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N T Bech-Hansen

Publications and source records attributed to N T Bech-Hansen.

At least 19 recordsLinked to original sources
PubMed1999

Physical map covering a 2 Mb region in human xp11.3 distal to DX6849.

A 2Mb contig was constructed of yeast artificial chromosomes (YACs) and P1 artificial chromosomes (PACs), extending from DXS6849 to a new marker EC7034R, 1Mb distal to UBE1, within the p11.3 region of the human X chromosome. This contig, which has on average four-fold cloned coverage, was assembled using 37 markers, including 13 new sequence tagged sites (STSs) developed from YAC and PAC end-fragments, for an average inter-marker distance of 55kb. The inferred marker order predicted from SEGMAP analysis, STS content and cell hybrid data is Xpter-EC7034R-EC8058R-FB20E11-DXS7804-D XS8308-(DXS1264, DXS1055)-DXS1003-UBE1-(UHX), PCTK1)-DXS1364-DXS1266-DXS337-SYN1-DXS6 849-cen. One (TC)n dinucleotide sequence from an end-clone was identified and found to be polymorphic (48% heterozygosity). The contig is merged with published physical maps both in the distal and in the centromeric direction of Xp, and provides reagents to aid in the DNA sequencing and the finding of genes in this region of the human genome.

Chromosomes, Artificial, Yeast↗
PubMed1998

Construction of a 1.5-Mb bacterial artificial chromosome contig in Xp11.23, a region of high gene content.

To generate sequence-ready templates for the gene-rich Xp11.23 region, we have constructed a 1.5-Mb bacterial artificial chromosome (BAC) contig spanning the interval between the DNA markers OATL1 and DXS255. The contig includes 28 BACs, ranging in size from 58 to 258 kb with an average size of 135 kb, which provide 2.5-fold coverage of the region. The BAC contig was constructed based entirely on the content of 40 DNA markers from a previously established YAC contig and 11 new markers developed from BAC-end DNA sequences, 4 of which were required to close gaps in the map. There was no evidence of rearrangement, instability, or chimerism in any of the BAC clones. The BAC cloning system appears to provide robust and total physical coverage of this gene-rich region with clones that are suitable for DNA sequencing.

Chromosome Mapping↗
PubMed1998

Localization of a gene for incomplete X-linked congenital stationary night blindness to the interval between DXS6849 and DXS8023 in Xp11.23.

Congenital stationary night blindness (CSNB) is a nonprogressive retinal disorder characterized by night blindness, nystagmus, myopia, a variable decrease in visual acuity, an abnormal electroretinographic response, and a disturbance in dark adaptation. Two forms of X-linked CSNB have been defined, complete CSNB in which rod function is extinguished, and incomplete CSNB in which rod function is reduced but not extinguished, as seen by electroretinography and dark adaptometry. In studying a large family of Mennonite ancestry, we have confirmed linkage between the locus (CSNB2) for incomplete CSNB and genetic markers in the Xp11 region. In particular, lod scores of 12.25 and 15.26 at zero recombination were observed between CSNB2 and the markers DXS573 and DXS255. Detailed analysis of critical recombinant chromosomes in this extended family have refined the minimal region for the CSNB2 locus to the interval between DXS6849 and DXS8023 in Xp11.23.

Adaptation, Physiological↗
PubMed1998

Loss-of-function mutations in a calcium-channel alpha1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness.

X-linked congenital stationary night blindness (CSNB) is a recessive non-progressive retinal disorder characterized by night blindness, decreased visual acuity, myopia, nystagmus and strabismus. Two distinct clinical entities of X-linked CSNB have been proposed. Patients with complete CSNB show moderate to severe myopia, undetectable rod function and a normal cone response, whereas patients with incomplete CSNB show moderate myopia to hyperopia and subnormal but measurable rod and cone function. The electrophysiological and psychophysical features of these clinical entities suggest a defect in retinal neurotransmission. The apparent clinical heterogeneity in X-linked CSNB reflects the recently described genetic heterogeneity in which the locus for complete CSNB (CSNB1) was mapped to Xp11.4, and the locus for incomplete CSNB (CSNB2) was refined within Xp11.23 (ref. 5). A novel retina-specific gene mapping to the CSNB2 minimal region was characterized and found to have similarity to voltage-gated L-type calcium channel alpha1-subunit genes. Mutation analysis of this new alpha1-subunit gene, CACNA1F, in 20 families with incomplete CSNB revealed six different mutations that are all predicted to cause premature protein truncation. These findings establish that loss-of-function mutations in CACNA1F cause incomplete CSNB, making this disorder an example of a human channelopathy of the retina.

