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Biomedical subjects

M J Dixon

Publications and source records attributed to M J Dixon.

At least 19 recordsLinked to original sources
PubMed2001

Synaesthetic photisms influence visual perception.

When C, a digit-color synaesthete, views black digits, she reports that each digit elicits a highly specific color (a photism), which is experienced as though the color was externally projected onto the digit. We evaluated this claim by assessing whether C's photisms influenced her ability to perceive visually presented digits. C identified and localized target digits presented against backgrounds that were either congruent or incongruent with the color of her photism for the digits. The results showed that C was poorer at identifying and localizing digits on congruent than incongruent trials. Such differences in performance between congruent and incongruent trials were not found with nonsynaesthete control participants. These results suggest that C's colored photisms influence her perception of black digits. We propose a model in which color information influences the perception of digits through reentrant pathways in the visual system.

Adult↗
PubMed2001

Mutation of the gene encoding the enamel-specific protein, enamelin, causes autosomal-dominant amelogenesis imperfecta.

Amelogenesis imperfecta (AI) is a group of inherited defects of dental enamel formation that shows both clinical and genetic heterogeneity. To date, mutations in the gene encoding amelogenin have been shown to underlie a subset of the X-linked recessive forms of AI. Although none of the genes underlying autosomal-dominant or autosomal-recessive AI have been identified, a locus for a local hypoplastic form has been mapped to human chromosome 4q11-q21. In the current investigation, we have analysed a family with an autosomal-dominant, smooth hypoplastic form of AI. Our results have shown that a splicing mutation in the splice donor site of intron 7 of the gene encoding the enamel-specific protein enamelin underlies the phenotype observed in this family. This is the first autosomal-dominant form of AI for which the genetic mutation has been identified. As this type of AI is clinically distinct from that localized previously to chromosome 4q11-q21, these findings highlight the need for a molecular classification of this group of disorders.

Amelogenesis Imperfecta↗
PubMed2001

Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype--phenotype correlation.

Mutations in FOXL2, a forkhead transcription factor gene, have recently been shown to cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) types I and II, a rare genetic disorder. In BPES type I a complex eyelid malformation is associated with premature ovarian failure (POF), whereas in BPES type II the eyelid defect occurs as an isolated entity. In this study, we describe the identification of novel mutations in the FOXL2 gene in BPES types I and II families, in sporadic BPES patients, and in BPES families where the type could not be established. In 67% of the patients studied, we identified a mutation in the FOXL2 gene. In total, 21 mutations (17 of which are novel) and one microdeletion were identified. Thirteen of these FOXL2 mutations are unique. In this study, we demonstrate that there is a genotype--phenotype correlation for either types of BPES by the finding that mutations predicted to result in a truncated protein either lacking or containing the forkhead domain lead to BPES type I. In contrast, duplications within or downstream of the forkhead domain, and a frameshift downstream of them, all predicted to result in an extended protein, cause BPES type II. In addition, in 30 unrelated patients with isolated POF no causal mutations were identified in FOXL2. Our study provides further evidence that FOXL2 haploinsufficiency may cause BPES types I and II by the effect of a null allele and a hypomorphic allele, respectively. Furthermore, we propose that in a fraction of the BPES patients the genetic defect does not reside within the coding region of the FOXL2 gene and may be caused by a position effect.

Alleles↗
PubMed2001

Mutations of the mouse Twist and sy (fibrillin 2) genes induced by chemical mutagenesis of ES cells.

A prior phenotype-based screen of mice derived from ethylmethanesulfonate-mutagenized embryonic stem cells yielded two mouse limb defect mutants. Animals heterozygous for the polydactyly ems (Pde) mutation display preaxial polydactyly of the hindlimbs, and homozygous syndactyly ems (sne) animals are characterized by a fusion of the middle digits of their hindlimbs and sometimes forelimbs. We now report that Pde is a new allele of the basic helix-loop-helix protein gene Twist. Sequencing the full-length cDNA and several hundred basepairs of genomic DNA upstream of the coding region failed to reveal a mutation, suggesting that the lesion may be in a regulatory element of the gene. sne is a new fused phalanges (fp) allele of the shaker-with-syndactylism deletion complex (sy), and we show that the genomic lesion is a small deletion removing an entire exon, coincident with the insertion of the 3' end of a LINE element belonging to the TF subfamily.

