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Biomedical subjects

G Turner

Publications and source records attributed to G Turner.

At least 37 records · Page 2Linked to original sources
PubMed2001

An assessment of screening strategies for fragile X syndrome in the UK.

BACKGROUND: Fragile X syndrome is an inherited form of learning disability that was defined in the late 1970s by cytogenetic detection of an associated fragile site on the X chromosome (Xq27.3). Cytogenetic estimates of the prevalence of fragile X syndrome were as high as 1 in 1039 males but have since been revised downwards. Fragile X syndrome is associated with few medical problems and the subtle physical features make clinical diagnosis difficult. The unusual pattern of inheritance, delineated in the 1980s, was explained once the fragile X syndrome gene (FMR1) had been identified in 1991. This gene contains a highly variable repeat of the nucleotide triplet, cytosine-guanine-guanine (CGG). Fragile X syndrome is caused by a large expansion of this CGG repeat (full mutation) that leads to silencing of the FMR1 gene so no gene product (FMRP) is made. This is the ultimate cause of the learning disability that, in males, is sufficient to preclude independent living. Family studies show that all individuals with a full mutation inherit it from a female (usually unaffected) who carries either a full mutation or a premutation, a smaller repeat expansion (approximately 55-200 repeats) that is unstable on female transmission. The chance of a premutation expanding to a full mutation is positively associated with the size of the repeat (approximately 95% by 90 repeats) but only for female transmissions. When a man transmits a premutation, it remains a premutation; his children are, therefore, unaffected by overt learning difficulties. The potential for population screening or systematic case-finding and extended family testing exists because every unaffected mother of an affected child has a detectable CGG repeat expansion. Reliable prenatal diagnosis is possible in males. OBJECTIVES: To assess the feasibility and acceptability of population screening by addressing the following questions in the context of existing services for families with fragile X syndrome. (1) Is there a suitable test for all fragile X genotypes? (2) What are the UK population distribution of FMR1 repeat sizes, and the prevalence of full and premutations in both sexes? (3) What reliable information, in terms of the chance of an affected child, is available to women with premutations between 55 and 200 repeats? (4) What is the effect of a premutation on the person who carries it? (5) What information is available to women with intermediate alleles of 41 to 54-60 repeats? (6) How many affected people are diagnosed? (7) Given the practice of offering extended family testing (cascade testing), what is the population prevalence of 'as-yet-undiagnosed' female carriers of a full or premutation? What proportion of women at risk can be reached by cascade testing? (8) What are the costs of fragile X syndrome to an affected person and their family and to the NHS and society? (9) What is the attitude of families to the benefits and costs of a diagnosis of fragile X syndrome, and to the prospect of population screening? (10) What data are available from existing population screening programmes? (11) What alternatives to population screening exist and are these feasible? METHODS: A key aspect of the review process was to assemble a team with extensive first-hand experience of all aspects of fragile X syndrome, including affected families and the services they use, and a wide knowledge of the relevant literature. They had followed the critical discussions at all the biennial international workshops on fragile X syndrome, including a special session at the 7th International Workshop in 1995 at which an earlier (and substantially different) draft of this report was discussed. The biomedical literature review of 2429 papers was based on MEDLINE searches, extending to PsycINFO and BIDS for the psychological aspects of [fragile X syndrome] screening. Questionnaire-based information was obtained from the UK Fragile X Society and data were collected directly from all the regional clinical genetics centres in 1995 and 1998. RESULTS: Unlike cytogenetic approaches, DNA analysis can reliably determine the FMR1 CGG repeat number and detect full mutations; however, a combination of polymerase chain reaction and Southern blotting tests is required, which limits high throughput. There are UK population-based data on FMR1 repeat sizes of up to 60 repeats but insufficient to provide a reliable estimate of the prevalence of premutations (approximately 60-200 repeats). The few data and estimates in the literature of women carriers of the premutation range from 1 in 246 to 1 in 550. Two UK DNA-based estimates of the prevalence of males with the full mutation are 1 in 4090 (Coventry) and 1 in 5530 (Wessex). There are reasonable family-based data for the risk of expansion to a full mutation for the larger premutations but in the 50-69 repeat range the estimates are less secure. (ABSTRACT TRUNCATED)

Cost of Illness↗
PubMed2001

A new class of glutaminase from Aspergillus oryzae.

