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S Chamberlain

Publications and source records attributed to S Chamberlain.

At least 37 records · Page 2Linked to original sources
PubMed1996

The Friedreich's ataxia gene encodes a novel phosphatidylinositol-4- phosphate 5-kinase.

The STM7 gene on chromosome 9 was recently 'excluded' as a candidate for Friedreich's ataxia following the identification of an expanded intronic GAA triplet repeat in the adjacent gene, X25, in patients with the disease. Using RT-PCR, northern and sequence analyses, we now demonstrate that X25 comprises part of the STM7 gene, contributing to at least four splice variants, and report the identification of new coding sequences. Functional analysis of the STM7 recombinant protein corresponding to the reported 2.7-kilobase transcript has demonstrated PtdlnsP 5-kinase activity, supporting the idea that the disease is caused by a defect in the phosphoinositide pathway, possibly affecting vesicular trafficking or synaptic transmission.

Adult↗
PubMed1995

Limitations in the clinical prediction of intrapartum fetal asphyxia.

OBJECTIVE: Our purpose was to demonstrate the predictive value of clinical risk scoring and fetal assessment for intrapartum fetal asphyxia. STUDY DESIGN: Intrapartum fetal asphyxia was defined by an umbilical artery buffer base < 34 mmol/L. The predictive value of 20 antepartum and intrapartum risk factors was examined in 1909 consecutive pregnancies. The predictive value of clinical risk factors with periodic fetal assessment was examined in a second population of 100 consecutive pregnancies with biochemically determined intrapartum fetal asphyxia. RESULTS: The incidence of intrapartum was 2.3%. Two problems were apparent in these studies. A significant proportion of intrapartum fetal asphyxia occurred in pregnancies with no risk factors. The positive predictive value of clinical risk factors was low, 3%, resulting in a large number of false positives requiring clarification. CONCLUSION: Screening and fetal assessment methods must be improved to ensure the early recognition of intrapartum fetal asphyxia that may require intervention during labor to avoid morbidity and mortality.

Delivery, Obstetric↗
PubMed1995

Friedreich's ataxia: a defect in signal transduction?

We have previously assigned the mutation causing Friedreich's ataxia (FRDA) to 9q13 by genetic linkage and fluorescent in situ hybridization analysis, and identified recombination events which position the gene centromeric to D9S5. We report here the extension of a yeast artificial chromosome contig to span the 860 kb interval immediately proximal to this marker, which includes the D9S886 and D9S887/888 loci reported to flank the FRDA locus, and the construction of a high resolution cosmid contig initiated from the D9S888 locus. Exon trapping and cDNA library screening strategies have resulted in the isolation of a candidate gene which traverses the centromeric boundary of the FRDA critical region. The gene spans a genomic interval greater than 220 kb with at least two of the coding exons located proximal to the D9S887/888 loci. Expression is complex, with multiple transcripts detected in a variety of tissues and evidence of alternative splicing and developmental control. The predicted amino acid sequence for the 2.7 kb transcript reported here shows a marked homology to the deduced amino acid sequence of the Saccharomyces cerevisiae MSS4 protein, proposed to function within the phosphoinositide cycle, suggesting a potential role for the human homologue in signal transduction. Whilst no evidence for mutation has been detected in this transcript, the sequence represents only one of the shorter alternatively spliced species identified by Northern analysis and direct sequencing. This gene remains a strong candidate for FRDA.

Alternative Splicing↗
PubMed1995

Pholedrine: a substitute for hydroxyamphetamine as a diagnostic eyedrop test in Horner's syndrome.

