in humans, with both genetic and environmental causes. HPE has a prevalence of 1:250 during embryogenesis and 1:16,000 newborn infants, and involves incomplete development and septation of midline structures in the central nervous system (CNS) with a broad spectrum of clinical severity. Alobar HPE, the most severe form which is usually incompatible with postnatal life, involves complete failure of division of the forebrain into right and left hemispheres and is characteristically associated with facial anomalies including cyclopia, a primitive nasal structure (proboscis) and/or midfacial clefting. At the mild end of the spectrum, findings may include microcephaly, mild hypotelorism, single maxillary central incisor and other defects (Fig. 1). This phenotypic variability also occurs between affected members of the same family. The molecular basis underlying HPE is not known, although teratogens, non-random chromosomal anomalies and familial forms with autosomal dominant and recessive inheritance have been described. HPE3 on chromosome 7q36 is one of at least four different loci implicated in HPE. Here, we report the identification of human Sonic Hedgehog (SHH) as HPE3-the first known gene to cause HPE. Analyzing 30 autosomal dominant HPE (ADHPE) families, we found five families that segregate different heterozygous SHH mutations. Two of these mutations predict premature termination of the SHH protein, whereas the others alter highly conserved residues in the vicinity of the alpha-helix-1 motif or signal cleavage site.

Alleles↗
PubMed1996

Characterization of the split hand/split foot malformation locus SHFM1 at 7q21.3-q22.1 and analysis of a candidate gene for its expression during limb development.

Split hand/split foot malformation (SHFM) is a heterogeneous limb developmental disorder, characterized by missing digits and fusion of remaining digits. An autosomal dominant form of this disorder (SHFM1) has been mapped to 7q21.3-q22.1 on the basis of SHFM-associated chromosomal rearrangements. Utilizing a YAC contig across this region, we have defined a critical interval of 1.5 Mb by the analysis of six interstitial deletion patients and mapped the translocation breakpoints of seven ectrodactyly patients within the interval. To delineate the basic molecular defect underlying SHFM, we have searched for candidate genes in a 500 kb region containing five of the translocation breakpoints. Three genes were identified, two genes of the Distal-less (dii) homeobox gene family, DLX5 and DLX6 and a novel gene, which we named DSS1. DSS1 is predicted to encode a highly acidic polypeptide with no significant similarity to any known proteins but 100% amino acid sequence identify with its murine homolog (Dss1). Using RNA in situ hybridization analysis, we detected a tissue-specific expression profile for Dss1 in limb bud, craniofacial primordia and skin. A deficiency in expression of Dss1, DLX5 and/or DLX6 during development may explain the SHFM phenotypes.

Amino Acid Sequence↗
PubMed1996

Positional candidate genes for congenital chloride diarrhea suggested by high-resolution physical mapping in chromosome region 7q31.

Congenital chloride diarrhea affects intestinal transportation of electrolytes, resulting in potentially fatal diarrhea. Linkage disequilibrium analyses have suggested the congenital chloride diarrhea gene (CLD) to lie within 0.37 cM from D7S496 in human chromosome 7q31. To clone the CLD gene, we have constructed and refined a physical map based on a 2.7-Mb YAC contig around D7S496 and identified two candidate genes. The physical positions of 4 known genes (DRA, PRKAR2B, LAMB1, DLD), 7 polymorphic repeat markers, and 13 CpG islands were established. DRA (down-regulated in adenoma) is expressed in the gut and encodes a protein with sequence homology to anion transporters, whereas PRKAR2B encodes a regulatory subunit for protein kinase A. Both genes map within 450 kb from D7S496, making them functionally and positionally relevant candidates for CLD.

Base Sequence↗
PubMed1996

Split hand/split foot malformation, deafness, and mental retardation with a complex cytogenetic rearrangement involving 7q21.3.

Split hand/split foot malformation (SHSF) has been described in several patients associated with cytogenetically visible rearrangements involving chromosome 7q. Characterisation of these patients has led to localisation of an autosomal dominant form of SHSF to 7q21-22; the locus has been designated SHFM1. We describe a patient with a complex, apparently balanced cytogenetic rearrangement, including a translocation breakpoint at 7q21.3 near the DSS1 gene. In addition to ectrodactyly of all four limbs, the patient has congenital deafness, submucous cleft palate, microcephaly, and mental retardation. This patient represents an additional case of syndromic ectrodactyly related to the SHFM1 gene region, which may be responsible for both syndromic and non-syndromic ectrodactyly.

Abnormalities, Multiple↗
PubMed1996

Classification of deletions and identification of cryptic translocations involving 7q by fluorescence in situ hybridization (FISH).