Amino Acid Sequence↗
PubMed1998

Evidence for genetic heterogeneity in X-linked congenital stationary night blindness.

X-linked congenital stationary night blindness (CSNB) is a nonprogressive retinal disorder characterized by disturbed or absent night vision; its clinical features may also include myopia, nystagmus, and impaired visual acuity. X-linked CSNB is clinically heterogeneous, and it may also be genetically heterogeneous. We have studied 32 families with X-linked CSNB, including 11 families with the complete form of CSNB and 21 families with the incomplete form of CSNB, to identify genetic-recombination events that would refine the location of the disease genes. Critical recombination events in the set of families with complete CSNB have localized a disease gene to the region between DXS556 and DXS8083, in Xp11.4-p11.3. Critical recombination events in the set of families with incomplete CSNB have localized a disease gene to the region between DXS722 and DXS8023, in Xp11.23. Further analysis of the incomplete-CSNB families, by means of disease-associated-haplotype construction, identified 17 families, of apparent Mennonite ancestry, that share portions of an ancestral chromosome. Results of this analysis refined the location of the gene for incomplete CSNB to the region between DXS722 and DXS255, a distance of 1.2 Mb. Genetic and clinical analyses of this set of 32 families with X-linked CSNB, together with the family studies reported in the literature, strongly suggest that two loci, one for complete (CSNB1) and one for incomplete (CSNB2) X-linked CSNB, can account for all reported mapping information.

Female↗
PubMed1997

Integration of 101 DNA markers across human Xp11 using a panel of somatic cell hybrids.

One hundred and one DNA markers previously assigned to the short arm of the human X chromosome were localized on a hybrid mapping panel consisting of ten radiation-reduced, and four classical somatic cell hybrids. Of the 101 DNA markers, 16 are genes, two are pseudogenes, 13 are expressed sequence tags, 32 are simple tandem repeats (STRs), four are restriction fragment length polymorphisms, one is a variable number of tandem repeats, and 33 are sequence tagged sites (STSs). Three of these markers, two STSs and one STR, were generated from the products of an inter-Alu PCR library of a radiation-reduced hybrid containing Xp11.4-->p11.22 as its only human DNA content. A second STR was isolated from a region-specific cosmid containing the gene ZNF21. The 101 DNA markers fell into 22 bins based on their retention on the hybrids of this panel, which, in combination with YAC contig data, could be further resolved into 24 bins. This hybrid map of Xp11 has an average resolution of approximately 0.8 Mb.

Animals↗
PubMed1996

A 2-megabase physical contig incorporating 43 DNA markers on the human X chromosome at p11.23-p11.22 from ZNF21 to DXS255.

A comprehensive physical contig of yeast artificial chromosomes (YACs) and cosmid clones between ZNF21 and DXS255 has been constructed, spanning 2 Mb within the region Xp11.23-p11.22. As a portion of the region was found to be particularly unstable in yeast, the integrity of the contig is dependent on additional information provided by the sequence-tagged site (STS) content of cosmid clones and DNA marker retention in conventional and radiation hybrids. The contig was formatted with 43 DNA markers, including 19 new STSs from YAC insert ends and an internal Alu-PCR product. The density of STSs across the contig ranges from one marker every 20 kb to one every 60 kb, with an average density of one marker every 50 kb. The relative order of previously known genes and expressed sequence tags in this region is predicted to be Xpter-ZNF21-DXS7465E (MG66)-DXS7927E (MG81)-WASP, DXS1011E, DXS7467E (MG21)-DXS- 7466E (MG44)-GATA1-DXS7469E (Xp664)-TFE3-SYP (DXS1007E)-Xcen. This contig extends the coverage in Xp11 and provides a framework for the future identification and mapping of new genes, as well as the resources for developing DNA sequencing templates.

