Search PubMed⌕ Search

Biomedical subjects

R Williamson

Publications and source records attributed to R Williamson.

At least 181 records · Page 10Linked to original sources
PubMed1993

Haplotype analysis to determine the position of a mutation among closely linked DNA markers.

Positional cloning involves first finding linkage between an inherited phenotype (such as a disease) and a DNA marker, followed by the use of a variety of physical and genetic mapping techniques to move from linkage to mutation. If there is a founder effect within a population, crossovers are often rare between the mutation causing the phenotype and closely situated markers and increasing disequilibrium may be observed as the site of the mutation is approached. Standard coefficients of disequilibrium may, however, be insensitive to the relative position of close markers and the mutation, because they depend upon allele frequencies in the normal population compared to those of the founder chromosome. Using cystic fibrosis in European populations as a model system, alternative methods for determining the position of a mutation are discussed. These include haplotype parsimony and three-way interval likelihood analysis. Both methods predict the location of the major CF mutation accurately from a real set of more than 600 European CF chromosomes.

Alleles↗
PubMed1993

Variation of short tandem repeats within and between populations.

Using the polymerase chain reaction (PCR) the frequency distributions of three short tandem repeats (STR) were investigated in five populations: North European, Cypriot, Pakistani, Gujarati and Vietnamese. Each STR is situated within an intron; the markers are in the genes for human coagulation factor XIII (4bp repeat), lipoprotein lipase (4bp repeat) and CD4 (5bp repeat). Population data were generated for each STR and allele frequencies calculated. A calculation of the level of population substructuring for the three systems was also made. The lipoprotein lipase STR data showed no evidence for population substructuring, but there was a significant level of substructuring in the other two systems. This initial pilot study demonstrates the need to validate each marker used for DNA profiling in different human populations, and that some markers (such as LPL) can be used with confidence in widely differing ethnic groups, while others (such as CD4 and F13A) may be of value in distinguishing sub-groups.

Alleles↗
PubMed1993

Evidence for a single gene effect causing polycystic ovaries and male pattern baldness.

OBJECTIVE: Polycystic ovary syndrome is one of the most common endocrine disorders but its aetiology remains unknown. It is highly prevalent within families, suggesting a genetic basic for the syndrome, but the mode of inheritance is unclear. The purpose of this study was to determine the mode of inheritance of polycystic ovary syndrome, within the families of affected individuals, by classic segregation analysis. DESIGN: All first degree relatives of affected individuals were screened for the presence or absence of polycystic ovaries in post-menarchal-premenopausal women and early onset male pattern baldness (MPB) in the males. In extended pedigrees, assignment of affected status in post-menopausal women was made by consideration of the clinical history alone. PATIENTS: Fourteen women (probands), presenting with a variety of clinical symptoms, were identified sequentially as having polycystic ovaries (PCO) by ultrasound scan. They were examined in detail to determine their family structure, clinical and endocrine status. Ten families were found to have sufficient members for further study. MEASUREMENTS: All family members had their body mass index calculated, their degree of hirsutism assessed using the Ferriman and Gallwey score and serum levels of gonadotrophins (FSH and LH), testosterone, prolactin and 17 alpha-hydroxyprogesterone measured by radioimmunoassay. A careful reproductive history was taken for each woman and any menstrual disturbance was noted. Obese probands had their glucose and insulin response to a standard 75-g oral glucose tolerance test determined. Each male family member was also assessed for the degree and time of onset of balding. RESULTS: First degree female relatives of affected individuals had a 51% chance of being affected. Early onset male pattern baldness (MPB) was found to be an accurate phenotype for obligate male carriers. Each family showed autosomal dominant inheritance for PCO with greater than 90% penetrance. CONCLUSIONS: We postulate that PCO and male pattern baldness are caused by alleles of the same gene which affect androgen production or action. The different frequencies of PCO and male pattern baldness arise from differing thresholds for phenotypic expression in females and males respectively. The modifying effects of other genes is the most likely explanation of the somewhat variable phenotype.

Adult↗
PubMed1993

Identification of a mutation in the beta cardiac myosin heavy chain gene in a family with hypertrophic cardiomyopathy.

