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J Overhauser

Publications and source records attributed to J Overhauser.

At least 37 records · Page 2Linked to original sources
PubMed1998

Molecular cloning and mapping of human semaphorin F from the Cri-du-chat candidate interval.

Cri-du-chat is a human contiguous gene deletion syndrome resulting from hemizygous deletions of chromosome 5p. Here we describe the isolation from within this interval of the human Semaphorin F (SEMAF) gene, a member of a family of proteins that has been implicated in axonal pathfinding. The human SEMAF gene covers at least 10% of the deleted region and defines a new class within this large gene family characterized by the presence of seven type 1 thrombospondin repeats. Prominent expression of murine semaphorin F (Semaf) was observed in the mouse brain, consistent with a role for semaphorin F as a signaling molecule that guides axons or migrating neuronal precursors during development. The known functions of semaphorins and the interesting pattern of expression for Semaf suggest that haploinsufficiency for SEMAF may disrupt normal brain development and might lead to some of the features of Cri-du-chat.

Amino Acid Sequence↗
PubMed1998

t(1;18)(q32.1;q22.1) associated with genitourinary malformations.

We report a male infant who has impaired penile development, hypospadias, and mild developmental delay with a 46,XY,t(1;18)(q32.1;q22.1) karyotype. Fluorescent in situ hybridization (FISH) was performed to more precisely map the translocation breakpoint. The translocation breakpoint maps to a region that has been implicated in genitourinary malformations in the 18q- syndrome. This case report suggests that a gene involved in genitourinary development maps at or near the chromosome 18 translocation breakpoint.

Chromosomes, Human, Pair 1↗
PubMed1997

Cytoplasmic antiproteinase 2 (PI8) and bomapin (PI10) map to the serpin cluster at 18q21.3.

High-molecular-weight serine proteinase inhibitors (serpins) regulate a diverse set of intracellular and extracellular processes such as complement activation, fibrinolysis, coagulation, cellular differentiation, tumor suppression, apoptosis, and cell migration. The ov-serpins are a subset of the serpin superfamily and are characterized by their high degree of homology to chicken ovalbumin, the lack of N- and C-terminal extensions, the absence of a signal peptide, and a Ser rather than an Asn residue at the penultimate position. Recently, we mapped four members of the family [SCCA1, SCCA2, PAI2, and PI5 (maspin)] to a 300-kb region within 18q21.3. Using a panel of 18q21.3 YAC clones, PCR, and DNA blotting, we mapped two additional ov-serpins, cytoplasmic antiproteinase 2 [CAP2 (PI8)] and bone marrow-associated serpin [bomapin (PI10)], to the same region. Three of the serpins, PI8, PI10, and PAI2 mapped to the same YACs, yA27D8 and yA24E4. We estimated that the size of the 18q21.3 serpin cluster spanned approximately 500 kb and contained at least six serpin genes. The order was cen-PI5, SCCA2, SCCA1, PAI2, PI10, PI8-tel. The clustering of serpins at 18q21 provides new opportunities to study coordinate gene regulation and the evolution of gene families.

Amino Acid Sequence↗
PubMed1997

The human gene ZFP161 on 18p11.21-pter encodes a putative c-myc repressor and is homologous to murine Zfp161 (Chr 17) and Zfp161-rs1 (X Chr)

A clone from a lambda gt11 cDNA expression library of HeLa cells was isolated, sequenced, and shown to encode a new human zinc finger protein. The cDNA of the gene termed ZFP161 has an open reading frame of 1347 bp. The predicted protein comprises 449 amino acid residues and contains five zinc finger motifs of the Krüppel type near the C-terminus and a BTB/POZ domain in the N-terminal region. The protein is 98% homologous to a murine zinc finger protein, ZF5 (M. Numoto et al., 1993, Nucleic Acids Res. 21: 3767-3775), which is a putative transcriptional repressor of c-myc and exhibits growth-suppressive activity in mouse cell lines. Through the use of a panel of somatic cell hybrids for chromosomal assignment and DNAs of somatic cell hybrids containing a deleted chromosome 18 for fine mapping, the human gene ZFP161 was localized to 18p11.21-pter. Therefore, ZFP161 is a candidate gene by position for the holoprosencephaly type 4 gene, HPE4, which is involved in congenital malformations. With DNAs from an interspecific backcross, two homologous mouse genes, Zfp161 and Zfp161-rs1, were mapped to chromosome 17 and the X chromosome, respectively. Mapping of Zfp161 confirms and extends a region of homology between distal mouse chromosome 17 and human 18p.

Amino Acid Sequence↗
PubMed1997

Isolation of chromosome 18-specific brain transcripts as positional candidates for bipolar disorder.