The koji mold Aspergillus oryzae is able to produce glutaminase which converts glutamine to glutamic acid, one of the most important flavor components in soy sauce. We present here the isolation and the complete nucleotide sequence of the glutaminase- encoding gene from A. oryzae U212, an industrial strain used in Thailand. N-terminal and internal amino acid sequences were determined from purified glutaminase. A 700-bp fragment was amplified by PCR using oligonucleotide primers designed from partial amino acid sequences. This PCR fragment was used as a homologous probe for screening an A. oryzae genomic DNA library. RT-PCR showed that the gene contained seven short introns. Sequence analysis revealed an open reading frame that encodes a protein of 690 amino-acid residues with a predicted molecular mass of 76 kDa. The N-terminal and internal amino acid sequences of the deduced protein exactly matched the ones determined from the purified protein. Comparison of the amino acid sequence with glutaminase sequences from other origins showed that A. oryzae glutaminase shares little homology with those of bacteria, eukaryote and mammals. The A. oryzae glutaminase gene was expressed in A. nidulans to confirm the presence of a functional glutaminase gene in the cloned DNA. To our knowledge, this is the first reported glutaminase gene cloned from filamentous fungi.

Amino Acid Sequence↗
PubMed2001

A human glucocorticoid receptor gene variant that increases the stability of the glucocorticoid receptor beta-isoform mRNA is associated with rheumatoid arthritis.

OBJECTIVE: To study the occurrence and function of polymorphism in the human glucocorticoid receptor (hGR) gene in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). METHODS: We used single stranded conformation polymorphism (SSCP) and direct sequencing to study the hGR gene in 30 patients with RA, 40 with SLE, and 24 controls. A newly identified polymorphism was transfected in COS-1 cells and the stability of the mRNA containing the polymorphism was tested using real-time PCR. RESULTS: A polymorphism in the hGR gene in exon9beta, in an "ATTTA" motif, was found to be significantly associated with RA. Introduction of this polymorphism in the hGRb mRNA was found to significantly increase stability in vitro compared to the wild-type sequence. CONCLUSION: Our findings show an association between RA and a previously unreported polymorphism in the hGR gene. This polymorphism increased stability of hGRbeta mRNA, which could contribute to an altered glucocorticoid sensitivity since the hGRbeta is thought to function as an inhibitor of hGRalpha activity.

Animals↗
PubMed2000

Extinct (129)I in halite from a primitive meteorite: evidence for evaporite formation in the early solar system

Halite crystals from the Zag H3-6 chondrite contain essentially pure (monoisotopic) xenon-129 ((129)Xe) produced in the early history of the solar system by the decay of short-lived iodine-129 ((129)I) (half-life = 15.7 million years). Correlated release of (129)Xe and (128)Xe, produced artificially from (127)I by neutron irradiation, corresponds to an initial ((129)I/(127)I) ratio of (1.35 +/- 0.05) x 10(-4), close to the most primitive early solar system value. If the (129)Xe was produced by in situ decay, then the halite formed from an aqueous fluid within 2 million years of the oldest known solar system minerals.

Journal Article↗
PubMed2000

Genes on the X chromosome are important in undiagnosed mental retardation.

The clinical genetic diagnosis was reviewed in 429 subjects with intellectual disability in the Australian Child and Adolescent Development (ACAD) study of behavioural problems. With minor differences, the overall "general distribution by causation" was similar to that to that found by the Consensus Conference of the American College of Medical Genetics in 1995. There was a significant male excess in the whole series which was shown to reside in those with "autism," those with undiagnosed nonsyndromic mental retardation (NSMR) and those with X-linked monogenic disorders. It is argued that a substantial proportion of undiagnosed NSMR is caused by genes on the X chromosome. Some of the practical problems of assigning individuals to diagnostic groups are discussed.

