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A Hanauer

Publications and source records attributed to A Hanauer.

70 records · Page 4Linked to original sources
PubMed1989

The polymorphic marker DXS304 is within 5 centimorgans of the fragile X locus.

The fragile X syndrome, which is the most common cause of inherited mental retardation, poses important diagnostic problems for genetic counseling. The development of diagnostic strategies based on DNA analysis has been impaired by the lack of polymorphic markers very close to the disease locus. Here we report that the polymorphic probe U6.2 (locus DXS304) is much closer to the fragile X locus than all the previously reported markers. A recombination fraction of 0.02 between DXS304 and the fragile X locus was estimated by multipoint linkage analysis (confidence interval 0.002 to 0.05). Our data suggest that DXS304 is distal to the fragile X locus. This marker thus represents a major improvement for carrier detection and prenatal diagnosis in fragile X families.

Chromosome Mapping↗
PubMed1989

Confirmation of linkage of Friedreich ataxia to chromosome 9 and identification of a new closely linked marker.

A linkage analysis with chromosome 9 markers was performed in 33 families with Friedreich ataxia (FA). Linkage with D9S15, previously established by S. Chamberlain et al. (1988, Nature London 334:248-249) was confirmed in our sample (z(theta) = 6.82 at theta = 0.02) while INFB (interferon-beta gene) shows looser linkage. An additional marker, D9S5, was also shown to be closely linked to FA (z(theta) = 5.77 at theta = 0.00).

Chromosomes, Human, Pair 9↗
PubMed1988

Genetic mapping of anhidrotic ectodermal dysplasia: DXS159, a closely linked proximal marker.

Three families with anhidrotic ectodermal dysplasia (AED) have been studied by linkage analysis with seven polymorphic DNA markers from the Xp11-q21 region. Previously reported linkage to DXYS1 (Xq13-q21) has been confirmed (z (theta) = 4.08 at theta = 0.05) and we have also established linkage to another polymorphic locus, DXS159, located in Xq11-q12 (z (theta) = 4.28 at theta = 0.05). Physical mapping places DSX159 proximal to the Xq12 breakpoint of an X autosome translocation found in a female with clinical signs of ectodermal dysplasia. Of all markers that have been used in linkage analysis of AED, DXS159 would appear the closest on the proximal side of the disease locus.

Chromosome Mapping↗
PubMed1988

Conservation and reorganization of loci on the mammalian X chromosome: a molecular framework for the identification of homologous subchromosomal regions in man and mouse.

By means of cross-reacting molecular probes, some 18 loci specific for the X chromosome of both man and mouse have been localized on the mouse X chromosome using an interspecific mouse cross involving the inbred SPE/Pas strain derived from Mus spretus. Comparison of the localizations of these loci on the mouse X with their positions on the human X chromosome suggests that intrachromosomal rearrangements involving at least five X chromosome breakage events must have occurred during the period of evolutionary divergence separating primates from rodents. Within the five blocks of chromosomal material so defined, there is for the moment little or no evidence that either chromosomal inversion events or extensive rearrangements have occurred. These data confirm the remarkable evolutionary conservation of the X chromosome apparent in mammalian species, compared to autosomal synteny groups in which both inter- and intrachromosomal rearrangement events appear to have occurred frequently. The breakage events described here for the X chromosome should therefore provide a minimal estimate for the frequency of chromosomal rearrangement events, such as breakage and inversion, which have affected autosomal synteny groups during the evolutionary period separating man from mouse. The definition of the number of chromosome breakage events by which the X chromosomes of these species differ, together with their localization, provides a framework for the use of interspecies mouse crosses for further detailed mapping of particular subchromosomal regions of the human X chromosome and for defining loci in the mouse homologous to those implicated in human congenital diseases.

Animals↗
PubMed1987

Multipoint genetic mapping of the Xq26-q28 region in families with fragile X mental retardation and in normal families reveals tight linkage of markers in q26-q27.

The q26-q28 region of the human X chromosome contains several important disease loci, including the locus for the fragile X mental retardation syndrome. We have characterized new polymorphic DNA markers useful for the genetic mapping of this region. They include a new Bell restriction fragment length polymorphism (RFLP) detected by the probe St14-1 (DXS52) and which may therefore be of diagnostic use in hemophilia A families. A linkage analysis was performed in fragile X families and in large normal families from the Centre d'Etude du Polymorphisme Humain (CEPH) by using seven polymorphic loci located in Xq26-q28. This multipoint linkage study allowed us to establish the order centromere-DXS100-DXS86-DXS144-DXS51-F9-FRAX+ ++-(DXS52-DXS15). Together with other studies, our results define a cluster of nine loci that are located in Xq26-q27 and map within a 10 to 15 centimorgan region. This contrasts with the paucity of markers (other than the fragile X locus) between the F9 gene in q27 and the G6PD cluster in q28, which are separated by about 30% recombination.