Alleles↗
PubMed2001

Mutation of the gene encoding fibrillin-2 results in syndactyly in mice.

Fibrillins are large, cysteine-rich glycoproteins that form microfibrils and play a central role in elastic fibrillogenesis. Fibrillin-1 and fibrillin-2, encoded by FBN1 on chromosome 15q21.1 and FBN2 on chromosome 5q23-q31, are highly similar proteins. The finding of mutations in FBN1 and FBN2 in the autosomal dominant microfibrillopathies Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA), respectively, has highlighted their essential role in the development and homeostasis of elastic fibres. MFS is characterized by cardiovascular, skeletal and ocular abnormalities, and CCA by long, thin, flexed digits, crumpled ears and mild joint contractures. Although mutations arise throughout FBN1, those clustering within exons 24-32 are associated with the most severe form of MFS, so-called neonatal MFS. All the mutations described in CCA occur in the "neonatal region" of FBN2. Both MFS and CCA are thought to arise via a dominant negative mechanism. The analysis of mouse mutations has demonstrated that fibrillin-1 microfibrils are mainly engaged in tissue homeostasis rather than elastic matrix assembly. In the current investigation, we have analysed the classical mouse mutant shaker-with-syndactylism using a positional candidate approach and demonstrated that loss-of-function mutations outside the "neonatal region" of Fbn2 cause syndactyly in mice. These results suggest that phenotypes distinct from CCA may result in man as a consequence of mutations outside the "neonatal region" of FBN2.

Amino Acid Sequence↗
PubMed2001

Cis-elements governing trinucleotide repeat instability in Saccharomyces cerevisiae.

Trinucleotide repeat (TNR) instability in humans is governed by unique cis-elements. One element is a threshold, or minimal repeat length, conferring frequent mutations. Since thresholds have not been directly demonstrated in model systems, their molecular nature remains uncertain. Another element is sequence specificity. Unstable TNR sequences are almost always CNG, whose hairpin-forming ability is thought to promote instability by inhibiting DNA repair. To understand these cis-elements further, TNR expansions and contractions were monitored by yeast genetic assays. A threshold of approximately 15--17 repeats was observed for CTG expansions and contractions, indicating that thresholds function in organisms besides humans. Mutants lacking the flap endonuclease Rad27p showed little change in the expansion threshold, suggesting that this element is not altered by the presence or absence of flap processing. CNG or GNC sequences yielded frequent mutations, whereas A-T rich sequences were substantially more stable. This sequence analysis further supports a hairpin-mediated mechanism of TNR instability. Expansions and contractions occurred at comparable rates for CTG tract lengths between 15 and 25 repeats, indicating that expansions can comprise a significant fraction of mutations in yeast. These results indicate that several unique cis-elements of human TNR instability are functional in yeast.

Endodeoxyribonucleases↗
PubMed2000

Increased levels of apoptosis in the prefusion neural folds underlie the craniofacial disorder, Treacher Collins syndrome.

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of human craniofacial development that results from loss-of-function mutations in the gene TCOF1. Although this gene has been demonstrated to encode the nucleolar phosphoprotein treacle, the developmental mechanism underlying TCS remains elusive, particularly as expression studies have shown that the murine orthologue, Tcof1, is widely expressed. To investigate the molecular pathogenesis of TCS, we replaced exon 1 of Tcof1 with a neomycin-resistance cassette via homologous recombination in embryonic stem cells. Tcof1 heterozygous mice die perinatally as a result of severe craniofacial anomalies that include agenesis of the nasal passages, abnormal development of the maxilla, exencephaly and anophthalmia. These defects arise due to a massive increase in the levels of apoptosis in the prefusion neural folds, which are the site of the highest levels of Tcof1 expression. Our results demonstrate that TCS arises from haploinsufficiency of a protein that plays a crucial role in craniofacial development and indicate that correct dosage of treacle is essential for survival of cephalic neural crest cells.

