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A Hanauer

Publications and source records attributed to A Hanauer.

At least 55 records · Page 3Linked to original sources
PubMed1992

Two hot spots of recombination in the DMD gene correlate with the deletion prone regions.

Genetic mapping has indicated that meiotic recombination occurs about 4 time more frequently in the dystrophin gene than expected on the basis of its length. To detect where recombinations occur within the gene, we have studied the CEPH families panel using highly polymorphic microsatellite markers located at the ends of the gene or flanking the major deletion hot spot in intron 44. We found a major hot spot of recombination between markers STR44 and STR50(1), i.e., between exons 44 and 51. Within this hot spot, a peak of recombination was located in the large intron 44. A second minor recombination prone region was found between DXS 206, (XJ, in the large intron 7) and the 5' end of the DMD gene. The distribution of the recombination events in the gene of healthy individuals was very similar to that of deletion breakpoints in DMD/BMD patients, suggesting that the two phenomenon may share a common mechanism. These results should also improve efficiency and accuracy of linkage analysis applied to carrier detection and prenatal diagnosis. In particular, if markers located at the very 3' end of the gene are not informative, the highly polymorphic ones located between exons 50 and 60 can be used instead of presently available extragenic markers, with a very low risk of diagnostic error due to recombination.

Dystrophin↗
PubMed1992

Phenotype-genotype correlations in X linked retinitis pigmentosa.

Retinitis pigmentosa (RP) represents a group of clinically heterogeneous retinal degenerations in which all modes of inheritance have been described. We have previously found two different clinical profiles in X linked RP as a function of age and mode of onset. The first clinical form has very early onset with severe myopia. The second form starts later with night blindness with mild myopia or none. At least two genes have been identified in X linked forms, namely RP2 (linked to DXS7, DXS255, and DXS14) and RP3 (linked to DXS84 and OTC) on the short arm of the X chromosome. In order to contribute to phenotype-genotype correlations in X linked RP, we tested the hypothesis that the two clinical profiles could be accounted for by the two different gene loci. The present study provides evidence for linkage of the clinical form with early myopia as the onset symptom with the RP2 gene (pairwise linkage to DXS255: Z = 3.13 at theta = 0), while the clinical form with later night blindness as the onset symptom is linked to the RP3 gene (pairwise linkage to OTC: Z = 4.16 at theta = 0).

Female↗
PubMed1992

Gerstmann-Sträussler-Scheinker disease in an Alsatian family: clinical and genetic studies.

The clinical progression of Gerstmann-Sträussler-Scheinker disease in a family of Alsatian origin is reported. The age of onset and the duration of evolution were variable. The clinical picture became more complex over the generations: in the first generations, isolated dementia and in later generations a triad of pyramidal, pseudobulbar syndromes and dementia associated with spinal cord and cerebellar features. Prion gene analysis showed that four surviving patients carry double missense changes at codons 117 and 129, identical to those found in one case at necropsy and 10 other healthy members of the family. The missense changes were not found in 100 controls. No member of the family had modification of condons 102, 178, or 200. The lod score suggests linkage between the missense change at codon 117 and Gerstmann-Sträussler-Scheinker disease in this family.

Adult↗
PubMed1991

Up-regulation of dopamine D2 receptor mRNA in rat striatum by chronic neuroleptic treatment.

The effect of prolonged administration of antagonists on rat striatal dopamine D2 receptor binding and mRNA content was examined. Both haloperidol (2 and 4 mg/kg) and sulpiride (10 mg/kg) induced a significant rise in total D2 and D2(444) mRNA level and in Bmax. Regulation of messenger RNA accumulation is thus an important determinant of dopamine D2 receptor density.

Animals↗
PubMed1991

Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome.

The fragile X syndrome, a common cause of inherited mental retardation, is characterized by an unusual mode of inheritance. Phenotypic expression has been linked to abnormal cytosine methylation of a single CpG island, at or very near the fragile site. Probes adjacent to this island detected very localized DNA rearrangements that constituted the fragile X mutations, and whose target was a 550-base pair GC-rich fragment. Normal transmitting males had a 150- to 400-base pair insertion that was inherited by their daughters either unchanged, or with small differences in size. Fragile X-positive individuals in the next generation had much larger fragments that differed among siblings and showed a generally heterogeneous pattern indicating somatic mutation. The mutated allele appeared unmethylated in normal transmitting males, methylated only on the inactive X chromosome in their daughters, and totally methylated in most fragile X males. However, some males had a mosaic pattern. Expression of the fragile X syndrome thus appears to result from a two-step mutation as well as a highly localized methylation. Carriers of the fragile X mutation can easily be detected regardless of sex or phenotypic expression, and rare apparent false negatives may result from genetic heterogeneity or misdiagnosis.