Several studies have proposed the existence of susceptibility loci for bipolar disorder on chromosome 18. To identify possible candidate genes for this disease, we isolated brain-expressed transcripts by direct cDNA selection on chromosome 18-specific biotinylated cosmid clones. Longer cognate cDNA clones of the selected cDNAs were isolated from a normalized infant brain cDNA library. Physical mapping by PCR on a panel of somatic cell hybrids was conducted by the use of primers derived from partial sequences on either the 5' or 3' ends of the clones. In our initial analysis, 48 cDNA clones were found to be chromosome 18-specific, mapping to different subchromosomal regions. Sequence redundancy among these clones yielded 30 unique transcripts, five of which were represented in previously known genes. Further sequencing of the remaining 25 unique cDNA clones confirmed the absence of significant homology to known genes, indicating that these transcripts represented novel genes. Mapping with the use of a radiation hybrid panel positioned the brain cDNAs to within = 100 to 1100 kb from reference sequence tag sites (STSs) and assembled them into six high resolution linkage groups. The majority of the transcripts were found to cluster to discrete locations on 18p and 18q, previously hypothesized as susceptibility regions for bipolar disorder, identifying them as positional candidate genes.

Bipolar Disorder↗
PubMed1997

Isolation of cDNAs from the Cri-du-chat critical region by direct screening of a chromosome 5-specific cDNA library.

Chromosome-specific cDNA libraries are new tools for the isolation of genes from specific genomic regions. We have used two YACs than span the approximately 2-Mb cri-du-chat critical region (CDCCR) of chromosome 5p to directly screen a chromosome 5-specific (CH5SP) fetal brain cDNA library. To compare this library with other sources for new gene discovery, the YACs were hybridized to a normalized infant brain (NIB) cDNA library that has been used extensively for expressed sequence tag (EST) generation. These screens yielded 12 cDNAs from the CH5SP fetal brain library and four cDNAs from the NIB library that mapped to discrete intervals within the CDCCR. Four cDNAs mapped within the minimal CDCCR deletion interval, with the remaining cDNAs being located beyond the boundaries. Only one cDNA shared sequence overlap between the CH5SP and NIB sets of clones. None of the remaining 11 CH5SP cDNAs were homologous to EST sequences, suggesting, in common with previous data on these libraries, that chromosome-specific cDNA libraries are a rich source of new expressed sequences. The single cDNA that did overlap with the NIB library contained two copies of a sequence motif shared with thrombospondin, properdin, and several complement proteins. This motif is usually present in adhesive proteins, and appears to mediate cell-cell or cell-substrate interactions. This new thrombospondin-like gene, and the other three cDNAs that map within the CDCCR, represent candidate genes for the cri-du-chat contiguous gene deletion syndrome.

Amino Acid Sequence↗
PubMed1997

Development of diagnostic tools for the analysis of 5p deletions using interphase FISH.

Cri-du-chat syndrome is associated with a deletion of the short arm of chromosome 5. Through the phenotypic and molecular analyses of individuals with a subset of the features associated with the syndrome, the genes involved in the syndrome have been mapped to two distinct critical regions. Deletion of a critical region in 5p15.2 results in the distinct facial features associated with the syndrome as well as the severe mental and developmental delay, while a deletion of 5p15.3 is associated only with the characteristic cat-like cry, the key diagnostic feature of the syndrome. Therefore, subtle differences in the extent of the 5p deletion can have a profound affect on the prognosis of the patient. In order to more easily differentiate between deletions that lead to the cri-du-chat syndrome phenotype and deletions that lead only to the isolated cat-like cry, we have constructed YAC contigs that span both critical regions. The YAC clones have been used to isolate cosmids mapping to each critical region and cosmids that lie just within the two critical region boundaries have been identified. We report here on the use of these cosmids as probes for fluorescent in situ hybridization experiments on interphase nuclei as a means of more accurately differentiating between small 5p deletions that coincide with a complete cri-du-chat syndrome phenotype and the severe mental and developmental delay that is associated with it and deletions that only delete the distal critical region that coincide with the isolated cat-like cry and a much improved prognosis.

Animals↗
PubMed1997

Molecular characterization of patients with 18q23 deletions.

The 18q- syndrome is a deletion syndrome that is characterized by mental retardation, hearing loss, midfacial hypoplasia, growth deficiency, and limb anomalies. Most patients with this syndrome have deletions from 18q21-qter. We report on three patients with deletions of 18q23. A mother and daughter with identical deletions of 18q23 have many of the typical features of the 18q- syndrome, including midfacial hypoplasia and hearing loss. In contrast, the third patient has few of the symptoms of the 18q- syndrome. A contig of the 18q23 region was generated to aid in the mapping of the breakpoints. FISH was used to map both breakpoints to the same YAC clone. Furthermore, somatic-cell hybrids from the daughter and the third patient were isolated. The mapping results of sequence-tagged sites relative to the two breakpoints were identical, suggesting that the two deletion breakpoints map very close to one another. The analyses of these patients demonstrate that the critical region for the 18q- syndrome maps to 18q23 but that a deletion of 18q23 does not always lead to the clinical features associated with the syndrome. These patients demonstrate the wide phenotypic variability associated with deletions of 18q.

