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S Shackleton

Publications and source records attributed to S Shackleton.

14 recordsLinked to original sources
PubMed2000

LMNA, encoding lamin A/C, is mutated in partial lipodystrophy.

The lipodystrophies are a group of disorders characterized by the absence or reduction of subcutaneous adipose tissue. Partial lipodystrophy (PLD; MIM 151660) is an inherited condition in which a regional (trunk and limbs) loss of fat occurs during the peri-pubertal phase. Additionally, variable degrees of resistance to insulin action, together with a hyperlipidaemic state, may occur and simulate the metabolic features commonly associated with predisposition to atherosclerotic disease. The PLD locus has been mapped to chromosome 1q with no evidence of genetic heterogeneity. We, and others, have refined the location to a 5.3-cM interval between markers D1S305 and D1S1600 (refs 5, 6). Through a positional cloning approach we have identified five different missense mutations in LMNA among ten kindreds and three individuals with PLD. The protein product of LMNA is lamin A/C, which is a component of the nuclear envelope. Heterozygous mutations in LMNA have recently been identified in kindreds with the variant form of muscular dystrophy (MD) known as autosomal dominant Emery-Dreifuss MD (EDMD-AD; ref. 7) and dilated cardiomyopathy and conduction-system disease (CMD1A). As LMNA is ubiquitously expressed, the finding of site-specific amino acid substitutions in PLD, EDMD-AD and CMD1A reveals distinct functional domains of the lamin A/C protein required for the maintenance and integrity of different cell types.

Amino Acid Sequence↗
PubMed2000

Lamin A/C gene: sex-determined expression of mutations in Dunnigan-type familial partial lipodystrophy and absence of coding mutations in congenital and acquired generalized lipoatrophy.

Missense mutations of the lamin A/C gene, LMNA, have been recently identified in Dunnigan-type familial partial lipodystrophy (FPLD), which belongs to a heterogeneous group of rare disorders affecting adipose tissue distribution and metabolism. In this study, we sequenced the LMNA coding region from patients presenting with FPLD or other forms of lipodystrophy. We identified two heterozygous mutations in exon 8, R482W and R482Q, in FPLD patients (six families and one individual) with various clinical presentations. In addition, we found a novel heterozygous mutation (R584H) in exon 11, encoding specifically the lamin A isoform, in a patient with typical FPLD. Clinical and biochemical investigations in FPLD patients revealed that the expression and the severity of the phenotype were markedly dependent on sex, with female patients being more markedly affected. In subjects with generalized lipoatrophy, either congenital (13 case subjects) or acquired (14 case subjects), or Barraquer-Simon syndrome (2 case subjects), the entire LMNA coding sequence was normal. Although FPLD mutations are predominantly localized in exon 8 of LMNA, the finding of a novel mutation at codon 584, together with the R582H heterozygous substitution recently described, confirms that the C-terminal region specific to the lamin A isoform is a second susceptibility region for mutations in FPLD.

Adipose Tissue↗
PubMed1994

The stop mutation R553X in the CFTR gene results in exon skipping.

Stop or nonsense mutations are known to disrupt gene function in a number of different ways. We have studied the effects of the stop mutation R553X in exon 11 of the CFTR gene by analyzing mRNA extracted from nasal epithelial cells harvested from patients with cystic fibrosis. Four patients who were compound heterozygotes for the R553X mutation were studied. Ten non-CF control subjects were also studied. In all four patients, full-length CFTR mRNA was identified, but only a very small proportion of this was derived from the R553X allele. A smaller transcript, lacking exon 11, was also seen in the R553X patients but not in the controls. Most of this transcript was derived from the R553X allele. These results suggest that the R553X mutation results in skipping of the exon in which it is located.

Alleles↗
PubMed1994

Identification of rare and novel mutations in the CFTR genes of CF patients in southern England.

Cystic fibrosis patients referred to two genetics centres in southern England and not found to carry common CF-associated mutations in one or both of their CFTR genes have been subjected to an extensive mutation search. The whole of the coding region of the CFTR gene, all intron-exon boundaries and 5' and 3' untranslated regions have been examined by a combination of single stranded conformational polymorphism analysis and chemical mismatch detection; 48 chromosomes with rare mutations have been identified, including 7 novel mutations, 182delT in exon 1, G27X in exon 2, Q151X in exon 4, Q220X in exon 6a, Q525X in exon 10, 3041delG in exon 16, and 4271delC in exon 23.