Mydriatic responses to eyedrops containing the indirect acting sympathomimetic amines tyramine, hydroxyamphetamine, and pholedrine have been compared in 10 healthy subjects. Pholedrine, the n-methyl derivative of hydroxyamphetamine, at a concentration of 1% had effects similar to those produced by 0.5% hydroxyamphetamine itself. Pretreatment with topical guanethidine attenuated its responses and in 13 patients with unilateral Horner's syndrome it distinguished clearly those five patients who had preganglionic from the eight with postganglionic lesions. It is concluded that 1% pholedrine may be substituted for 0.5% hydroxyamphetamine, which is no longer available, as a diagnostic agent for use in Horner's syndrome.

Adolescent↗
PubMed1995

Physical evidence for the position of the Friedreich's ataxia locus FRDA proximal to D9S5.

Orientation of the Friedreich's ataxia locus (FRDA) with respect to D9S15 and D9S5 has proved critical to the design of subsequent cloning strategies. The rarity of recombination events between FRDA and these markers, originally used to determine assignment to human chromosome region 9q13-->q21.1, has necessitated the instigation of physical mapping studies to determine order and, hence, the precise location of the disease gene. Simultaneous fluorescence in situ hybridisation using cosmid clones located in close proximity to the ends of a 1.2-Mb yeast artificial chromosome clone extending into the FRDA candidate region provides physical evidence for the order of the marker loci to be cen-D9S202-D9S5-D9S15-qter. The possibility that a pericentric inversion, occurring naturally in approximately 1% of the normal population, may affect the order of markers within this region has been eliminated. Considered in association with the interpretation of a recombination event detected in a single affected individual, these data indicate that the FRDA locus is located proximal to D9S5.

Adaptor Proteins, Signal Transducing↗
PubMed1994

Machado Joseph disease is not an allele of the spinocerebellar ataxia 2 locus.

Machado Joseph disease (MJD) is a progressive, spinocerebellar ataxia (SCA) with an autosomal dominant mode of inheritance and almost complete penetrance. Clinically, it is difficult to distinguish it from other autosomal dominantly inherited ataxias, and it has been suggested that MJD may be caused by an allelic variant of SCA. Exclusion of MJD from the SCA1 locus on chromosome 6p has previously been demonstrated. However, following the recent assignment of a second locus for spinocerebellar ataxia (SCA2) to chromosome 12q in a large Cuban kindred of Spanish origin, we have investigated linkage in MJD families using the two markers, D12S58 and PLA2, that flank this disease gene. The MJD locus was definitively excluded from an interval spanning approximately 70 cM, which includes these loci. These studies demonstrate that MJD and SCA2 are genetically distinct despite similarities in disease phenotype and ancestral origins of the patients. Thus, the as yet unmapped MJD locus represents a third SCA locus, providing further evidence for genetic heterogeneity within these disorders.

Alleles↗
PubMed1994

The electrocardiogram is a more sensitive indicator than echocardiography of hypertrophic cardiomyopathy in families with a mutation in the MYH7 gene.

BACKGROUND: Mutations in the cardiac beta myosin heavy chain gene causing hypertrophic cardiomyopathy have been identified, and to assist both diagnosis and prediction of outcome attempts have been made to correlate phenotype and genotype. Two new mutations in codon 403 of the gene in three unrelated families are described and attention drawn to variable or even absent phenotypic expression in different family members. METHODS AND RESULTS: The polymerase chain reaction and heteroduplex analysis on Mutation Detection Enhancement gels were used to search for mutations in the globular head of the beta myosin heavy chain gene in families with hypertrophic cardiomyopathy. Two mutations were found in exon 13 (codon 403) of the gene. In two unrelated Polish families the mutation resulted in the conversion of arginine to tryptophan (CGG: >TGG). A second mutation, found in a British family, converted the same arginine to leucine (CGG: >CTG). These mutations were detected in family members who had electrocardiographic and echocardiographic features typical of hypertrophic cardiomyopathy; however, they were also detected in 7 other adult relatives with an abnormal electrocardiogram but a normal echocardiogram. Two unrelated adult relatives had completely normal clinical findings but carried the gene mutation. CONCLUSIONS: Identification of a specific mutation gives no guide to the clinical phenotype. There is considerable variability in the phenotypic expression of hypertrophic cardiomyopathy. Mutations were detected in adults previously regarded as normal or in whom the diagnosis was questionable. The fact that the clinical significance of the mutation in these people is still unknown emphasises the dilemma facing screening programmes. Isolated, unexplained electrocardiographic abnormalities in first degree relatives in a family with a definitive diagnosis of hypertrophic cardiomyopathy should be regarded as evidence of a carrier state.