Animals↗
PubMed2000

Molecular cytogenetic evaluation in a patient with a translocation (3;21) associated with blepharophimosis, ptosis, epicanthus inversus syndrome (BPES).

Blepharophimosis, ptosis, epicanthus inversus syndrome type I (BPES; OMIM 110100) is an autosomal dominant disorder affecting craniofacial development and ovarian function. We have identified a patient with BPES who carried a de novo reciprocal translocation [46, XX,t(3;21)(q23;q22.1)]. Fluorescence in situ hybridization analysis at band 3q23 using probes derived from BAC 175G20 (Research Genetics), PACs 108L15 and 169C10 (RPCI1), and cosmids AC174D4, AC68D3, AC44F5, and AC125C5 (Lawrence Livermore National Laboratory) was performed. The patient's breakpoint was found to lie within the overlapping region of the BAC and PACs but centromeric to all the cosmids. However, a 10.5-kb BamHI-digested fragment, common to the BAC and PAC clones, was shown to cross the breakpoint. The results have placed our patient's breakpoint proximal to that of the previously reported patient [46,XY,t(3;4)(q23;p15.2)] and within a 10.5-kb interval. This is the second patient in which a breakpoint was refined by molecular cytogenetics. Our findings emphasize the significance of this region for BPES.

Adult↗
PubMed2000

Task demands and limb apraxia in stroke.

The present study was designed to examine the frequency and severity of apraxia in patients with left- or right-hemisphere stroke in both pantomime and imitation conditions and to compare the frequency of apraxia in each stroke group across the three patterns of apraxia described in Roy's model (Roy, 1996). Ninety-nine stroke patients and 15 age-matched healthy adults performed eight transitive gestures to pantomime and to imitation. Gestural performance was quantified as accuracy on five performance dimensions; a composite score, an arithmetic combination of the five performance dimensions, was used as an index of the overall accuracy. Analyses revealed a comparable proportion of patients in each stroke group were classified as apraxic in the imitation condition, but a higher proportion of left stroke patients were apraxic in the pantomime condition. The severity of apraxia in each stroke group and the performance dimensions affected were, however, comparable. Analyses of the patterns of apraxia (pantomime alone, imitation alone or apraxia in both conditions) revealed a higher frequency of apraxia in both stroke groups for the pattern reflecting apraxia in both conditions, indicating that a disruption at the movement execution stage of gesture performance was most common.

Aged↗
PubMed2000

Fine mapping of the neurally expressed gene SOX14 to human 3q23, relative to three congenital diseases.

Members of the Sox gene family encode transcription factors that have diverse and important functions during development. We have recently described the cloning of chick and mouse Sox14 and the expression of these genes in a population of ventral interneurons in the embryonic spinal cord. We report here the cloning and sequencing of the human orthologue of Sox14. Human SOX14 shows remarkable sequence conservation compared with orthologues from other vertebrate species and probably mirrors the expression of these genes in the developing brain and spinal cord. Using radiation hybrid mapping and fluorescence in situ hybridisation, we have localised SOX14 close to the sequence tagged site D3S1576 on human chromosome 3q23. Three congenital disorders have been localised to this region: blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), Charcot-Marie-Tooth neuropathy type IIB (CMT2B) and Mobius syndrome type 2 (MBS2). We have found that SOX14 is unlikely to be involved in any of these disorders because of the position of SOX14 proximal to a BPES breakpoint and the lack of SOX14 coding region alterations in BPES, CMT2B and MBS2 patients.

Amino Acid Sequence↗
PubMed2000

Mismatch repair blocks expansions of interrupted trinucleotide repeats in yeast.