Animals↗
PubMed1995

X-linked retinitis pigmentosa: re-evaluation of fundus findings and the use of haplotype analysis in clarification of carrier female status.

The identification by fundus examination of those females carrying an X-linked retinitis pigmentosa (RP) gene can reportedly be as high as 87%. In genetic counselling sessions with young females with a 50% risk of being a carrier who wished to know their status, it has not been possible to achieve such a level of success. A review and reanalysis of previous reports indicated that if a tapetal-like reflex was not present in those age 35 years or less, the likelihood of identifying a carrier by fundus examination was small. A family with 7 females with a 50% risk of being a carrier of X-linked RP was evaluated using haplotype analysis in an attempt to identify the X chromosome carrying the RP gene. In the family described, it was possible to establish that a mutation in the RP3 locus most likely causes the disease. This has permitted the determination of the carrier status in each of the females with a high degree of certainty.

Adolescent↗
PubMed1994

Clustered organization of Krüppel zinc-finger genes at Xp11.23, flanking a translocation breakpoint at OATL1: a physical map with locus assignments for ZNF21, ZNF41, ZNF81, and ELK1.

The ZNF21, ZNF41, and ZNF81 genes encode Krüppel-type zinc-finger proteins (ZFPs) and have previously been mapped to chromosome Xp. Published data describing the clustering of ZFP genes on human autosomes led us to investigate the organization of ZNF21, ZNF41, and ZNF81 on the X chromosome. Rodent-human hybrid analysis sublocalized all three genes to Xp22.11-p11.23. ZNF21, ZNF41, and ZNF81 were then shown to segregate within a series of YACs (95 to 730 kb) containing known markers at Xp11.23, such that these YACs could be assembled into a contig spanning approximately 1.5 Mb of DNA. Southern analysis of intact YACs and YAC DNAs cut with rare-cutter restriction enzymes enabled us to establish the spatial organization of the ZFP gene cluster, the OATL1 pseudogene, the recurrent t(X;18) chromosome translocation breakpoint in synovial sarcoma, and the previously described cluster of ARAF1, SYN1, TIMP, and PFC genes. We have assigned the ETS-related gene ELK1 to a locus tightly linked to the PFC gene; the entire cluster of five genes is contained within a distance of 120 kb. ZNF41 maps to a 440-kb YAC spanning this region, while a more proximal cluster comprising the ZNF21 and ZNF81 genes lies 150 kb distal to the chromosome breakpoint associated with synovial sarcoma.

Base Sequence↗
PubMed1993

Manifestations of X-linked congenital stationary night blindness in three daughters of an affected male: demonstration of homozygosity.

X-linked congenital stationary night blindness (CSNB1) is a hereditary retinal disorder in which clinical features in affected males usually include myopia, nystagmus, and impaired visual acuity. Electroretinography demonstrates a marked reduction in b-wave amplitude. In the study of a large Mennonite family with CSNB1, three of five sisters in one sibship were found to have manifestations of CSNB1. All the sons of these three sisters were affected. Each of the two nonmanifesting sisters had at least one unaffected son. Analysis of Xp markers in the region Xp21.1-Xp11.22 showed that the two sisters who were unaffected had inherited the same maternal X chromosome (i.e., M2). Two of the daughters who manifested with CSNB had inherited the other maternal X chromosome (M1). The third manifesting sister inherited a recombinant X chromosome with a crossover between TIMP and DXS255, which suggests that the CSNB1 locus lies proximal to TIMP. One of the affected daughters' sons had inherited the maternal M1 X chromosome, a finding consistent with that chromosome carrying a mutant CSNB gene; the other affected sons inherited the grandfather's X chromosome (i.e., P). Molecular analysis of DNA from three sisters with manifestations of CSNB is consistent with their being homozygous at the CSNB1 locus and with their mother being a carrier of CSNB1.

Adolescent↗
PubMed1992

Diagnosis of Duchenne and Becker muscular dystrophies by polymerase chain reaction. A multicenter study.