Adult↗
PubMed1993

Late-onset Friedreich's ataxia. Molecular genetics, clinical neurophysiology, and magnetic resonance imaging.

OBJECTIVE--To clarify the nosological classification of late-onset Friedreich's ataxia (LOFA), ie, patients who have later onset of Friedreich's ataxia (FRDA), often after 25 years of age. DESIGN--Comparison of clinical examination data, nerve conduction studies, electronystagmographic recording, and magnetic resonance imaging of a family with LOFA with a group of patients with FRDA. Genetic linkage analysis was performed in the family with LOFA. SETTING--Referral center. PATIENTS--Thirteen patients satisfied classic diagnostic criteria of FRDA, and three patients from one family satisfied all diagnostic criteria of FRDA but with disease onset after 25 years. RESULTS--Results of nerve conduction studies, electronystagmographic recording, and magnetic resonance imaging in patients with LOFA closely corresponded to observations made in patients with FRDA. In addition, genetic linkage analysis using markers tightly linked to the FRDA locus on chromosome 9 showed that all affected members of the LOFA family, but not their unaffected siblings, had inherited identical paternal and maternal genotypes. CONCLUSIONS--Data suggest that LOFA may also result from mutation within the FRDA locus.

Adolescent↗
PubMed1993

The clinical spectrum of Friedreich's ataxia in German families showing linkage to the FRDA locus on chromosome 9.

The clinical features of Friedreich's ataxia are described and reevaluated in a group of 14 German patients from 9 independent families. In contrast to previous studies, demonstration of linkage to the Friedreich's ataxia locus (FRDA) on chromosome 9p allowed confirmation of the genetic homogeneity of the disease in the patients under study. Marked variability within families was observed for age of onset of the disease (4-24 years) and for age of becoming wheelchair bound (17-37 years). Electrocardiographic changes were present in all and echocardiographic changes in 50% of the patients. Pathological changes of visual evoked potentials were detected in only 50% of the patients while brainstem auditory evoked potentials and somatosensory evoked potentials were always abnormal.

Adolescent↗
PubMed1993

Differences between contractions in vitro of slow and fast rat skeletal muscle persist after random reinnervation.

1. The medial popliteal nerve was sectioned in adult rats, and reinnervation was permitted after nerve reunion. Reinnervation was observed in soleus (slow twitch) and plantaris (fast twitch) muscles for periods of 4-21 months after the initial operation. 2. In the reinnervated muscles, isometric twitch time to peak (contraction time) and time to half-relaxation were longer in soleus than plantaris in every muscle examined. 3. Some of the muscles were stained for actomyosin ATPase activity. The proportion of type I fibres (presumed slow) was at least twice as high in soleus compared with plantaris muscles. The proportion in the latter was similar to that predicted from random reinnervation. 4. The effects of differing proportions of fast and slow fibres on the twitch contraction and half-relaxation times were modelled, and the experimental twitch data were found to be compatible with the proportions of fibre types in individual muscles. 5. It is speculated that the mechanism accounting for the higher proportion of slow fibres in soleus muscle probably does not involve selective reinnervation. It is suggested that fast motoneurones may be transformed to slow by a trophic chemical released by slow muscle fibres; such a process would be more extensive in predominantly slow twitch soleus than a fast muscle, and the resulting decrease in the proportion of fast motoneurones would account for the less extensive conversion in soleus.

Adenosine Triphosphatases↗
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

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↗
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↗