Base Sequence↗
PubMed1994

Analysis of mutations and alternative splicing patterns in the CFTR gene using mRNA derived from nasal epithelial cells.

Ten to fifteen percent of CF chromosomes carry mutations which are not detected by routine screening of the CFTR gene for known mutations. Many techniques have been used to screen the CFTR gene for these remaining mutations. Most of the methods use genomic DNA, and since the CFTR gene contains 27 exons, are necessarily labour intensive. We have screened the entire coding region of CFTR, by chemical cleavage of 7 overlapping segments of amplified cDNA. Using this method we have identified 4 sequence changes which had not been detected by screening genomic DNA, and successfully detected 10 out of 13 known mutations. In addition, we have identified 8 alternatively spliced forms of CFTR mRNA, 4 of which have not been described previously. These include transcripts lacking a) exon 3, b) exons 2 + 3, c) exons 9 + 12, and d) the final 357 bp of exon 15 as a result of use of the cryptic splice donor site CA2863/GTTCGT).

Base Sequence↗
PubMed1993

Abnormal mRNA splicing resulting from three different mutations in the CFTR gene.

Three different putative splicing mutations in the CFTR gene have been studied by analysing mRNA extracted from nasal epithelial cells harvested from patients with cystic fibrosis. Six patients were analysed, all of whom had classical symptoms of cystic fibrosis (CF). Two patients carried the 621 + 1G-->T mutation, 3 patients carried the 1717 - 1G-->A mutation and 1 patient carried the 1898 + 1G-->A mutation. All patients carried the delta F508 mutation on the other chromosome. Ten non-CF control subjects were also studied. The 621 + 1G-->T mutation resulted in activation of an alternative splice site within exon 4 in one patient and activation of this site or skipping of exon 4 in the other patient. The 1717 - 1G-->A mutation resulted in skipping of exon 11 in all 3 patients studied and the 1898 + 1G-->T mutation resulted in skipping of exon 12. These experiments demonstrate that these mutations do result in aberrant splicing of CFTR mRNA as predicted from the changes in genomic sequence.

Base Sequence↗
PubMed1989

Non-occupational factors in occupational morbidity and mortality.

This report forms a background paper for a World Health Organization document on "Assessment of the role of lifestyles in influencing workers' health risks". It identifies occupational and non-occupational factors which contribute to occupational mortality and morbidity. Eight categories of mortality and morbidity are identified as priorities for discussion, based on UK data. These are cardiovascular disease; lung cancer; chronic obstructive pulmonary disease; occupational deafness; dermatitis; vibration white finger; tenosynovitis; and suicide. Non-occupational factors associated with these include age, sex, race, smoking, social class, alcohol consumption, diet, exposures in leisure time, exercise, atopy, heredity, personal hygiene, personality type, stress, past or predisposing illness or injury, weather/climate and air pollution. Smoking is identified as the most widely studied non-occupational factor in occupational disease. Smoking interacts with some occupational exposures to produce more disease than the sum of both agents separately. Smoking and asbestos interact multiplicatively in lung cancer causation. The ability to quantify interactions between occupational and non-occupational factors in disease etiology is important in assessing priorities for preventive action. Despite this, only the interactions of smoking have begun to be defined. The many other non-occupational factors mentioned above have each been studied individually but their interactions with occupational factors have not been assessed. This report describes models of quantifying interactions and recommends that further work is carried out to assess the interactions of non-occupational factors other than smoking in disease causation.

Female↗
PubMed1984

Chromosome aberrations and sister-chromatid exchange frequencies in pathology staff occupationally exposed to formaldehyde.

Past studies have shown that formaldehyde is mutagenic in microbial tests and Drosophila and causes chromosomal aberrations in cultured mammalian cells. Chromosomal analysis of bone marrow cells and spermatocytes from exposed laboratory animals has failed to show any genotoxic effect. Information on individuals occupationally exposed is limited and there is no evidence to date that formaldehyde can induce chromosome damage at occupational levels of exposure. This study examines the chromosome aberration and sister-chromatid exchange frequencies in lymphocytes from a group of 6 pathology workers and 5 unexposed controls. No detectable differences could be found between the groups in either chromosomal aberration induction or sister-chromatid exchange frequencies.

Cells, Cultured↗