Abnormalities, Multiple↗
PubMed1996

Localization of the homolog of a mouse craniofacial mutant to human chromosome 18q11 and evaluation of linkage to human CLP and CPO.

The transgene-induced mutation 9257 and the spontaneous mutation twirler cause craniofacial and inner ear malformations and are located on mouse chromosome 18 near the ataxia locus ax. To map the human homolog of 9257, a probe from the transgene insertion site was used to screen a human genomic library. Analysis of a cross-hybridizing human clone identified a 3-kb conserved sequence block that does not appear to contain protein coding sequence. Analysis of somatic cell hybrid panels assigned the human locus to 18q11. The polymorphic microsatellite markers D18S1001 and D18S1002 were isolated from the human locus and mapped by linkage analysis using the CEPH pedigrees. The 9257 locus maps close to the centromeres of human chromosome 18q and mouse chromosome 18 at the proximal end of a conserved linkage group. To evaluate the role of this locus in human craniofacial disorders, linkage to D18S1002 was tested in 11 families with autosomal dominant nonsyndromic cleft lip and palate and 3 families with autosomal dominant cleft palate only. Obligatory recombinants were observed in 8 of the families, and negative lod scores from the other families indicated that these disorders are not linked to the chromosome 18 loci.

Alleles↗
PubMed1996

Neuropsychiatry of 18q- syndrome.

Our understanding of neuropsychiatric abnormalities in patients with deletions of the long arm of chromosome 18 (18q- syndrome) is based mainly on sporadic case reports. We characterized the neuropsychiatric phenotype in 27 patients across a wide age range (2-47 years) with breakpoints ranging from 18q22.3-18q21.2. Adaptive behavior scores (Vineland Composite) were significantly higher in females than in males (62 +/- 5 vs. 43 +/- 3). Intelligence ranged from borderline to severely deficient (IQ, 73- < 40), with academic achievement similarly impaired. Performance in specific neuropsychological functions, including attention, novel problem solving, memory, language, visuomotor integration, and fine motor dexterity, was consistently in the moderately-to-severely impaired range. Behavioral problems were common in both sexes, including aggressivity, hyperactivity, and temper tantrums. Contrary to the few previous reports, we found no evidence of psychosis in any patients. In a subset of patients selected on the basis of no prior knowledge of behavioral problems, 1 of 16 patients (6%) had autism, as defined by the Autistic Diagnostic Interview--Revised (ADI-R) [Lord et al., 1994: J Autism Dev Disord 24:659-685]. Thus, the prevalence of autism in 18q- syndrome is probably no greater than that in other developmental disabilities with a similar level of cognitive impairment. In contrast to what has been believed since 18q- was first described 30 years ago, we found no relationship between chromosome deletion size and any measure of cognition or behavior; nor were there any correlations between any of these measures with the presence or absence of abnormalities on MRI or somatosensory-evoked potentials.

Adaptation, Psychological↗
PubMed1996

The generation and regional localization of 303 new chromosome 5 sequence-tagged sites.

With the ultimate goal of creating a sequence-ready physical map of all of chromosome 5, 303 new human chromosome 5-specific STS markers have been systematically generated and regionally ordered. Chromosome 5 DNA prepared from flow-sorted chromosomes was digested with restriction enzymes BamHI and HindIII and cloned in bacteriophage M13mp18. Random clones were sequenced, and appropriate PCR deoxyoligomers were synthesized. An acceptable sequence-tagged site (STS)-PCR assay yielded the appropriate size amplification product from both total human DNA and hybrid cell line DNA containing only human chromosome 5. Each STS has been regionally localized by breakpoint analysis using a set of hybrid cell panels consisting of natural deletions or translocations of human chromosome 5. This hybrid cell panel was able to localize the STSs to 1 of 51 bins on the short arm and 1 of 15 bins on the long arm. The STS markers appear to be randomly distributed along the length of this 194-Mb chromosome. The current overall density of these markers (approximately 1 STS/640 kb), combined with the numerous PCR-based physical and genetic markers generated by other groups, will provide sufficient "nucleation points" for YAC contig assembly and verification in any region of human chromosome 5.

Animals↗
PubMed1996

Ablepharon macrostomia syndrome with associated cutis laxa: possible localization to 18q.