Adolescent↗
PubMed2000

The crystal structure and active site location of isocitrate lyase from the fungus Aspergillus nidulans.

BACKGROUND: Isocitrate lyase catalyses the first committed step of the carbon-conserving glyoxylate bypass, the Mg(2+)-dependent reversible cleavage of isocitrate into succinate and glyoxylate. This metabolic pathway is an inviting target for the control of a number of diseases, because the enzymes involved in this cycle have been identified in many pathogens including Mycobacterium leprae and Leishmania. RESULTS: As part of a programme of rational drug design the structure of the tetrameric Aspergillus nidulans isocitrate lyase and its complex with glyoxylate and a divalent cation have been solved to 2.8 A resolution using X-ray diffraction. Each subunit comprises two domains, one of which adopts a folding pattern highly reminiscent of the triose phosphate isomerase (TIM) barrel. A 'knot' between subunits observed in the three-dimensional structure, involving residues towards the C terminus, implies that tetramer assembly involves considerable flexibility in this part of the protein. CONCLUSIONS: Difference Fourier analysis together with the pattern of sequence conservation has led to the identification of both the glyoxylate and metal binding sites and implicates the C-terminal end of the TIM barrel as the active site, which is consistent with studies of other enzymes with this fold. Two disordered regions of the polypeptide chain lie close to the active site, one of which includes a critical cysteine residue suggesting that conformational rearrangements are essential for catalysis. Structural similarities between isocitrate lyase and both PEP mutase and enzymes belonging to the enolase superfamily suggest possible relationships in aspects of the mechanism.

Amino Acid Sequence↗
PubMed2000

Thioesterase domain of delta-(l-alpha-Aminoadipyl)-l-cysteinyl-d-valine synthetase: alteration of stereospecificity by site-directed mutagenesis.

The carboxy-terminal thioesterase domain of delta-(l-alpha-aminoadipyl)-l-cysteinyl-d-valine synthetase catalyzes the hydrolytic release of the tripeptide product (LLD-ACV). By site-directed mutagenesis an S3599A change was introduced into the highly conserved GXSXG motif, resulting in a more than 95 % decrease of penicillin production. Purification of the modified multienzyme showed surprisingly only a 50 % reduction of the peptide formation rate, with the stereoisomer delta-(l-alpha-aminoadipyl)-l-cysteinyl-l-valine (LLL-ACV) as the dominating product. Thioesterases of ACV synthetases differ from other thioesterases integrated in non-ribosomal peptide synthetases in their direct association with an epimerase domain, and their respective GXSXG-seryl residue is apparently not essential in acyl transfer leading to peptide release. Instead, this motif may be involved in the control of tripeptide epimerization by selection of the isomer to be released, and the construct supports the presence of LLL-ACV as an intermediate in penicillin biosynthesis.

Acylation↗
PubMed2000

Linkage and LOH studies in 19 cylindromatosis families show no evidence of genetic heterogeneity and refine the CYLD locus on chromosome 16q12-q13.

Familial cylindromatosis is an autosomal dominant predisposition to multiple neoplasms of the skin appendages. The susceptibility gene has previously been mapped to chromosome 16q12-q13 and has features of a recessive oncogene/tumour suppressor gene. We have now evaluated 19 families with this disease by a combination of genetic linkage analysis and loss of heterozygosity in cylindromas from affected individuals. All 15 informative families show linkage to this locus, providing no evidence for genetic heterogeneity. Recombinant mapping has placed the gene in an interval of approximately 1 Mb. There is no evidence, between families, of haplotype sharing that might be indicative of common founder mutations.

Carcinoma, Adenoid Cystic↗
PubMed2000

Identification of the familial cylindromatosis tumour-suppressor gene.