Base Composition↗
PubMed1991

Early prenatal diagnosis of the fragile site at Xq27.3 associated with Martin-Bell syndrome.

Early prenatal diagnosis of the fragile X was attempted in 44 pregnancies, including one twin pregnancy at risk of Martin-Bell (MB) syndrome. The sex ratio was 24M:21F. The fragile site was reproducibly demonstrated in cultured chorionic villus (CV) cells in eight male and five female fetuses. Six of the male and three of the female fetuses were terminated. Simultaneous RFLP analysis provided confirmative data with flanking DNA markers in 3 of 13 analysed cases. Recombination and/or non-informativeness at available distal and/or proximal loci were found in nine cases. In one male fetus, discordance between the haplotype and cytogenetics (fragile-X-negative) suggested the presence of a normal male transmitter, a double meiotic cross-over within the region, or a false-negative cytogenetic diagnosis. However, discordance between prenatal and post-termination/postnatal cytogenetic findings was not observed in this series. The use of excess thymidine for induction of the fragile X in cultured CV cells provided in the majority of cases a safe and rapid method for cytogenetic diagnosis, with options for early induced termination in fragile-X-positive pregnancies, for simultaneous RFLP analysis, and for subsequent second-trimester analysis of fetal blood in complicated cases.

Adolescent↗
PubMed1991

Oto-palato-digital syndrome type I: further evidence for assignment of the locus to Xq28.

The oto-palato-digital syndrome (OPD) is a rare X-linked disease with diagnostic skeletal features, conduction deafness, cleft palate and mild mental retardation. Differences in clinical presentation between families have led investigators to classify OPD into two subtypes: type I and type II. A linkage study performed in one family segregating for OPD I has recently suggested linkage to three marker loci: DXS15, DXS52 at Xq28, and DXS86 at Xq26. We have investigated an additional OPD I family for linkage by using distal chromosome Xq DNA probes. The linkage data and the analysis of recombination events that have occurred in this family excluded, definitively, the Xq26 region for OPD I, and provide further support for mapping the mutant gene close to the cluster of tightly linked markers DXS15, DXS52 and DXS305 at Xq28.

Abnormalities, Multiple↗
PubMed1991

Physical mapping of two loci (D9S5 and D9S15) tightly linked to Friedreich ataxia locus (FRDA) and identification of nearby CpG islands by pulse-field gel electrophoresis.

The Friedreich's ataxia locus (FRDA) has recently been mapped to 9q13-q21 by tight linkage to D9S15 and D9S5 loci. The present lack of recombination between these loci precludes further genetic mapping and suggests that the distances involved are in the megabase range. We have established a 1-Mb map around loci D9S15 (defined by probe MCT112) and D9S5 (defined by probe DR47) and found that they are at most 260 apart. Six rare cutting site clusters were found in a 450-kb segment containing both loci. Three clusters were completely unmethylated in two cell lines tested and might correspond to CpG islands flanking transcribed sequences. Cosmid mapping of a 52-kb region around D9S5 and pulse-field gel electrophoresis analysis showed the presence of three other CpG clusters that were partially or completely methylated. Two of them were present in the cosmid clones available and were associated with sequences conserved in other vertebrate species. The CpG islands and conserved sequences presented here can be used to search for genes defective in Friedreich's ataxia.

Animals↗
PubMed1991

Nonradioactive assay for new microsatellite polymorphisms at the 5' end of the dystrophin gene, and estimation of intragenic recombination.