Monosomy 7 (-7) and deletion of the long arm of chromosome 7, del(7q), are frequent non-random findings in the myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), particularly associated with therapy-related disease (t-MDS and t-AML). The cytogenetic breakpoints of 7q deletions are variable, with both terminal and interstitial deletions reported. It is now believed that most deletions are interstitial, and that the variability in reported breakpoints may be due to the difficulty in determining whether the terminal, pale staining G band is present. It has also been suggested that some reported deletions of 7q may be cryptic translocations. To address these questions, we carried out fluorescence in situ hybridization (FISH) studies on leukaemic cells from a large series of patients using a chromosome 7-specific paint and a 7q telomere-specific probe. Of the 26 cases studied, seven were 'pure' deletions (ie without the involvement of other chromosomes); four were interstitial and two terminal. One further patient had two clones each with a different deletion: one with a terminal del(7)(q22) and the second with an interstitial del(7)(q32-qter). A further nine cases had unbalanced translocations with deletion of 7q terminal sequences. The remaining 10 cases were translocations and complex rearrangements, some involving interstitial deletions of 7q. In two cases in which del(7q) was reported as the sole cytogenetic abnormality by G-banding, FISH revealed cryptic translocations involving 7q.

Adult↗
PubMed1995

Sequence analysis and chromosomal localization of human Cap Z. Conserved residues within the actin-binding domain may link Cap Z to gelsolin/severin and profilin protein families.

From a human retinal cDNA library, we have isolated cDNAs that are homologs for the alpha 2 and beta subunits of chicken Cap Z. The derived human alpha subunit shares 95% amino acid identity with the chicken alpha 2 subunit; the beta subunit is 99% identical to the chicken subunit residues 1-243. The remaining portion of the human beta subunit (244-272) diverges significantly with only 8 out of 29 C-terminal amino acids conserved between the two species. This lack of conservation is of particular interest because the chicken C terminus contains an actin-binding domain. Cosedimentation assays with F-actin show that human Cap Z binds actin with an affinity equal that of chicken Cap Z. These results point to the eight shared amino acids as critical for actin binding, three of which are regularly spaced leucines. These apolar residues and one outside the region of divergence align well with those residues of the actin-binding alpha-helix proposed for gelsolin segment 1. The apolar residues as well as three polar amino acids are also conserved in other capping, capping and severing, and monomer-binding proteins. Amino acid substitutions in the chicken beta subunit of the two most highly conserved leucines result in significant decreases in F-actin binding activity. The human alpha 2 gene (CAPZA2) has been mapped to chromosome 7 position q31.2-q31.3 and the beta gene (CAPZB) to chromosome 1 region p36.1.

Actins↗
PubMed1995

Genome analysis.

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Chromosome Mapping↗
PubMed1995

Localization to chromosome 7q36.1 of the human XRCC2 gene, determining sensitivity to DNA-damaging agents.

The identification of genes controlling cellular response to DNA damage is of considerable importance, and cell lines showing hypersensitivity to DNA-damaging agents can be used as vehicles to map and clone these genes. In this study the hamster cell line irs1, showing hypersensitivity to a number of different DNA-damaging agents, was fused to normal human cells to complement the defect. The resultant hybrids were analysed by Alu-PCR, chromosome painting, and with DNA markers to map the complementing gene (named XRCC2) to a specific chromosomal region. These hybrids showed correction of sensitivity to both X-rays and to mitomycin-C, and contained human chromosome 7, often as their only human component. Hybrids showing unstable retention of human chromosomes were sub-cloned to show that loss of chromosome 7 and loss of resistance to mitomycin-C occurred concordantly. Two separate hybrids were found to have a smaller piece of chromosome 7, and specific DNA probes and microsatellite markers defined this as a contiguous region at 7q35-36. Hybrid irradiation-fusion methods were used to further reduce the size of the complementing genomic region and to localize the gene to an approximately 3-5 Mb region at 7q36.1.

Animals↗
PubMed1995

A YAC-based contig of 1.5 Mb spanning the human multidrug resistance gene region and delineating the amplification unit in three human multidrug-resistant cell lines.

A contig of 21 nonchimeric yeast artificial chromosomes (YACs) has been assembled across 1.5 Mb of the multidrug resistance (MDR) gene region located at 7q21, and formatted with four previously reported probes, six newly isolated probes, and three sequence-tagged sites (STSs) from internal and end fragments of YACs. A physical map of rare cutter restriction enzyme sites across the region was also constructed by pulsed-field gel electrophoretic (PFGE) analysis of four overlapping YAC clones. The amplification unit of this region in different cell lines was then determined by Southern blot analysis on the basis of the physical map and probes. Amplified DNA was located in extrachromosomal elements in human MDR cell lines studied here, and the size of the amplification unit was determined to be discrete in one MDR amplification but variable in others.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1995

Identification of a yeast artificial chromosome clone spanning a translocation breakpoint at 7q32.1 in a Smith-Lemli-Opitz syndrome patient.

Smith-Lemli-Opitz syndrome (SLOS) is a mental retardation/multiple congenital anomaly syndrome. The gene(s) involved has not been mapped or cloned, but, recently, a biochemical abnormality in cholesterol biosynthesis has been shown to occur in most SLOS patients. The defect is suspected to occur in the penultimate step of the cholesterol pathway, involving the enzyme 7-dehydrocholesterol reductase, which has not been isolated. On the basis of the hypothesis that a de novo balanced translocation [t(7;20)(q32.1;q13.2)] in an SLOS patient directly interrupts the SLOS gene, positional cloning techniques are being employed to localize and identify the SLOS gene. We report the identification of a chromosome 7-specific YAC that spans the translocation breakpoint, as detected by FISH. This is the first study narrowing a candidate SLOS region and placing it on physical and genetic maps of the human genome.

Abnormalities, Multiple↗