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S Chamberlain

Publications and source records attributed to S Chamberlain.

At least 37 records · Page 2Linked to original sources
PubMed1997

Polycystin expression is temporally and spatially regulated during renal development.

Mutations in PKD1 cause autosomal dominant polycystic kidney disease (ADPKD), a common genetic disease in which cysts form from kidney tubules. The predicted product of this gene is a novel protein with cell-adhesive and membrane-spanning domains. To test the hypothesis that polycystin, the product of the PKD1 gene, is a cell adhesion molecule, we raised antibodies against peptides derived from the unduplicated, membrane-spanning portion of the predicted amino acid sequence. These antibodies recognized membrane-associated polypeptides of 485 and 245 kDa in human fetal kidney homogenates. Expression was greater in fetal than adult kidney by both Western blot analysis and immunofluorescence. In fetal kidney, polycystin was localized to the plasma membranes of ureteric bud and comma and S-shaped bodies. However, in more mature tubules in fetal kidney, in adult kidney, and in polycystic kidney, the majority of polycystin staining was intracellular. The temporal and spatial regulation of polycystin expression during renal development lead us to speculate that polycystin may play a role in nephrogenesis.

Adult↗
PubMed1997

Human androgen receptor expression in prostate cancer following androgen ablation.

OBJECTIVE: Metastatic prostate cancer kills patients because their tumor cells fail to respond to combined androgen blockade (CAB) or respond and then relapse. To understand the molecular basis of androgen-insensitive growth of prostate tumor cells, we evaluated changes in human androgen receptor gene (hAR) mRNA levels in patients with prostate cancer treated with CAB. METHODS: The study was carried out using quantitative reverse-transcriptase polymerase chain reaction analysis. The level of hAR mRNA were compared to serum prostate-specific antigen and the mutant status of p53 in the tumor. RESULTS: hAR was expressed in 44 of 46 tumors from untreated patients, as opposed to 30 of 45 from those who had received CAB (p = 0.001). These 30 were from 8 of 9 stage D patients and from 22 of 36 patients on downsizing CAB therapy prior to radical prostatectomy. Expression was most often seen in high stages (56% of stage B vs. 89% of stage D) and high grades (52% of Gleason 3-7 vs. 92% of Gleason 8-10, p = 0.015). No tumor with a missense p53 mutation had hAR expression following CAB. Twenty-two patients following CAB were found to have undetectable serum prostate-specific antigen levels, while their tumor expressed hAR. CONCLUSIONS: hAR expression after CAB is seen preferentially in high-grade, high-stage tumors, the type of prostate carcinomas that fail to have a durable remission. Undetectable serum prostate-specific antigen from tumors that remain hAR positive may predict relapse after hormonal ablative therapy.

Androgen Antagonists↗
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↗