Disease-causing expansions of trinucleotide repeats (TNRs) can occur very frequently. In contrast, expansions are rare if the TNR is interrupted (imperfect). The molecular mechanism stabilizing interrupted alleles and thereby preventing disease has been elusive. We show that mismatch repair is the major stabilizing force for interrupted TNRs in Saccharomyces cerevisiae. Interrupted alleles expand much more often when mismatch repair is blocked by mutation or by poorly corrected mispairs. These results suggest that interruptions lead to mismatched expansion precursors. In normal cells, expansions are prevented in trans by mismatch repair, which coexcises the mismatches plus the aberrant, TNR-mediated secondary structure that otherwise resists removal. This study indicates a novel role for mismatch repair in mutation avoidance and, potentially, in disease prevention.

Alleles↗
PubMed2000

Characterization of the nucleolar gene product, treacle, in Treacher Collins syndrome.

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development caused by mutations in the gene TCOF1. Its gene product, treacle, consists mainly of a central repeat domain, which shows it to be structurally related to the nucleolar phosphoprotein Nopp140. Treacle remains mostly uncharacterized to date. Herein we show that it, like Nopp140, is a highly phosphorylated nucleolar protein. However, treacle fails to colocalize with Nopp140 to Cajal (coiled) bodies. As in the case of Nopp140, casein kinase 2 appears to be responsible for the unusually high degree of phosphorylation as evidenced by its coimmunoprecipitation with treacle. Based on these and other observations, treacle and Nopp140 exhibit distinct but overlapping functions. The majority of TCOF1 mutations in TCS lead to premature termination codons that could affect the cellular levels of the full-length treacle. We demonstrate however, that the cellular amount of treacle varies less than twofold among a collection of primary fibroblasts and lymphoblasts and regardless of whether the cells were derived from TCS patients or healthy individuals. Therefore, cells of TCS patients possess a mechanism to maintain wild-type levels of full-length treacle from a single allele.

Cell Nucleolus↗
PubMed2000

Alcohol affects processing of ignored stimuli in a negative priming paradigm.

OBJECTIVE: This research examined the effect of alcohol on negative priming, which is considered to reflect a basic process of selective attention. METHOD: Male social drinkers (N = 28) performed a color naming reaction time (RT) task that measured negative priming. After a baseline test on the task, they received either 0.56 g/kg of alcohol or a placebo; they then performed the task twice. RESULTS: In accord with the hypotheses, alcohol suppressed negative priming during the ascending limb but not during the descending limb of the blood alcohol curve. No suppression of negative priming was evident under placebo. CONCLUSIONS: The suppression of this process by alcohol may represent a basic mechanism by which the drug reduces the ability to efficiently allocate attention and leads to impaired performance on various attention-based tasks (e.g., divided attention and vigilance tasks).

Adult↗
PubMed2000

Differential effects of alcohol on responses to negatively and positively primed stimuli.

OBJECTIVE: As shown in previous research, alcohol suppresses negative priming, an effect that normally occurs when subjects are required to respond to information that had been previously ignored. The present research examined the generality of this effect by testing the effect of alcohol on responses to positively primed stimuli that did not require responding to previously ignored information. METHOD: Twenty-eight male social drinkers performed a color-naming reaction time task that measured both negative and positive priming effects. After a baseline test on the task, they received either 0.56 g/kg of alcohol or a placebo, and then performed the task twice. RESULTS: The results showed a differential effect of alcohol on negative and positive priming. Alcohol suppressed negative priming, but had no effect on the magnitude of positive priming. CONCLUSIONS: Evidence for a selective effect of alcohol on negative, but not positive, priming suggests that the drug does not reduce negative priming by impairing memory of priming stimulus information. Rather, the findings provide further support for a specific impairment of an inhibitory process that normally serves to prevent interference from distracting, to be ignored, stimuli. Impairment of this process by alcohol could represent a basic cognitive mechanism by which the drug disrupts performance of laboratory tasks that require visual attention, such as divided attention and vigilance tasks.

Adult↗