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S Chamberlain

Publications and source records attributed to S Chamberlain.

At least 19 recordsLinked to original sources
PubMed1991

Identification of CpG islands in a physical map encompassing the Friedreich's ataxia locus.

The Friedreich's ataxia locus has been previously assigned to chromosome 9q 13-21.1 by the demonstration of tight linkage to two anonymous DNA markers. MCT112 (Z greater than 80, theta = 0) and DR47 (Z greater than 50, theta = 0). The absence of recombination between these three loci has prevented the resolution of gene/probe order in this region, impeding strategies for gene isolation. We report physical mapping over a 4-Mb genomic interval, linking the markers MCT112 and DR47 on a common 460-kb NotI fragment and identifying 11 CpG islands in the 1.7-Mb interval most likely to contain the Friedreich's ataxia locus. Four of these islands were detected only by analysis of three YAC clones spanning a 700-kb interval including the MCT112/DR47 cluster. Without clear evidence of the precise location of the disease locus from recombination events, each of these regions must be considered as specifying a potential "candidate" sequence for the mutated gene.

Chromosome Mapping↗
PubMed1991

Autosomal dominant inheritance of autoantibodies to thyroid peroxidase and thyroglobulin--studies in families not selected for autoimmune thyroid disease.

Recently the tendency to produce autoantibodies to thyroid peroxidase (TPO Ab) and thyroglobulin (Tg Ab) was shown to be inherited as an autosomal dominant characteristic in women but not in men. Because of potential bias in this study which was carried out in families with autoimmune thyroid disease (AITD), the inheritance of thyroid autoantibodies has been evaluated in 49 families unselected for autoimmune thyroid disease. Among these families (24 with facioscapulohumeral disease, 10 with Friedreich's ataxia, and 15 with schizophrenia) the prevalences of TPO Ab and Tg Ab were 27.8% and 26.7%, respectively, in women and 9.2% and 11.7%, respectively, in men. In 40 families where one or more individual had TPO Ab and/or Tg Ab, segregation analysis showed that the tendency to make antibodies was consistent with a Mendelian dominant trait in women but not in men. In young women, however, the prevalence of both TPO Ab and Tg Ab increased with age, rising from 14% and 10%, respectively, at age 15-24 to 35% and 40% at age 35-44. As this is inconsistent with a simple dominant hypothesis, a further segregation analysis by age was carried out in the families unselected for thyroid disease together with 16 pedigrees with AITD previously studied and two additional large AITD families. The results of the combined analysis provided strong support for the hypothesis of dominant inheritance but also showed significant reduction in gene expression among women aged 15-24 yr.

Adolescent↗
PubMed1990

Identification of a hypervariable microsatellite polymorphism within D9S15 tightly linked to Friedrich's ataxia.

We have identified a hypervariable microsatellite sequence within the chromosome 9 marker MCT112 (D9S15), which we have previously shown to be tightly linked to Friedreich's ataxia (FRDA). The system detects 7 alleles ranging in size from 195 to 209 base pairs, and substantially increases informativity at the MCT112 locus. This enhances its use for genetic counselling in affected families. Recalculated combined linkage data between the FRDA locus and MCT112 gives a maximal lod score of 66.91 at a recombination fraction of theta = 0). There is no evidence of linkage disequilibrium.

Alleles↗
PubMed1990

Regional localisation of the Friedreich ataxia locus to human chromosome 9q13----q21.1.

We have previously assigned the Friedreich ataxia locus (FRDA) to chromosome 9; the current maximal lod score between FRDA and MCT112 (D9S15) is greater than 50 at a recombination fraction of theta = 0. The physical assignment of the locus defined by MCT112, and hence FRDA, has not been determined, although linkage analysis of MCT112 with other chromosome 9 markers inferred a location close to the centromere. We have used in situ hybridisation with MCT112, a corresponding cosmid MJ1, and DR47 (D9S5), coupled with mapping studies on hybrid cell panels, to define more precisely the location of the disease locus. The in situ location of all three probes is 9q13----q21.1, distal to the variable heterochromatin region. Physical assignment of FRDA will allow us to identify hybrid cell lines containing the mutated gene.

Chromosome Mapping↗
PubMed1990

Effect of menstrual cycle phase and oral contraceptive use on serum lithium levels after a loading dose of lithium in normal women.