Chromosome Mapping↗
PubMed1987

Detailed ordering of markers localizing to the Xq26-Xqter region of the human X chromosome by the use of an interspecific Mus spretus mouse cross.

Five probes localizing to the Xq26-Xqter region of the human X chromosome have been genetically mapped on the mouse X chromosome using an interspecific cross involving Mus spretus to a contiguous region lying proximally to the Tabby (Ta) locus. Pedigree and recombinational analysis establish the marker order as being Hprt-FIX-c11-G6PD-St14-1. The size of this contiguous region is such that the X-linked muscular dystrophy (mdx) mouse mutation probably maps within this segment. This in turn suggests that it is highly improbable that the mouse mdx locus represents a model for Duchenne muscular dystrophy (DMD). It is, however, compatible with the idea that this mutation may correspond in man to Emery Dreifuss muscular dystrophy. The high frequency of restriction fragment length polymorphisms found in this interspecific system for all the human cross-reacting probes examined up until now, using only a limited number of restriction enzymes, suggests that the Mus spretus mapping system may be of great potential value for establishing the linkage relationships existing in man when conserved chromosomal regions are concerned and human/mouse cross-reacting probes are available or can be obtained.

Animals↗
PubMed1984

Actin-like sequences are present on human X and Y chromosomes.

The human genome contains greater than 20 actin-related sequences, six of which at least are expressed as protein. We have shown by blot hybridization the presence of actin-like sequences on both the X and the Y chromosomes. These sequences can be detected in HindIII digests of genomic DNA, using as probe cDNA clones corresponding to human alpha skeletal actin or to a hamster (beta or gamma) cytoskeletal actin; they show more homology to the latter probe. The actin probes also detect a polymorphic DNA fragment showing autosomal inheritance with a frequency for the major allele of 0.55 in the population studied. The X-linked actin sequence has been assigned to a centromeric region between Xp11 and Xq11 by hybridization to DNAs from a panel of human-mouse hybrid cell lines, and thus lies outside the postulated region of homology between the X and Y chromosomes. The Y-linked actin sequence can serve as a marker to analyse anomalies of sex determination or of gametogenesis in man. It was found in all XY males studied but was absent from the genomic DNA of four unrelated 'XX male' subjects and two XX hermaphrodites. This shows that the region of chromosome Y which contains the actin sequence is not translocated onto the X chromosome (or onto autosomes) in these patients.

Actins↗
PubMed1984

The glyceraldehyde 3 phosphate dehydrogenase gene family: structure of a human cDNA and of an X chromosome linked pseudogene; amazing complexity of the gene family in mouse.

In an experiment designed to find sequences common to a skeletal muscle cDNA library and an X chromosome specific library, we have isolated cDNA clones corresponding to glyceraldehyde 3 phosphate dehydrogenase (GAPD), (whose gene is assigned to chromosome 12), and a DNA fragment from the X chromosome short arm which contains an intron-less GAPD pseudogene. A 1210-bp cDNA sequence has been established which covers all of the protein-coding region, most of the 5' non-coding region and part of the 3' non-coding region. It corresponds to the major (and possibly unique) GAPD mRNA present in skeletal muscle. Unexpectedly, the amino acid sequence derived from the cDNA clones differs at 10% of the residues from that established for the human protein purified from skeletal muscle. The X-linked pseudogene has been localised in the p22-p11 region of the human X chromosome. It has the structure of a complete retrotranscript of a processed mRNA, including the poly(A) tail and is 96% homologous to the cDNA sequence. The pseudogene is flanked by a 15-bp direct repeat, and an Alu-like sequence is found in the 3'-flanking region. About 25 GAPD sequences are found in the human genome, 12 of which have high homology to the cDNA probe. A similar complexity is found in hamster. In contrast, the mouse genome contains an amazing number of GAPD related fragments (at least 200). The hybridization pattern suggests that this multiplicity has been generated by two different mechanisms: first the generation of approximately 40 different sequences, which were subsequently amplified (probably by tandem duplication).

Animals↗
PubMed1983

Isolation and characterization of cDNA clones for human skeletal muscle alpha actin.