OBJECTIVE--To assess the efficiency, reliability, and ease of use of DNA diagnosis for Duchenne and Becker muscular dystrophies (DMD/BMD) using the polymerase chain reaction (PCR). DESIGN--DNA from the patients was screened for deletion mutations using multiplex PCR, and the results were compared with those obtained by Southern blot analysis. The PCR multiplex reaction detects nine specific "hot-spot" exons in the dystrophin gene while the Southern analysis detects 66 specific dystrophin gene restriction fragments. The multiplex reaction requires 50-fold less DNA than Southern analysis and thus is considerably more sensitive. SETTING--Fourteen university-affiliated and private genetic disease diagnostic laboratories. PATIENTS--Male patients with clinical signs of DMD/BMD. Cases were selected for analysis randomly, without knowledge of whether a deletion was present within the dystrophin gene. MAIN OUTCOME MEASURES--The percentage of cases that were detectable by multiplex PCR in comparison with Southern analysis, the frequency, extent, and location of the detected deletion mutations. In some cases, duplication mutations were monitored. RESULTS--The accuracy of a single PCR multiplex amplification (nine exons) was compared with Southern analysis with 10 cDNA probes that cover the full length of the gene. The multiplex PCR analytic method detected 82% of those deletions detected by Southern analysis methods. In one of 745 analyses, the multiplex method suggested a single exon deletion, which was not confirmed by Southern analysis, representing a false-positive rate of 0.013%. CONCLUSIONS--Multiplex PCR represents a sensitive and accurate method for deletion detection of 46% of all cases of DMD/BMD. The method requires 1 day for analysis, is easy to perform, and does not use radioactive tracers. As such, multiplex PCR represents an efficient and rapid method for prenatal or postnatal diagnosis of DMD/BMD.

Blotting, Southern↗
PubMed1992

Mapping of locus for X-linked congenital stationary night blindness (CSNB1) proximal to DXS7.

A recombinant chromosome in a male affected with X-linked congenital stationary night blindness (CSNB1) provides new information on the location of the CSNB1 locus. A four-generation family with five males affected with X-linked CSNB was analyzed with five polymorphic markers for four X-chromosome loci spanning the region OTC (Xp21.1) to DXS255 (Xp11.22). Four of the males inherited the same X chromosome; one male inherited a chromosome that from OTC to DXS7, inclusive, was derived from the normal X chromosome of his unaffected grandfather and that from a location between DXS7 and DXS426 proximally was derived from the chromosome carrying the CSNB1 locus. This recombinant maps the CSNB1 locus in this family to a region on the short arm of the X chromosome proximal to the DXS7 locus.

Alleles↗
PubMed1991

Genetic heterogeneity in tuberous sclerosis. Study of a large collaborative dataset.

Tuberous sclerosis (TSC) is a multisystem autosomal dominant hamartosis whose genetics is complicated by reduced penetrance and widely varying clinical expression. Results of linkage analyses have variously suggested two different locations for a TSC gene. A collaborative dataset has been assembled to clarify the issue of genetic heterogeneity. We have now analyzed the data from a combined sample of 111 families. Using Ott's HOMOG programs, we completed three tests of homogeneity: (1) for chromosome 9q, (2) for chromosome 11q, and (3) for the combined 9q and 11q data. For test 1 the chi-square (1 df) was 21.54 (p less than 0.001), for test 2 the chi-square (1 df) was 0.13 (p greater than 0.35), and for test 3 the chi-square (2 df) was 37.61 (p less than 0.0001). Additionally, we examined the combined data for evidence that a third, as yet unlinked locus exists. Results of this last test were suggestive but not significant. Clearly loci for TSC are present on both chromosomes 9q and 11q. The maximum likelihood estimate of the proportion of chromosome 9q-linked families is 0.38, for chromosome 11q-linked families is 0.47, and for the unlinked type 0.15. Alternative explanations for these latter families include chance sampling of recombinants, nongenetic phenocopies, or misclassification.

Chromosomes, Human, Pair 11↗
PubMed1990

A locus for X-linked congenital stationary night blindness is located on the proximal portion of the short arm of the X chromosome.

Linkage between X-linked congenital stationary night blindness (CSNB1) and seven markers on the X chromosome was investigated in a large four-generation Albertan kindred. We detected significant linkage between the CSNB1 locus and the locus DXS255 (maximum lod score = 6.73 at a recombination fraction of 6%; confidence interval of 1% to 18%), which anchors the CSNB1 locus to the proximal region near p11.22 on the short arm of the X chromosome.

Female↗