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J Collinge

Publications and source records attributed to J Collinge.

At least 109 records · Page 6Linked to original sources
PubMed1993

Deletions in the prion protein gene are not associated with CJD.

The human prion diseases (spongiform encephalopathies) Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler syndrome (GSS), are neurodegenerative disorders characterised by the accumulation of an abnormal isoform of the prion protein. The normal prion protein is a phosphatidyl inositol anchored, membrane bound sialoglycoprotein of widespread tissue distribution but expressed predominantly in the brain. 15% of prion diseases are autosomal dominant genetic disorders associated with mutations in the gene encoding the prion protein. To date six pathogenic amino acid substitutions have been identified in affected family members, in addition to five distinct insertional events which occur within a region of the protein comprising four tandem octapeptide repeats. We have investigated deletions within this region and have identified three specific deletions. We report here that these deletions are not associated with CJD and represent a new class of polymorphism within the prion protein gene.

Amino Acid Sequence↗
PubMed1992

Prion protein immunocytochemistry helps to establish the true incidence of prion diseases.

Creutzfeldt-Jakob disease (CJD) and Gerstmann-Strüssler-Scheinker disease (GSSD) are transmissible spongiform encephalopathies or prion diseases affecting man. It has been reported that prion diseases may occur without the histological hallmarks of spongiform encephalopathies: vacuolation of the cerebral grey matter, neuronal loss and astrocytosis. These cases without characteristic neuropathology may go undiagnosed and consequently the true incidence of transmissible dementias is likely to have been under-estimated. Immunocytochemistry using antibodies to prion protein gives positive staining of these cases, albeit the pattern of immunostaining differs from that seen in typical forms. Accumulation of prion protein is a molecular hallmark of prion diseases, and thus a reproducible, speedy and cost-efficient immunocytochemical screening of unusual dementias may help to establish the true incidence of prion diseases.

Adult↗
PubMed1992

A dementing illness associated with a novel insertion in the prion protein gene.

Following our previous report of an 144-bp insertion in the open reading frame of the prion protein (PrP) gene, we have now identified a larger, 216-bp, insertion in the gene. The insertion which is in frame encodes 9 extra octapeptide repeat sequences in addition to the 5 repeats normally present and represents the largest insertion so far detected in the PrP gene.

Alleles↗
PubMed1992

Prion diseases.

There have been remarkably rapid advances in the understanding of prion diseases over the past year. The controversial notion that the transmissible agent may be an abnormal isoform of a host-encoded protein, the prion protein, is now gaining wide acceptance. The conundrum of how a disease can both be inherited as an autosomal dominant condition and also be experimentally transmissible by inoculation is beginning to make sense.

Animals↗
PubMed1992

Inherited prion disease with 144 base pair gene insertion. 1. Genealogical and molecular studies.

Genealogical and molecular studies were carried out in four families in which early onset dementia is inherited as an autosomal dominant. These studies indicated that the four families derive from four siblings whose parents were born in the late 18th century in South-East England. The disease was found to be closely linked to a 144 bp insertion within the open reading frame of the prion protein (PrP) gene with a maximum LOD score of 11.02 at zero recombination. Within the general population the PrP gene is polymorphic at codon 129 (allele frequency approximately 30% valine, 70% methionine). The insertion in this family is always within a methionine-129 allele. The age at death of affected individuals whose normal allele encoded methionine at codon 129 was significantly lower than those whose normal allele encoded valine. The clinical features which were very variable and the neuropathological findings, which sometimes included spongiform encephalopathy, but which often did not, are described fully in the accompanying article (Collinge et al., 1992).

Base Sequence↗
PubMed1992

Inherited prion disease with 144 base pair gene insertion. 2. Clinical and pathological features.

A large family with autosomal dominant segregation of presenile dementia, and other neurological and behavioural features is described. At various times, family members have carried diagnoses of Alzheimer's disease, Huntington's disease, Parkinson's disease, myoclonic epilepsy, atypical dementia, Pick's disease, Creutzfeldt-Jakob disease and Gerstmann-Sträussler syndrome. Molecular genetic studies have enabled classification of this disease at the molecular level as one of the group of inherited prion diseases. Here we describe the phenotype of inherited prion disease (PrP 144 bp insertion).

Adult↗
PubMed1992

Human prion diseases.

The past year has seen considerable advances in our understanding of the prion diseases, and there is increasing acceptance that the transmissible agent in these diseases may be an abnormal isoform of a normal host encoded protein. Molecular genetic studies have led to a new appreciation of the phenotypic spectrum of the prion diseases as the inherited forms of these conditions can now be diagnosed by a direct gene test. The conundrum of how a disease can be both inherited and transmissible is beginning to make sense.

Animals↗
PubMed1991

Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease.

The human prion diseases, Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler syndrome (GSS), are neurodegenerative diseases that are unique in being both infectious and genetic. Transmission of both diseases and the animal spongiform encephalopathies (for example, scrapie and bovine spongiform encephalopathy) to experimental animals by intracerebral inoculation with brain homogenates is well documented. Despite their experimental transmissibility, missense and insertional mutations in the prion protein gene are associated with both GSS and familial CJD, demonstrating that the human familial cases are autosomal dominant diseases. More than 80% of CJD cases occur sporadically, however, and are not known to be associated with mutations. Here we report that 21 of 22 sporadic CJD cases and a further 19 of 23 suspected sporadic CJD cases are homozygous at the polymorphic amino-acid residue 129; 51% of the normal population are heterozygous at this site. We argue that homozygosity predisposes towards sporadic CJD and that this directly supports the hypothesis that interaction between prion protein molecules underlies the disease process.