Serum lithium levels were analyzed in six healthy, normal women during the midfollicular, midluteal, and premenstrual phases of their menstrual cycles after they had received 300 mg of lithium carbonate orally. An identical protocol was followed for seven women with artificial cycles induced by oral contraceptive steroids. Analysis of variance for repeated measures over time showed no significant differences between groups or between cycle phases. Therefore, hormonal effects of ovarian or contraceptive steroids per se do not appear to alter serum lithium concentrations. Other factors may account for changing lithium requirements during the menstrual cycle in some patients with affective illness.

Contraceptives, Oral↗
PubMed1990

Autosomal dominant ataxia: genetic evidence for locus heterogeneity from a Cuban founder-effect population.

The locus for autosomal dominant ataxia with a diagnosis of olivo-ponto-cerebellar atrophy at autopsy has been previously assigned to chromosome 6p. However, evidence for two alternative locations has been reported. We have recently described a large potential founder-effect population of such patients in the Holguin province of Cuba. With an estimated 1,000 patients available for analysis, this extensive cluster of families provides a unique opportunity for the definitive localization of the genetic mutation. Linkage analysis between the disease locus in this population and markers within and flanking the HLA region on chromosome 6 were undertaken in 12 families comprising over 100 affected individuals. Despite similarity in the clinical phenotype between those families where the disease locus has been reported to be linked to the HLA locus and the Cuban patients, no evidence of linkage to this region could be demonstrated in the latter. The disease locus was excluded from a 96-cM genetic interval of the short arm of chromosome 6, encompassing the F13A1-HLA-GLO1-MUT/D6S4 loci. These data strongly support the existence of genetic heterogeneity for the disease.

Chromosomes, Human, Pair 6↗
PubMed1989

"Acadian" and "classical" forms of Friedreich ataxia are most probably caused by mutations at the same locus.

"Acadian ataxia" is a form of Friedreich ataxia found in individuals of Acadian ancestry. It was described by Barbeau (in Sobue I (ed): Spinocerebellar Degeneration; Tokyo: Univ. Tokyo Press, pp 121-142, 1980) as having a slower course of degeneration and less severe secondary symptoms than "classical" Friedreich ataxia. He suggested that these 2 forms of the disease may be distinct. The mutation causing "classical" Friedreich ataxia has recently been mapped to chromosome 9 through genetic linkage studies, and here we show that the locus causing Friedreich ataxia in Acadian families from southwestern Louisiana is tightly linked to the same DNA marker, D9S15. Thus, these 2 disorders, which may be differentiated clinically, are most probably due to mutation(s) at the same locus on chromosome 9.

Chromosome Mapping↗
PubMed1989

Prenatal diagnosis of Friedreich ataxia.

Friedreich ataxia is a progressive neurodegenerative disorder affecting the peripheral and central nervous systems. One in 50,000 of the population are affected by this recessively inherited disorder, with onset usually before puberty. The recent localization of the disease locus to chromosome 9 has made it possible to provide genetic counselling to families with at least one affected child. Tight linkage of the disease mutation to an anonymous DNA marker MCT112 (D9S15) has been shown with a pairwise lod score of 36.1 at 0 = 0. We report here the first prenatal diagnosis in Friedreich ataxia. Using MCT112 and the confidence interval approach, we have calculated risks for a fully informative family with one affected sib.

Amniocentesis↗
PubMed1989

Adult rat lumbrical muscle fibres are not polyneuronally innervated.

The existence of polyneuronal innervation in adult rat skeletal muscle reported by Taxt (1983) has been reinvestigated. The extent of polyneuronal innervation was measured by intracellular recording in cut muscle fibre preparations. Only fibres in which spontaneously occurring miniature end-plate potentials were visible were tested for the presence of multiple inputs. Only one in sixty-nine fibres penetrated was found to have more than one axonal input. High-threshold, low-amplitude end-plate potentials were sought, but none was found. Thus we were unable to find any evidence for extensive polyneuronal innervation persisting in rats of 40 days of age.

Action Potentials↗
PubMed1989

Contractile characteristics and innervation ratio of rat soleus motor units.