Indirect tracking of mutation by DNA polymorphisms is still essential for carrier and prenatal diagnosis of Duchenne/Becker muscular dystrophy, at least in the families where no deletion can be detected. Because of the relatively high level of intragenic recombination, informative and easily testable markers at both ends of the gene are necessary for efficient and accurate diagnosis. We report the characterization of two polymorphic microsatellite sequences (TG repeats) at the 5' end of the dystrophin gene, within 40 kb of the muscle-specific promoter. The most useful one (5' DYS MSA) has 10 alleles with a 57% heterozygosity and can be tested on small polyacrylamide gels in a nonradioactive PCR-based assay. Despite its large number of alleles, this microsatellite shows strong linkage disequilibrium with a two-allele polymorphism reported by Roberts et al., an indication of the stability of this type of sequences. We have used the new microsatellites at the 5' end, along with one we reported previously for the 3' end, to type the families in the CEPH (Centre d'Etude du Polymorphisme Humain) panel. While the number of informative families has increased by a factor of about two with respect to the study of Abbs et al., the estimates of the recombination fractions are in good agreement with this previous report, suggesting a 11% recombination across the gene (3% between the 5' end and the pERT87 region, 8% between pERT87 and the 3' end), which is about fivefold more than expected. However, these estimates still have wide confidence limits.

Alleles↗
PubMed1990

Additional polymorphisms at marker loci D9S5 and D9S15 generate extended haplotypes in linkage disequilibrium with Friedreich ataxia.

The gene for Friedreich ataxia (FA), a severe recessive neurodegenerative disease, has previously been shown to be tightly linked to the polymorphic markers D9S15 and D9S5 on human chromosome 9. In addition, the observation of linkage disequilibrium suggested that D9S15 is within 1 centimorgan (cM) of the disease locus, FRDA. Although D9S5 did not show recombination with FRDA, its localization was less precise (0-5 cM) due to its lower informativeness. We have now identified additional polymorphisms at both marker loci. Two cosmids spanning 50 kilobases around D9S5 were isolated, and a probe derived from one of them detects an informative three-allele polymorphism. We have found a highly polymorphic microsatellite sequence at D9S15 which is rapidly typed by the DNA polymerase chain reaction. The polymorphism information contents at the D9S5 and D9S15 loci have been increased from 0.14 to 0.60 and from 0.33 to 0.74, respectively. With the additional polymorphisms the lod (log10 odds ratio) score for the D9S15-FRDA linkage is now 48.10 at recombination fraction theta = 0.005 and for D9S5-FRDA, the lod score is 27.87 at theta = 0.00. We have identified a recombinant between D9S15 and FRDA. However, due to the family structure, it will be of limited usefulness for more precise localization of FRDA. The linkage disequilibrium previously observed between D9S15 and FRDA is strengthened by analysis of the haplotypes using the microsatellite polymorphism, while weaker but significant disequilibrium is found between D9S5 and FRDA. Extended haplotypes that encompass D9S5 and D9S15 show a strikingly different distribution between chromosomes that carry the FA mutation and normal chromosomes. This suggests that both marker loci are less than 1 cM from the FRDA gene and that a small number of mutations account for the majority of FA cases in the French population studied. D9S5 and D9S15 are thus excellent start points to isolate the disease gene.

Cell Line↗
PubMed1990

Common intragenic and extragenic polymorphisms of blood coagulation factors VIII and IX are different in Chinese and Caucasian populations.

In order to examine the possibilities of carrier detection and prenatal diagnosis in hemophilia A and B in the Chinese region of Suzhou, we analyzed four different RFLPs within the factor IX gene and two intragenic RFLPs and one extragenic RFLP for the factor VIII gene. The results obtained show important differences between the Chinese and Caucasian populations. No polymorphism was found within the factor IX gene in the Chinese population and the informativity obtained for the factor VIII gene was quite different between the two populations for each RFLP studied.

Adult↗
PubMed1990

Glutamate dehydrogenase in cerebellar mutant mice: gene localization and enzyme activity in different tissues.

Many similarities of both the inheritance pattern and the neuropathology can be observed between olivopontocerebellar atrophies, or so-called multiple system atrophies (MSAs), and murine cerebellar mutations like Purkinje cell degeneration, nervous, staggerer, weaver, and reeler. Our study aimed to test whether the glutamate dehydrogenase (GDH) deficiency observed in some MSA patients could be found also in any of the murine mutants. GDH activity was assayed in several organs of these mutants, and no general deficiency was detected. By contrast, the level was found to be elevated in the cerebellum. The GDH gene was localized on mouse chromosome 14 and does not map close to any known neurological mutation in the mouse. We conclude, for the moment, that none of these cerebellar mutant mice can be considered as an animal model for GDH-deficient MSA.

Animals↗
PubMed1990

Sublocalisation of the X breakpoint in the translocation (X; 18)(p11.2; q11.2) primary change in synovial sarcomas.