OBJECTIVE: To investigate the molecular genetic basis of the cause of disease in a family with hypertrophic cardiomyopathy. BACKGROUND: Mutation within the beta cardiac myosin heavy chain gene has been shown to be the pathogenetic mechanism underlying the disease in several families, though clear evidence of heterogeneity has been reported. PATIENTS: A family with a history of hypertrophic cardiomyopathy. RESULTS AND CONCLUSION: This paper reports a mutation at aminoacid position 908 within exon 23 of the beta cardiac myosin heavy chain gene, resulting in a conversion of a leucine to valine. This base substitution was identified in an individual with a confirmed family history but with equivocal symptoms of the disease. Inheritance of the mutation by his symptom free juvenile offspring demonstrates the application of the technique to presymptomatic diagnosis.

Adolescent↗
PubMed1993

Meiotic crossing-over in nondisjoined chromosomes of children with trisomy 21 and a congenital heart defect.

We have used DNA polymorphisms to study meiotic crossovers of chromosome 21q in 27 nuclear families. Each family had a child with Down syndrome and a congenital heart defect. Twenty DNA polymorphisms on chromosome 21 were used to determine parental and meiotic origin of nondisjunction and to identify crossovers. Twenty-four cases were of maternal origin, and three were of paternal origin. Twenty-two unequivocal crossover events were identified. Sixteen crossovers were observed in 22 chromosome pairs nondisjoining at the second meiotic division. Fifty percent of crossover events in MI nondisjunction are detectable by molecular genetic means. Thus, the results suggest that, in this sample, each nondisjoined chromosome 21 pair has been involved in at least one crossover event.

Adolescent↗
PubMed1993

The statocysts of molluscs.

This article presents a brief review of the morphology and physiology of molluscan statocysts. These sense organs provide the animals with information on orientation and, in some cases, velocity of movement. They vary in sophistication from rudimentary, to organs almost as complex as those found in higher vertebrates. The morphology of different types of statocysts is described as well as their afferent responses, efferent systems and pharmacology.

Animals↗
PubMed1993

Genetic recombination events which position the Friedreich ataxia locus proximal to the D9S15/D9S5 linkage group on chromosome 9q.

The absence of recombination between the mutation causing Friedreich ataxia and the two loci which originally assigned the disease locus to chromosome 9 has slowed attempts to isolate and characterize the genetic defect underlying this neurodegenerative disorder. A proximity of less than 1 cM to the linkage group has been proved by the generation of high maximal lod score (Z) to each of the two tightly linked markers D9S15 (Z = 96.69; recombination fraction [theta] = .01) and D9S5 (Z = 98.22; theta = .01). We report here recombination events which indicate that the FRDA locus is located centromeric to the D9S15/D9S5 linkage group, with the most probable order being cen-FRDA-D9S5-D9S15-qter. However, orientation of the markers with respect to the centromere, critical to the positional cloning strategy, remains to be resolved definitively.

Adolescent↗
PubMed1993

Pin-retained restorations for severely worn posterior teeth.

Restoring severely worn posterior teeth with cast restorations presents a challenge to the dentist. The shortened clinical crowns have insufficient axial wall length for adequate retention and resistance form. Pins, along with other preparation retentive forms, can avoid periodontal support loss created by lengthening procedures. This article describes pin preparation of severely worn mandibular premolars and molar restoration by pin-retained gold castings. These and other teeth are used for retention of a mandibular removable partial denture.

Aged↗
PubMed1992

Marked reduction of high density lipoprotein cholesterol in mice genetically modified to lack apolipoprotein A-I.

Atherosclerosis is a major cause of morbidity and mortality in developed countries. In humans the risk of atherosclerosis is inversely correlated with plasma levels of high density lipoprotein (HDL). As a step in determining whether the experimental reduction of plasma HDL level will increase susceptibility to atherosclerosis, we have used gene targeting in embryonic stem cells to produce mice lacking apolipoprotein A-I, the major protein component of HDL particles. Mice homozygous for the disrupted gene have no plasma apolipoprotein A-I detectable by double immunodiffusion; their total plasma cholesterol and HDL-cholesterol levels after overnight fasting are reduced to about one-third and one-fifth of normal levels, and they are grossly deficient in alpha-migrating HDL particles.