1. Physiological properties of motor units in the soleus muscle were studied in anaesthetized rats using ventral root splitting to isolate single units. 2. Motor unit types were classified by the same criteria used to classify cat hindlimb motor units into types FR (fast-twitch, fatigue-resistant) and type S (slow-twitch, fatigue-resistant). Type FR units were estimated to generate 10% of whole-muscle tension and type S 90%. All FR units showed sag in the unfused tetanus at frequencies with interpulse intervals greater than 175% of twitch time to peak, but not at 125% (Burke, Levine, Tsairis & Zajac, 1973). 3. The muscle fibres belonging to twelve single motor units were depleted of glycogen by prolonged stimulation, permitting analysis of their histochemical profiles. Type FR units were found to consist of type IIA muscle fibres and type S units of type I muscle fibres. 4. Direct determinations were made of fibre area, innervation ratio (number of muscle fibres supplied by one motoneurone) and hence specific tension (tetanic tension generated per unit cross-sectional area) of individually identified motor units. Motoneurons were found to innervate between 84 and 178 muscle fibres (mean 110) in type S units and between 126 and 161 fibres in type FR units (mean 142). Fibre areas were larger for type FR units and there was a significant difference in specific tension of the two unit types (type S lower). 5. Indirect estimates of innervation ratio and specific tension were obtained from counts of muscle fibre types, and relative frequencies of motor unit types in the soleus unit pool. Observations agreed well with results of direct measurements. 6. The evidence provided suggests that differences in tension generated by type FR and S units in rat soleus muscle are primarily due to differences in innervation ratio and fibre area, with a small contribution from differences in specific tension.

Animals↗
PubMed1989

Genetic homogeneity at the Friedreich ataxia locus on chromosome 9.

Classical Friedreich ataxia, a progressive, neurodegenerative disorder involving both the central and peripheral nervous systems, has been subclassified according to the observed clinical heterogeneity. The variations in the age at onset and in the spectrum and severity of symptoms have previously been interpreted as evidence of genetic heterogeneity. We have studied the linkage between the disorder and closely linked DNA markers in families of distinct ethnic origins, including the "typical" French-Canadians and the Acadian population of Louisiana. The disease in these two populations, both of continental French origin, has a very similar initial clinical picture. However, a marked difference in the rate of progression of the obligatory symptoms after 10 years of apparent disease is observed. A total of 553 individuals from 80 families with 202 affected members have been typed with the chromosome 9 marker MCT112, which we have previously shown to be closely linked to the disease locus. Evidence for linkage was observed in all families with the generation of a combined total lod score of 25.09 at a recombination fraction of theta = .00, providing strong evidence for genetic homogeneity at this locus for the classical form of this disease.

Canada↗
PubMed1988

Mapping of mutation causing Friedreich's ataxia to human chromosome 9.

Friedreich's ataxia is an autosomal recessive disease with progressive degeneration of the central and peripheral nervous system. The biochemical abnormality underlying the disorder has not been identified. Prompted by the success in localizing the mutations causing Duchenne muscular dystrophy, Huntington's disease and cystic fibrosis, we have undertaken molecular genetic linkage studies to determine the chromosomal site of the Friedreich's ataxia mutation as an initial step towards the isolation and characterization of the defective gene. We report the assignment of the gene mutation for this disorder to chromosome 9p22-CEN by genetic linkage to an anonymous DNA marker MCT112 and the interferon-beta gene probe. In contrast to the clinical variation seen for the disorder, no evidence of genetic heterogeneity is observed.

Chromosome Mapping↗
PubMed1987

Exclusion of the Friedreich ataxia gene from chromosome 19.

Friedreich ataxia, a progressive neurodegenerative disorder, is an autosomal recessive disease with a carrier frequency of 1/110 in the United Kingdom. The pathophysiological basis for the disease is not known and the chromosomal location of the mutation remains unidentified. As part of an attempt to map the mutation using linked DNA markers, we demonstrate that the Friedreich ataxia gene is excluded from human chromosome 19. This study also demonstrates that the insulin receptor, which maps to chromosome 19 and may be associated with abnormal biochemical features in some patients, is not the basic defect.

Alleles↗
PubMed1982

Studies of cellular hypersensitivity to ionising radiation in Friedreich's ataxia.

Skin fibroblasts from seven patients with Friedreich's ataxia showed a small but significant increase in sensitivity to ionising radiation, as measured by post-irradiation clonal growth, when compared with cells from ten age-matched control subjects and from eight patients with motor neuron disease. Fibroblasts from three patients with Friedreich's ataxia also showed impairment of their ability to repair potentially lethal damage after ionising radiation. These findings are consistent with the view that defective DNA reparative mechanisms may be involved in the pathogenesis of Friedreich's ataxia.

Adolescent↗