Familial cylindromatosis is an autosomal dominant genetic predisposition to multiple tumours of the skin appendages. The susceptibility gene (CYLD) has previously been localized to chromosome 16q and has the genetic attributes of a tumour-suppressor gene (recessive oncogene). Here we have identified CYLD by detecting germline mutations in 21 cylindromatosis families and somatic mutations in 1 sporadic and 5 familial cylindromas. All mutations predict truncation or absence of the encoded protein. CYLD encodes three cytoskeletal-associated-protein-glycine-conserved (CAP-GLY) domains, which are found in proteins that coordinate the attachment of organelles to microtubules. CYLD also has sequence homology to the catalytic domain of ubiquitin carboxy-terminal hydrolases (UCH).

Amino Acid Sequence↗
PubMed2000

Segmental timing in amyotrophic lateral sclerosis.

This study describes segmental timing patterns for a passage read by speakers with ALS and a group of age- and gender-matched neurologically healthy speakers. Segment durations for ALS speakers' habitual rates (ALS condition) were compared to segment durations for healthy speakers' habitual and slow reading rates (Control Habitual and Control Slow conditions). Temporal differences for pairs of sound classes (i.e., long-short vowels, voiceless-voiced fricatives, voiceless-voiced stop gaps, high-low vowels) and prepausal lengthening of vowels also were studied. The results of the ALS-Control Habitual comparison suggested that the slowed articulatory rate of ALS influences segmental timing for most phonetic events. The finding that local segmental cues for disordered speakers were broadly consistent with their overall (slow) articulatory rate suggests that duration likely does not contribute in a significant way to intelligibility deficits in ALS. A qualitative analysis further indicated that the slowed rate of ALS is not uniformly distributed across phonetic events, but influences segment durations of particular sound categories in ways consistent with the disease process. The analysis comparing segment durations for the ALS and Control Slow conditions suggested that the overall pattern of segmental timing for speakers with ALS was broadly similar to the pattern for voluntarily slowed speech of healthy talkers. Finally, temporal differences for sound classes (i.e., voiceless-voiced fricatives, long-short vowels) and prepausal lengthening for speakers with ALS typically were similar to healthy speakers' habitual and slow speech. There were substantial variability within speaker groups and reversals of expected effects, however. The implication is that temporal differences for sound classes, such as short and long vowels, are not a particularly reliable perceptual cue for listeners.

Adult↗
PubMed2000

Presymptomatic screening for schizophrenia: a geneticist's perspective.

OBJECTIVE: To examine whether the experience gained in offering various genetic tests may be of help in the planning for screening in schools for a personality profile that may identify those destined to develop schizophrenia. METHOD: To examine the outcomes in offering genetic testing: (i) to individuals at risk of developing Huntington's disease; (ii) to school pupils for carrier status for cystic fibrosis; and (iii) to the intellectually handicapped in schools to identify those with the fragile X syndrome. RESULTS: All programs however carefully planned, encounter the unexpected and unforeseen. CONCLUSIONS: It is essential to know the specificity and sensitivity of your screening test; to ensure that all have adequate knowledge before consenting to the testing; to ensure the confidentiality of the test results to the individual being tested and their families; and to ensure that funding is adequate and ongoing to provide continuing support and therapy to the families identified when research converts to service.

Attitude of Health Personnel↗
PubMed2000

A third novel locus for primary autosomal recessive microcephaly maps to chromosome 9q34.

Primary autosomal recessive microcephaly is a clinical diagnosis of exclusion in an individual with a head circumference >/=4 SDs below the expected age-and-sex mean. There is associated moderate mental retardation, and neuroimaging shows a small but structurally normal cerebral cortex. The inheritance pattern in the majority of cases is considered to be autosomal recessive. Although genetic heterogeneity for this clinical phenotype had been expected, this has only recently been demonstrated, with the mapping of two loci for autosomal recessive primary microcephaly: MCPH1 at 8p and MCPH2 at 19q. We have studied a large multiaffected consanguineous pedigree, using a whole-genome search, and have identified a third locus, MCPH3 at 9q34. The minimal critical region is approximately 12 cM, being defined by the markers cen-D9S1872-D9S159-tel, with a maximum two-point LOD score of 3.76 (recombination fraction 0) observed for the marker D9S290.

Chromosome Mapping↗