Animals↗
PubMed1992

Psychological and social consequences of community carrier screening programme for cystic fibrosis.

We have assessed the effect of screening for cystic fibrosis (CF) carrier status on anxiety levels, attitudes, knowledge and actions of participants in a pilot programme conducted through primary health care services. Over 3000 individuals were screened and 100 carriers with no previous family history were identified. Varying degrees of anxiety were found to be associated initially with a positive result, but most of this was allayed by genetic counselling, and we find no adverse long-term psychological consequences in carriers. Most discussed carrier status with their partner (89%), parents, other relatives and also with friends; 87% of partners to whom testing was suggested have been screened. Those testing positive indicated that knowledge of carrier status would be considered in future reproductive decisions, and after 6 months carriers retained a reasonable level of knowledge about CF and its inheritance. Carriers and non-carriers uniformly approve of screening and are glad to have been tested. Knowledge of CF in the sample of non-carriers has also increased after testing, suggesting screening may improve understanding of CF among the entire target population. Fears of possible social costs of screening may be ill-founded.

Adolescent↗
PubMed1992

Velo-cardio-facial syndrome associated with chromosome 22 deletions encompassing the DiGeorge locus.

The large clinical overlap between DiGeorge syndrome and velo-cardio-facial syndrome suggests an aetiological connection. DiGeorge syndrome is associated with microdeletions of chromosome 22q11 and is therefore likely to be caused by reduced dosage of genes within this region. We present preliminary data that velocardiofacial syndrome patients have similar chromosome deletions, a finding consistent with the hypothesis that these disorders represent part of a spectrum of abnormalities seen with monosomy for 22q11.

Abnormalities, Multiple↗
PubMed1992

Genotype analysis for delta F508, G551D and R553X mutations in children and young adults with cystic fibrosis with and without chronic liver disease.

Genetic factors have been implicated in the pathogenesis of liver disease in cystic fibrosis. To investigate whether liver disease is associated with particular mutations of the defective gene in cystic fibrosis, we have determined the frequencies of three mutations--delta F508, G551D and R553X--in 111 children and young adults with cystic fibrosis by analysis of genomic DNA segments amplified by the polymerase chain reaction. Twenty-nine patients had severe liver disease with portal hypertension, 19 had clinical and/or biochemical evidence of liver disease but no associated portal hypertension and 63 had no evidence of liver disease. No significant differences in the frequencies of the delta F508, G551D or R553X mutations in the three clinical subgroups were found, and we conclude that the development of liver disease in cystic fibrosis is unlikely to be associated with a specific mutation in the gene. However, because 27% of cystic fibrosis chromosomes do not have a defined mutation, this possibility cannot be ruled out. A familial concordance for clinical liver disease of 20% in this study, compared with a reported prevalence of 4.7%, suggests that genes outside the cystic fibrosis locus and/or environmental factors are involved in the pathogenesis of liver disease in cystic fibrosis.

Adolescent↗
PubMed1992

Interstitial deletions in DiGeorge syndrome detected with microclones from 22q11.

DiGeorge syndrome in humans is characterized by immunodeficiency, heart defects, mental retardation and facial dysmorphism; cytogenetic analysis has shown that deletions at 22q11 occur in approximately 25% of cases. To generate DNA markers from this region, we have microdissected and microcloned band q11 of human Chromosome (Chr) 22. Nineteen thousand clones were obtained from material dissected from 20 chromosome fragments. Seventeen of 61 clones analyzed (28%) were repetitive, 27 (44%) gave no signal, and 17 (28%) detected single copy sequences of which ten mapped to Chr 22. Two of these were found to be deleted in patients with DiGeorge syndrome and either monosomy for 22q11-pter or visible interstitial deletions of 22q11. These two markers are also hemizygous in patients with no visible chromosomal abnormality, demonstrating that submicroscopic deletions are common in DiGeorge syndrome patients.

Blotting, Southern↗