Two cDNA libraries corresponding to polyA+ RNA from human adult skeletal muscle have been constructed by cloning in the PstI site of pBR322. Skeletal alpha actin cDNA clones have been isolated and characterized. Three of these plasmids have overlapping inserts which together contain the complete 5' non-coding and protein-coding region and part of the 3' untranslated region. Determination of the sequence of the cloned cDNA confirms the complete conservation in human of the amino-acid sequence of skeletal alpha actin compared to the rabbit or rat proteins. The 5' untranslated region, but not the 3' untranslated region, shows good homology with the corresponding one in the rat gene. Analysis of changes at silent sites within the protein-coding region suggests that the divergence of skeletal and cardiac alpha actin took place much earlier than the mammalian radiation. The plasmids described here have been used as probes to detect the homologous gene among the about thirty actin sequences present in the human genome.

Actins↗
PubMedDate not supplied

Linkage analysis suggests at least two loci for X-linked non-specific mental retardation.

Epidemiological studies have suggested that non-specific X-linked mental retardation (XLMR) might be at least as frequent as the fragile X syndrome. The identification of all mutations causing XLMR would thus appear of prime importance. In the absence of other clinical signs the problem of genetic heterogeneity is acute. This can be partly overcome by the analysis of large families. We have been able to perform linkage analysis in 3 such families. The condition in family 1 was described as clinically resembling the fra (X) syndrome by Proops et al [1983]: the kindred includes 7 affected males in 3 sibships. Family 2 from Denmark has affected males in 4 generations; however, several affected relatives in this extended pedigree are deceased. Family 3 from France counts 6 affected males in two sibships. The families were analysed with about 25 X-linked markers. Linkage with markers in Xp22.2-p22.3 was found in family 1: z(theta) = 2.62 at theta = 0.06 for DXS85 (probe 782). Suggestion of linkage was found in family 2 with both the Duchenne muscular dystrophy region (DXS164 in Xp21.2) and with DXS1 (Xq11-q12). In family 3, DXS159 (Xq12-q13) gave a lod score of 2.53 at theta = 0; results were compatible with localisation of the putative XLMR locus in this family proximal to DXYS1 (Xq21). These data suggest that at least two non-specific XLMR loci could exist, one in Xp22 and the other in the q12-q13 region.

Chromosome Mapping↗
PubMedDate not supplied

Probable localisation of the Coffin-Lowry locus in Xp22.2-p22.1 by multipoint linkage analysis.

The Coffin-Lowry syndrome (McKusick No. 30360) is a rare genetically transmitted disorder characterized by severe mental retardation, "coarse" facial appearance, thick soft skin, tapering fingers, and progressive skeletal abnormalities. X-linked inheritance is implied since the males are severely affected with variably mild manifestations in carrier women. We have performed a linkage analysis with many X-linked RFLP markers in 4 families. Positive two-point lod scores were obtained with DXS28 (z(theta) = 2.00 at theta = 0.05) and DXS41 (z(theta) = 1.26 at theta = 0.10). We performed a 5-point linkage analysis using the LINKMAP program assuming that DXS16 and DXS43 are a single locus and using the following fixed map (distances in centimorgans): DXS85 - 18cM - (DXS16, DXS43) - 13cM - DXS41 - 5cM -DXS28. This gave a multipoint lod score of 3.41 for a localisation in Xp22.2-p22.1, between DXS43 and DXS41.

Bone Diseases, Developmental↗
PubMedDate not supplied

Improved DNA markers for efficient analysis of fragile X families.

We report the characteristics of two new probes that detect BclI RFLPs useful for analysis of fragile X families. With these two probes and a single blot, 34% of women are heterozygous both for the proximal marker DXS105 (closer to the fragile X locus than the factor IX gene) and for the distal markers DXS52 or the factor VIII gene. Combined with the analysis of previously described polymorphic markers, it is possible to have a majority of families fully informative for flanking markers using a limited number of probes and restriction digests.

DNA Probes↗
PubMedDate not supplied

Germline mosaicism in Coffin-Lowry syndrome.

We have identified a Coffin-Lowry syndrome pedigree where the disorder is associated with a novel splice site mutation in the RSK2 gene, leading to in-phase skipping of exon 5. Western blot analysis, using an antibody directed against the C-terminus of RSK2, failed to reveal RSK2 in this patient, suggesting strongly that the resulting internally deleted protein is unstable. The mutation was present in the DNA of one affected son and one manifesting daughter but was absent in two asymptomatic daughters, who carry the at-risk haplotype, and in the mother's somatic cell (lymphocyte) DNA. The results are consistent with the mutation arising as a postzygotic event in the mother, who therefore is a germinal mosaic. The application of linked markers to identify the disease allele for conventional genetic counselling would have been misleading in this family. This observation again highlights the importance of precise identification of the disease-causing mutation.

Abnormalities, Multiple↗