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Biomedical subjects

A D Roses

Publications and source records attributed to A D Roses.

331 records · Page 19Linked to original sources
PubMedDate not supplied

Development of a microsatellite genetic map spanning 5q31-q33 and subsequent placement of the LGMD1A locus between D5S178 and IL9.

Limb-girdle muscular dystrophy (LGMD) is a genetically and clinically heterogeneous group of disorders. We previously localized an autosomal dominant form of the disorder (LGMD1A) to chromosome 5q22-31 by linkage analysis in a single large pedigree. After developing a microsatellite genetic map incorporating six loci in q31-33 of chromosome 5 and spanning 35 cM, we have refined the original localization. Using multipoint analysis, LGMD1A is localised to a 7 cM region between the markers IL9 and D5S178 with odds > 1000:1.

Chromosome Mapping↗
PubMedDate not supplied

Cis-acting human ApoE tissue expression element is associated with human pattern of intraneuronal ApoE in transgenic mice.

Apolipoprotein E polymorphic variants (ApoE-epsilon2, epsilon3, and epsilon4) are associated with the age of onset distribution and risk of Alzheimer disease. The question of whether ApoE is expressed at a comparatively low level in human neurons compared to astrocytes, or whether ApoE enters neuronal cytoplasm via altered endosomal metabolism is important to understanding potential pathogenic roles for ApoE as a susceptibility gene in Alzheimer disease. ApoE deficient ("knock-out") mice received large human genomic DNA fragment transgenes for each of the three common apoE alleles. All transgenic mice demonstrated glial/astrocytic (normal rodent pattern), as well as cortical intraneuronal ApoE immunoreactivity with all three human isoforms and at multiple ApoE human allele doses (Xu et al. (32)). To test whether ApoE intraneuronal immunoreactivity was due to ApoE gene sequences between mouse and human, we examined another set of mice constructed using targeted replacement so that the human ApoE gene was placed under mouse gene promoters. Current analyses show that targeted replacement recombinant mice show normal rodent glial expression pattern, but no ApoE neuronal immunoreactivity through six months of age compared to large human genomic DNA fragment transgenic mice, which show neuronal content of ApoE throughout adult life. We conclude that cis-acting DNA sequences, rather than the specific sequence of the ApoE gene, may be responsible for low levels of transcription activity in cortical neurons.

Alleles↗
PubMedDate not supplied

Complete genomic screen in late-onset familial Alzheimer's disease.

Alzheimer's disease (AD) is a complex genetic disorder. Linkage analysis has helped unravel a portion of the genetic component of AD by identifying four loci that play a role in the genetics of AD (amyloid precursor protein, presenilin 1, presenilin 2, and apolipoprotein E). These loci account for approximately 50% of the genetic etiology of AD. A total genomic screen is an efficient way to identify additional genetic effects in AD. A series of multiplex late-onset (>60 years) AD families were ascertained (NINDS-ADRDA diagnostic criteria) and sampled. A subset (n = 16) of the largest families (52 affecteds with DNA, 83 unaffecteds with DNA) were used to rapidly screen the genome (n = 280 markers) for additional major genetic effects. Critical values for regional follow-up were p < or =0.05 for SimIBD or sibpair analysis and/or a LOD score > or = 1.00. Fifteen regions warranted initial follow-up based on these criteria. An additional screening set was used (n = 38 families, 89 affecteds with DNA, 216 unaffecteds with DNA) for the follow-up analysis. These analyses revealed four regions of continued interest on chromosomes 4, 6, 12, and 20. Chromosome 12 presented the strongest results. Peak two point "affecteds only" LOD scores were 1.3, 1.6, 2.7, and 2.2 and (affected relative pair SimIBD) p values were 0.04, 0.03, 0.14, and 0.04 for D12S373, D12S1057, D12S1042, and D12S390, respectively. These markers span approximately 30 cm near the centromeric region of chromosome 12. Sibpair analysis resulted in two point Maximum Lod Score (MLS) results of 0.4, 1.2, 3.2, and 1.0 for the above markers. Multipoint MLS analysis supported these findings. Saturation mapping of all available markers in the chromosome 12 region as well as further investigation of the regions on 4, 6, and 20 is ongoing with candidate gene analysis to follow.

Age of Onset↗
PubMedDate not supplied

Detection of deletions spanning the Duchenne muscular dystrophy locus using a tightly linked DNA segment.

The Duchenne muscular dystrophy (DMD) locus has been localized to the short arm of the human X chromosome (Xp21) by detection of structural abnormalities and by genetic linkage studies. A library highly enriched for human DNA from Xp21 was constructed using DNA isolated from a male patient who had a visible deletion and three X-linked disorders (DMD, retinitis pigmentosa and chronic granulomatous disease). Seven cloned DNA probes from this library and the probe 754 (refs 5, 8) are used in the present study to screen for deletions in the DNA isolated from 57 unrelated males with DMD. Five of these DMD males are shown to exhibit deletions for one of the cloned DNA segments and at least 38 kb of surrounding DNA. In addition, two subclones from the same region detect four restriction fragment length polymorphisms which exhibit no obligate recombination with DMD in 34 meiotic events. These new DNA segments will complement the existing Xp21 probes for use in carrier detection and prenatal diagnosis of DMD. Elucidation of the end points of the five deletions will help delineate the extent of the DMD locus and ultimately lead to an understanding of the specific sequences involved in DMD.

Alleles↗
PubMedDate not supplied

Analysis of deletions in DNA from patients with Becker and Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder for which the biochemical defect is as yet unknown. Recently, two cloned segments of human X-chromosome DNA have been described which detect structural alterations within or near the genetic locus responsible for the disorder. Both of these cloned segments were described as tightly linked to the locus and were capable of detecting deletions in the DNA of boys affected with DMD. In an attempt to determine more precisely the occurrence of these deletions within a large population of DMD patients and the accuracy of one of the segments, DXS164 (pERT87), in determining the inheritance of the DMD X chromosome, the subclones 1, 8 and 15 were made available to many investigators throughout the world. Here we describe the combined results of more than 20 research laboratories with respect to the occurrence of deletions at the DXS164 locus in DNA samples isolated from patients with DMD and Becker muscular dystrophy (BMD). The results indicate that the DXS164 locus apparently recombines with DMD 5% of the time, but is probably located between independent sites of mutation which yield DMD. The breakpoints of some deletions are delineated within the DXS164 locus, and it is evident that the deletions at the DMD locus are frequent and extremely large.

Chromosome Deletion↗
PubMedDate not supplied

Genetics of Alzheimer's disease.

Alzheimer's disease is the leading cause of dementia in the elderly. Most patients do not have an obvious family history and are classified as sporadic. Genetic factors in early and late-onset Alzheimer's disease are now well documented. This paper reviews the known genetic loci associated with Alzheimer's disease with an emphasis on the role of apolipoprotein E in late-onset familial and sporadic disease. Apolipoprotein E allele 4 is a susceptibility gene that is found in approximately 50% of patients with Alzheimer's disease. Hypotheses about apolipoprotein E function that may lead to Alzheimer's disease are also discussed.

Age of Onset↗