A specific translocation between chromosomes X and 18 was identified in synovial sarcomas. From a girl with synovial sarcoma, we isolated two clones with t(X; 18)(p11.2; q11.2) and which had lost the normal X chromosome. Southern blot analysis of DNA from the tumor, the patient and her parents demonstrated that the normal X chromosome, lost in the tumor, was the paternal one. A somatic hybrid cell line was established by fusing tumor cells (after passages on athymic mice) to an HPRT deficient hamster cell line. By cytogenetic, in situ hybridization and molecular analysis, it was found to contain the derivative (X) chromosome in the absence of the der (18) chromosome. To determine the position of the breakpoint on the X chromosome, Southern blots of DNA from this hybrid were hybridized to [32P]-labelled X chromosome probes. DXS146 and DXS255 were retained in the hybrid cell line whereas GAPDP1, the ARAF1 and TIMP proto-oncogenes were not present, indicating that the breakpoint lies proximal to GAPD1, ARAF1 and TIMP and distal to DXS255 and DXS146. Results obtained from other authors are compared. Further studies will be necessary to determine the extent of variation of the breakpoint in different tumors.

Blotting, Southern↗
PubMed1990

The Friedreich ataxia gene is assigned to chromosome 9q13-q21 by mapping of tightly linked markers and shows linkage disequilibrium with D9S15.

Chamberlain et al. have assigned the gene for Friedreich ataxia (FA), a recessive neurodegenerative disorder, to chromosome 9, and have proposed a regional localization in the proximal short arm (9p22-cen), on the basis of linkage to D9S15 and to interferon-beta (IFNB), the latter being localized in 9p22. We confirmed more recently the close linkage to D9S15 in another set of families but found much looser linkage to IFNB. We also reported another closely linked marker, D9S5. Additional families have now been studied, and our updated lod scores are z = 14.30 at theta = .00 for D9S15-FA linkage and z = 6.30 at theta = .00 for D9S5-FA linkage. Together with the recent data of Chamberlain et al., this shows that D9S15 is very likely within 1 cM of the FA locus. We have found very significant linkage disequilibrium (delta Std = .28, chi 2 = 9.71, P less than .01) between FA and the D9S15 MspI RFLP in French families, which further supports the very close proximity of these two loci. No recombination between D9S5 and D9S15 was found in the FA families or Centre d'Etude du Polymorphisme Humain families (z = 9.30 at theta = .00). Thus D9S5, D9S15, and FA define a cluster of tightly linked loci. We have mapped D9S5 by in situ hybridization to 9q13-q21, and, accordingly, we assign the D9S5, D9S15, and FA cluster to the proximal part of chromosome 9 long arm, close to the heterochromatic region.

Alleles↗
PubMed1990

Friedreich ataxia in Italian families: genetic homogeneity and linkage disequilibrium with the marker loci D9S5 and D9S15.

Friedreich ataxia (FA) is an autosomal recessive degenerative disease of the nervous system of unknown biochemical cause. The FA gene has been shown to be in close linkage with the two chromosome 9 markers D9S5 and D9S15, and linkage disequilibrium between FA and D9S15 has been detected in French families by Hanauer et al. We used new highly informative markers at the above loci to analyze Italian FA families for linkage and linkage disequilibrium. The new markers were a three-allele BstXI RFLP at D9S5 (PIC = .55) and a six-allele microsatellite, typed by polymerase chain reaction, at D9S15 (PIC = .75). We obtained maximum lod scores of 8.25 between FA and D9S5, 10.55 between FA and D9S15, and 9.52 between D9S5 and D9S15, all at zero recombination. Our results, combined with those reported by other authors, reduce maxlod-1 (maximum lod score minus 1) confidence limits to less than 1.1 cM between FA and D9S5, 1.2 cM between FA and D9S15, and 1.4 cM between D9S5 and D9S15. Linkage disequilibrium with FA was found only for D9S15 when all families were evaluated but was also found for a D9S5/D9S15 haplotype in a subgroup of southern Italian families. We conclude that FA, D9S5, and D9S15 are tightly clustered and that studies of geographically restricted groups may reveal a limited number of mutations responsible for the disease in the Italian population. We present preliminary evidence from pulsed-field gel electrophoresis that D9S5 and D9S15 may be less than 450 kb apart. Linkage disequilibrium between FA and D9S15 suggests that the disease gene may be at an even shorter distance from this marker locus, which therefore represents a very good starting point for cloning attempts.

Alleles↗