The ablepharon-macrostomia (AMS) and Barber-Say syndromes (BSS) are rare disorders characterized by absence of the eyelids or ectropion, macrostomia, ambiguous genitalia, abnormal ears, rudimentary nipples, and dry, redundant skin. Patients with Barber-Say syndrome also have hypertrichosis. We present a patient with a phenotype similar to AMS who has a complex rearrangement of chromosome 18, involving both an inversion and interstitial deletion. Our patient lacks the typical features of the 18q deletion syndrome. We review AMS and BSS as compared with our patient, and recognize cutis laxa as a feature shared by all. We propose that the gene(s) for this phenotype may lie on chromosome 18 in the region of the deletion or inversion breakpoints.

Abnormalities, Multiple↗
PubMed1996

Familial double pericentric inversion of chromosome 5 with some features of cri-du-chat syndrome.

Fluorescence in situ hybridization analysis was performed to characterize a complex pericentric inversion involving chromosome 5 in a mother and son. The mother had hypertelorism, epicanthal folds, and mild mental deficiency while the son had additional anomalies that have been observed in patients with cri-du-chat syndrome. Both individuals were found to have an identical double pericentric inversion [inv5(p15.1q31(inv5(p14q12)))]. Neither inversion breakpoint mapped near the chromosomal regions implicated in the cri-du-chat syndrome. The phenotype of the son suggests that the inversion process may have affected the expression of some of the cri-du-chat syndrome genes, suggestive of a genomic imprinting or penetrance effect.

Adult↗
PubMed1996

Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers.

Chromosome deletions are the most common genetic events observed in cancer. These deletions are generally thought to reflect the existence of a tumour suppressor gene within the lost region. However, when the lost region does not precisely coincide with a hereditary cancer locus, identification of the putative tumour suppressor gene (target of the deletion) can be problematic. For example, previous studies have demonstrated that chromosome 18q is lost in over 60% of colorectal as well as in other cancers, but the lost region could not be precisely determined. Here we present a rigorous strategy for mapping and evaluating allelic deletions in sporadic tumours, and apply it to the evaluation of chromosome 18 in colorectal cancers. Using this approach, we define a minimally lost region (MLR) on chromosome 18q21, which contains at least two candidate tumour suppressor genes, DPC4 and DCC. The analysis further suggested genetic heterogeneity, with DPC4 the deletion target in up to a third of the cases and DCC or a neighbouring gene the target in the remaining tumours.

Alleles↗
PubMed1996

A new deletion of 18q23 with few typical features of the 18q- syndrome.

We report on a patient with a deletion of 18q23. At both 2 and 4 years of age, she displayed few of the facial features or other clinical features associated with the 18q- syndrome. Fluorescent in situ hybridisation and microsatellite marker and RFLP analysis were performed to characterise the extent of the deletion, and a terminal deletion of 18q23 was confirmed. The deleted region includes the gene for myelin basic protein, suggesting that hemizygosity of this gene does not invariably lead to mental and developmental delay. The clinical presentation of this patient suggests that either she is not deleted for the genes involved in the 18q- clinical phenotype or this patient represents one end of the spectrum of the clinical variability seen with 18q terminal deletions.

Abnormalities, Multiple↗
PubMed1996

Tourette syndrome in a pedigree with a 7;18 translocation: identification of a YAC spanning the translocation breakpoint at 18q22.3.

Tourette syndrome is a neuropsychiatric disorder characterized by the presence of multiple, involuntary motor and vocal tics. Associated pathologies include attention deficit disorder and obsessive-compulsive disorder (OCD). Extensive linkage analysis based on an autosomal dominant mode of transmission with reduced penetrance has failed to show linkage with polymorphic markers, suggesting either locus heterogeneity or a polygenic origin for Tourette syndrome. An individual diagnosed with Tourette syndrome has been described carrying a constitutional (7;18) chromosome translocation (Comings et al. 1986). Other family members carrying the translocation exhibit features seen in Tourette syndrome including motor tics, vocal tics, and OCD. Since the disruption of specific genes by a chromosomal rearrangement can elicit a particular phenotype, we have undertaken the physical mapping of the 7;18 translocation such that genes mapping at the site of the breakpoint can be identified and evaluated for a possible involvement in Tourette syndrome. Using somatic cell hybrids retaining either the der(7) or the der(18), a more precise localization of the breakpoints on chromosomes 7 and 18 have been determined. Furthermore, physical mapping has identified two YAC clones that span the translocation breakpoint on chromosome 18 as determined by FISH. These YAC clones will be useful for the eventual identification of genes that map to chromosomes 7 and 18 at the site of the translocation.

Biomarkers↗