Amino Acid Sequence↗
PubMed1991

Genetic predisposition to iatrogenic Creutzfeldt-Jakob disease.

The spongiform encephalopathy Creutzfeldt-Jakob disease (CJD) has been transmitted to man via administration of growth hormone and gonadotropin extracted from large pooled batches of human cadaveric pituitary glands. In the UK, 1908 individuals were exposed to potentially contaminated growth hormone, of whom 6 have so far manifested CJD. Examination of the prion protein genes of all these cases and of a single case of gonadotropin-related CJD showed that 4 had the uncommon valine 129 homozygous genotype indicating genetic susceptibility to prion infection. Such genetic susceptibility may be important in the aetiology of sporadic CJD disease.

Alleles↗
PubMed1991

Insertions in the prion protein gene in atypical dementias.

A number of mutations have been demonstrated in the open reading frame (ORF) of the prion protein (PrP) gene in patients with familial Creutzfeldt-Jakob disease or Gerstmann-Sträussler syndrome. On the basis of detecting an insertion in the ORF of the PrP gene in a patient originally suspected to be suffering from familial Alzheimer-type dementia, we screened 101 individuals with atypical dementias for the known PrP gene mutations. Insertions were found in five individuals, whereas none of the other reported mutations in the PrP gene was detected in the present study. One of the five insertions was larger than that described previously, suggesting that the individuals with these mutations are unlikely to be all lineally related and that insertions in the PrP gene may not be uncommon in prion diseases.

Alzheimer Disease↗
PubMed1991

Genetic characterization of a novel familial dementia.

Clinical and neuropathologic findings from a Danish family in which a dementing illness is segregating as an apparent autosomal dominant disorder were previously described (Gydesen et al. 1987). We present here genetic findings from this family in which linkage analysis has excluded Huntington's disease and chromosome 21-encoded Alzheimer's disease. None of the known prion mutations has been detected in affected individuals from this family. However, linkage analysis with the prion gene has been uninformative. This family probably represents a novel genetic dementia.

DNA Probes↗
PubMed1991

Evidence for a pseudo-autosomal locus for schizophrenia using the method of affected sibling pairs.

A susceptibility locus for schizophrenia in the 'pseudo-autosomal' region has been proposed on the basis of the reported excess of sex-chromosome aneuploidies (e.g. XXY and XXX) among patients with schizophrenia and the finding that schizophrenic sib-pairs are more often of the same than of the opposite sex. This hypothesis has been tested in 83 sibships with two or more siblings fulfilling Research Diagnostic Criteria for schizophrenia or schizoaffective disorder. Alleles at the pseudo-autosomal telomeric locus DXYS14, which is unlinked with sex, were analysed using the method of affected sib-pairs. Affected sibs shared alleles at DXYS14 more frequently than expected by random Mendelian assortment, supporting genetic linkage between DXYS14 and schizophrenia.

Alleles↗
PubMed1991

Decreased hippocampal expression of a glutamate receptor gene in schizophrenia.

'A striking and specific loss of the messenger RNA that encodes a non-N-methyl D-aspartate (non-NMDA) glutamate receptor was found in hippocampal tissue obtained at necropsy from 6 patients with schizophrenia, when compared to specimens from 8 controls without neurological or psychiatric signs or symptoms. These findings support suggestions of aberrant glutamatergic function in schizophrenia. Evidence that gene expression may be abnormal in schizophrenia, with decreased production of an excitatory neurotransmitter receptor, may have therapeutic as well as pathogenetic implications.'

Gene Expression Regulation↗
PubMed1991

Presymptomatic detection or exclusion of prion protein gene defects in families with inherited prion diseases.

The identification of defects in the prion protein (PrP) gene in families with inherited Creutzfeldt-Jakob disease or Gerstmann-Straussler syndrome allows presymptomatic diagnosis or exclusion of these disorders in subjects at risk. After counseling, PrP gene analysis was performed in three such individuals: two from families with a 144-bp insert and one with a point mutation at codon 102 in the PrP gene. The presence of a PrP gene defect was confirmed in one and excluded in two. Despite the potential problems of using PrP gene analysis in genetic prediction - specifically, uncertainty about penetrance and, generally, problems of presymptomatic testing in any inherited late-onset neurodegenerative disorder - we conclude that it has a role to play in improved genetic counseling for families with inherited prion diseases.

Adult↗
PubMed1990

Prion dementia without characteristic pathology.

Gerstmann-Sträussler syndrome (GSS) was diagnosed in a family with presenile dementia by prion protein gene analysis. Extensive histological examination of the brain of an affected individual from this family showed no characteristic features of GSS or Creutzfeldt-Jakob disease (CJD). Thus "spongiform encephalopathy" (GSS or CJD) cannot always be excluded on neuropathological grounds in an individual dying of a dementing condition, and the true prevalence of these diseases is likely to be underestimated. Screening by prion protein gene analysis will help to determine the full clinical and neuropathological phenotype in familial cases. This observation may be relevant to the assessment of possible transmission of bovine spongiform encephalopathy to man.

Alleles↗