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Biomedical subjects

H M Gurling

Publications and source records attributed to H M Gurling.

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

Sex of parent transmission effect in Tourette's syndrome: evidence for earlier age at onset in maternally transmitted cases suggests a genomic imprinting effect.

Parent of origin effects caused by genomic imprinting may influence the phenotypic expression of a number of heritable human disorders. To test this phenomenon in Tourette's syndrome (TS), we studied 437 first degree relatives systematically ascertained through 57 probands. We compared age at onset, age at diagnosis, and phenotypic expressions as observed in the diagnosis of TS, chronic motor tics, and obsessive compulsive behavior in the offspring of affected males with the offspring of affected females. Of the 437 subjects, 16.7% had matrilineal inheritance and 13.9% had patrilineal inheritance, as determined by family history methodology. Chi-square analysis of the different phenotypic expressions and sex of the transmitting parent failed to provide evidence of significant group differences. We found no significant differences in the age at diagnosis either. However, the maternally transmitted offspring showed a significantly earlier age at onset. This points to a parent of origin effect on the putative TS gene that could be explained by meiotic events or even intrauterine environmental influences. These findings may help explain the hitherto conflicting reports about the nature of genetic transmission in TS, and suggest a need to re-examine family data separately for maternally and paternally transmitted cases, taking into account the possible role of imprinting.

Age of Onset↗
PubMed1996

Linkage analysis and exclusion of regions of chromosomes 3 and 8 in Gilles de la Tourette syndrome following the identification of a balanced reciprocal translocation 46 XY, t(3:8)(p21.3 q24.1) in a case of Tourette syndrome.

Gilles de la Tourette syndrome (GTS) and related disorders such as chronic multiple tics and obsessive compulsive behaviour are likely to be genetically transmitted with a Mendelian autosomal dominant mode of transmission. Following our discovery of a patient with GTS who also carried a balanced translocation 46 XY, t(3:8) (p21.3 q24.1), a linkage study of several families was performed covering the areas on chromosomes 3 and 8 implicated by the cytogenetic abnormality in this unique GTS patient. A positive multipoint lod score of 2.9 was obtained on chromosome 3 with markers at the loci RAF1, THRB and D3S11. Subsequently, the genetic map of this region was improved and new polymorphic markers close to our original three markers were identified. With the new map the maximum two-point lod with any marker was reduced to 1.77 at RAF1, and the FASTMAP approximate multipoint lod excluded the likely region of the breakpoint. After constructing a somatic cell hybrid, the original three markers were mapped relative to the break point of the translocation and to other new markers. It was confirmed that the original markers were at least 20 cM away from the position of the break point. In addition, we traced further family members of our translocation GTS proband, and identified affected individuals who did not possess the translocation. We concluded that the translocation was not responsible for the GTS symptoms in our affected proband.

Chromosome Mapping↗
PubMed1996

Linkage study of the D5 dopamine receptor gene (DRD5) in multiplex Icelandic and English schizophrenia pedigrees.

OBJECTIVE: The authors investigated the possibility that genetic variation or mutation of the dopamine D5 receptor gene might modify susceptibility to schizophrenia. METHOD: Twenty-three Icelandic and English pedigrees containing multiple cases of schizophrenia were genotyped by using a highly informative microsatellite for the D5 dopamine receptor gene DRD5. RESULTS: By means of three different affection models, negative lod scores were obtained under assumptions of autosomal dominant and recessive inheritance. There was no evidence for locus heterogeneity. Nonparametric extended relative pair analysis also produced negative results. CONCLUSIONS: These data indicate that mutations of the D5 dopamine receptor gene are not a major cause of schizophrenia in these pedigrees. Because of the probable existence of locus heterogeneity, the D5 receptor gene may be of etiologic importance in other families with schizophrenia.

Base Sequence↗
PubMed1996

Lack of evidence for close linkage of the glutamate GluR6 receptor gene with schizophrenia.

OBJECTIVE: Previous research has consistently implicated genetic factors in the pathogenesis of schizophrenia. It has been hypothesized that an abnormality in glutamatergic function is of etiologic importance in schizophrenia, and therefore the glutamate receptor family of genes are potential susceptibility loci for schizophrenia. To test this hypothesis the authors sought to detect linkage between the GluR6 glutamate receptor gene and schizophrenia. METHOD: Twenty-three English and Icelandic families containing multiple cases of schizophrenia were genotyped with a microsatellite trinucleotide repeat polymorphism localized at the GluR6 glutamate receptor locus. Lod scores, model-free linkage analysis, and extended relative pair analysis were used to test for linkage. RESULTS: No statistically significant evidence of linkage between GluR6 and schizophrenia was found. CONCLUSIONS: The results do not support the hypothesis that GluR6 allelic variants provide a major gene contribution to the etiology of schizophrenia in a large proportion of these pedigrees.

Alleles↗
PubMed1996

A genetic linkage study of the D2 dopamine receptor locus in heavy drinking and alcoholism.

BACKGROUND: Reports of an association between restriction fragment length polymorphisms (RFLPs) at the dopamine D2 receptor (DRD2) locus and alcoholism have suggested involvement of that locus in the aetiology of alcoholism. METHOD: Sib pair linkage analyses were conducted in families multiply affected by alcoholism, using both the Taql 'A' RFLP and a microsatellite repeat polymorphism at the DRD2 locus. RESULTS: The 'Identical By Descent' analysis provided significant evidence of an effect of the DRD2 locus on the liability to develop heavy drinking (P < 0.0016) and Research Diagnostic Criteria alcoholism (P < 0.0003) in the first sample of families studied. However, this result was explicable by the segregation of alleles in a single large sibship, and it was not replicated in a second sample of families. CONCLUSIONS: The results do not support linkage between the DRD2 locus and alcoholism in most of the families studied. It remains possible that this locus influences the predisposition to alcoholism in some families.

Alcoholism↗
PubMed1996

Point mutation analysis of the FMR-1 gene in autism.

We have analysed all 17 exons of the human FMR-1 gene for mutations in autistic individuals using single-stranded conformational polymorphism (SSCP) analysis. We have identified three new polymorphisms. SSCP DNA fragment shifts were found for exons, 5, 10 and 11 in autistic individuals and in normal controls. Sequence analysis showed the exon 10 and 11 polymorphisms to result from base substitutions within introns, 14 and 73 bp downstream from the splice site respectively. In exon 5, a G to A base substitution at codon 138 has no effect on amino acid sequence. The intronic polymorphism adjacent to exon 10 was analysed amongst two groups of unrelated autistic individuals-one from the UK and one from Germany- and amongst a control population. Comparison of allele frequencies between Caucasian autism cases and Caucasian controls show a significant increase in the presence of the polymorphic intronic sequence 3' to exon 10 (Fisher's exact test, P = 0.01). The base change is at a position where it is unlikely to affect splicing of the FMR-1 transcript and is most likely a neutral variant that has only a spurious false positive association with autism. However further linkage disequilibrium analyses are justifiable. The positive association with autism should be explored in further samples to determine whether it has any validity as a genetic marker for autism.

Autistic Disorder↗
PubMed1995

The genetic susceptibility to Gilles de la Tourette syndrome in a large multiple affected British kindred: linkage analysis excludes a role for the genes coding for dopamine D1, D2, D3, D4, D5 receptors, dopamine beta hydroxylase, tyrosinase, and tyrosine hydroxylase.

Segregation analyses have shown that Gilles de la Tourette Syndrome (GTS) is transmitted as an autosomal dominant gene disorder indicating that classical linkage analysis should be able to identify susceptibility loci. Previous studies of GTS have included investigations of neuroreceptor function, neurotransmitters, and their metabolites as well as neurotransmitter-related enzymes in an attempt to determine the pathophysiology of GTS. The neurotransmitter systems most often thought to be involved in GTS include those involving adrenaline, noradrenaline, and dopamine. We have carried out research to test the hypothesis that genes encoding proteins in the catecholamine pathways may contribute to the genetic etiology of GTS. Polymorphic markers at or near the D1, D2, D3, D4, D5 neuroreceptor gene loci as well as at the genes encoding dopamine beta hydroxylase (DBH), tyrosinase (TY) and tyrosine hydroxylase (TH) were studied in one large multiple affected pedigree. The linkage results of this investigation exclude a major role of these candidate genes in the etiology of GTS in the pedigree.

Chromosome Aberrations↗
PubMed1995

Exclusion of linkage of schizophrenia to the gene for the dopamine D2 receptor (DRD2) and chromosome 11q translocation sites.

There have been previous reports of a 1q43;11q21 translocation cosegregating with schizophrenia and a 9p22;11q22.3 translocation cosegregating with manic depression. In addition, the genes for the dopamine D2 receptor and for tyrosinase both map to chromosome 11q. Three 11q DNA markers were used to investigate 23 pedigrees containing multiple cases of schizophrenia. Strongly negative lod scores were obtained, providing evidence against linkage over a 70 cM region which included both translocation sites and both candidate genes.

Chromosome Mapping↗
PubMed1995

Exclusion of the 5-HT1A serotonin neuroreceptor and tryptophan oxygenase genes in a large British kindred multiply affected with Tourette's syndrome, chronic motor tics, and obsessive-compulsive behavior.

OBJECTIVE: Previous studies have demonstrated a relationship between obsessive-compulsive disorder or behavior and Gilles de la Tourette syndrome. It has been hypothesized that the serotonergic system is implicated in the etiology of obsessive-compulsive disorder. Therefore, the authors investigated whether genetic variation in a serotonergic receptor and a modifying enzyme were associated with Tourette's syndrome. METHOD: A linkage analysis using DNA and blood group markers was carried out in a large British kindred multiply affected with Tourette's syndrome, chronic motor tics, and obsessive-compulsive behavior. RESULTS: There was no evidence to support the hypothesis that genetic variation in the serotonin 5-HT1A receptor and tryptophan oxygenase genes causes susceptibility to Tourette's syndrome and chronic multiple tics. CONCLUSIONS: The results eliminate two possible candidate genes from having a role in the pathophysiology of Tourette's syndrome.

Female↗
PubMed1995

Investigation by linkage analysis of the XY pseudoautosomal region in the genetic susceptibility to schizophrenia.

BACKGROUND: A susceptibility locus for schizophrenia in the pseudoautosomal region has been proposed on the basis of a possible excess of sex chromosome aneuploidies among patients with schizophrenia and an increased sex concordance in affected sib pairs. Several studies investigating this hypothesis have produced conflicting evidence. METHOD: In a series of Icelandic and British families, we used lod score and sib pair linkage analyses with markers for the MIC2 and DXYS14 loci on the pseudoautosomal XY region. RESULTS: Lod and sib pair linkage analysis with these markers produced strongly negative scores. Heterogeneity testing also produced negative results. CONCLUSION: We conclude that the present study provides no support for the involvement of either the pseudoautosomal region or the nearby region of the sex chromosomes in the aetiology of schizophrenia.

Aneuploidy↗
PubMed1994

The Marfan syndrome gene locus as a favoured locus for susceptibility to schizophrenia.

Marfan syndrome (MS) is a rare autosomal dominant disorder of connective tissue with manifestations in the cardiovascular, ocular and skeletal systems. Genetic linkage analysis with random probes has mapped the MS locus to 15q21.1. There have been several reports of Marfan syndrome co-segregating with schizophrenia within families, which suggest that a common genetic factor may be shared between schizophrenia susceptibility and MS. This could be due to a cytogenetic abnormality affecting both genetic loci or due to co-segregation of two disease loci near each other on the same chromosome. We tested this hypothesis by using genetic linkage analysis with multiplex families. Using three genetic markers spanning the MS locus, we were unable to find evidence of linkage with schizophrenia across the Marfan syndrome locus on chromosome 15.

Chromosomes, Human, Pair 15↗
PubMed1994

Genomic cloning and localization by FISH and linkage analysis of the human gene encoding the primary subunit NMDAR1 (GRIN1) of the NMDA receptor channel.

A cDNA clone of the NMDAR1 (isoform E) has been used to screen both lambda and cosmid genomic libraries. A genomic phage clone was identified and sequenced and was found to contain some of the 3' coding regions of the GRIN1 gene. This clone was used to localize the gene using fluorescent in situ hybridization (FISH) to normal chromosomes, and also to a lymphoblastoid cell line containing a translocation involving chromosomes 9 and 15. FISH localized the gene to chromosome 9q34.3. The clone was used to screen a panel of genomic DNAs cut with 20 restriction enzymes. A VNTR sequence 5' to the gene, which was polymorphic for a number of restriction enzymes, was detected. A PvuII fragment of the genomic clone was found to detect the VNTR on Southern hybridization. The polymorphic VNTR marker was mapped against chromosome 9q34 markers using linkage analysis in the CEPH families. The GRIN1 gene was linked to D9S7 with a maximum lod score of 20.09 at zero recombination fraction in males and 0.03% recombination in females.

Alleles↗
PubMed1994

The D2 dopamine receptor gene and alcoholism: a genetic effect in the liability for alcoholism.

Three of five recent association studies have demonstrated an increased frequency of the A1 allele of the TaqI Restriction Fragment Length Polymorphism (RFLP) of the DRD2 locus in alcoholics compared to controls. One of three family studies has shown preliminary results in favour of linkage of this locus with alcoholism and heavy drinking. The possible mechanism of a genetic effect of the DRD2 locus in alcoholism remains open to speculation, but many involve personality characteristics such as impulsiveness or spontaneity. The applications of the findings of research in this field offer much potential for the prevention and treatment of alcoholism, but also raise certain ethical issues when applied to screening programmes. Future research will be assisted by the development of new, and more informative, genetic markers which are now available at this locus.

Alcoholism↗
PubMed1992

Autosomal dominant gene transmission in a large kindred with Gilles de la Tourette syndrome.

A multiplex kindred ascertained through a single proband with GTS has been systematically investigated with standardised diagnostic instruments for other cases of GTS and related disorders. Complex segregation analysis supported the hypothesis that a single major gene inherited in autosomal dominant fashion but with incomplete penetrance contributed most of the variance in the liability to develop GTS and related disorders. This result is consistent with previous segregation analyses which have employed different methods of ascertainment, and tends to confirm that a proportion of GTS is due to a dominant gene and is suitable for investigation with genetic markers for linkage analysis.

Causality↗