Biomedical subjects

Andrew Read

Publications and source records attributed to Andrew Read.

4 recordsLinked to original sources

PubMed2005

Identification of mutations in CUL7 in 3-M syndrome.

Intrauterine growth retardation is caused by maternal, fetal or placental factors that result in impaired endovascular trophoblast invasion and reduced placental perfusion. Although various causes of intrauterine growth retardation have been identified, most cases remain unexplained. Studying 29 families with 3-M syndrome (OMIM 273750), an autosomal recessive condition characterized by severe pre- and postnatal growth retardation, we first mapped the underlying gene to chromosome 6p21.1 and then identified 25 distinct mutations in the gene cullin 7 (CUL7). CUL7 assembles an E3 ubiquitin ligase complex containing Skp1, Fbx29 (also called Fbw8) and ROC1 and promotes ubiquitination. Using deletion analysis, we found that CUL7 uses its central region to interact with the Skp1-Fbx29 heterodimer. Functional studies indicated that the 3-M-associated CUL7 nonsense and missense mutations R1445X and H1464P, respectively, render CUL7 deficient in recruiting ROC1. These results suggest that impaired ubiquitination may have a role in the pathogenesis of intrauterine growth retardation in humans.

Carrier Proteins↗

PubMed2003

Imperfect vaccination: some epidemiological and evolutionary consequences.

An aim of some vaccination programmes is to reduce the prevalence of an infectious disease and ultimately to eradicate it. We show that eradication success depends on the type of vaccine as well as on the vaccination coverage. Vaccines that reduce the parasite within-host growth rate select for higher parasite virulence and this evolution may both increase the prevalence of the disease and prevent disease eradication. By contrast, vaccines that reduce the probability of infection select against virulence and may lead more easily to eradication. In some cases, epidemiological feedback on parasite evolution yields an evolutionary bistable situation where, for intermediate vaccination coverage, parasites can evolve towards either high or low virulence, depending on the initial conditions. These results have practical implications for the design and use of imperfect vaccines in public- and animal-health programmes.

Animals↗

PubMed2003

The presence of multiple regions of homozygous deletion at the CSMD1 locus in oral squamous cell carcinoma question the role of CSMD1 in head and neck carcinogenesis.

We and others previously identified a region of hemizygous or homozygous deletion at chromosome band 8p23 in oral and oropharyngeal squamous cell carcinomas (OSCCs) and many other cancer types, suggesting the presence of a tumor-suppressor gene (TSG) in this region. Recently, based on a single region of homozygous deletion in head and neck squamous cell carcinomas (HNSCC), a putative TSG, CUB and sushi multiple domains-1 (CSMD1), has been identified. In the present study, we mapped three OSCC cell lines with previously described homozygous deletions at a high resolution onto a detailed physical map. Critically, this map covered a wider region than that used in previous studies, and in contrast to these studies, our results revealed multiple regions of homozygous deletion within a small interval on 8p23. To investigate this deletion pattern further, we generated a panel of 34 sequence tagged site (STS) markers spanning the region and tested these three cell lines and an additional 34 OSCC cell lines, identifying homozygous deletions in a further four. Combining the results from all seven deleted cell lines identified three non-overlapping regions of homozygous deletion. This complex pattern could be consistent with the presence of multiple TSGs or one very large TSG in this region, and/or specific chromosomal instability. CSMD1 spans two of the three deleted regions and, therefore, would appear to be an excellent candidate for a TSG. However, deletion mapping with STSs corresponding to the exons of CSMD1 shows that some of the deletions do not interrupt its coding region, and in other cell lines the coding region is interrupted by two discontinuous homozygous deletions, suggesting the presence of redundant deletions. These results call into question whether the CSMD1 gene is the 8p23 TSG or whether this or any other genes at this locus are involved in the development of OSCC.

Carcinoma, Squamous Cell↗

PubMed1994

Structure and expression of the Huntington's disease gene: evidence against simple inactivation due to an expanded CAG repeat.

Huntington's disease, a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expanded, unstable trinucleotide repeat in a novel 4p16.3 gene. To lay the foundation for exploring the pathogenic mechanism in HD, we have determined the structure of the disease gene and examined its expression. The HD locus spans 180 kb and consists of 67 exons ranging in size from 48 bp to 341 bp with an average of 138 bp. Scanning of the HD transcript failed to reveal any additional sequence alterations characteristic of HD chromosomes. A codon loss polymorphism in linkage disequilibrium with the disorder revealed that both normal and HD alleles are represented in the mRNA population in HD heterozygotes, indicating that the defect does not eliminate transcription. The gene is ubiquitously expressed as two alternatively polyadenylated forms displaying different relative abundance in various fetal and adult tissues, suggesting the operation of interacting factors in determining specificity of cell loss. The HD gene was disrupted in a female carrying a balanced translocation with a breakpoint between exons 40 and 41. The absence of any abnormal phenotype in this individual argues against simple inactivation of the gene as the mechanism by which the expanded trinucleotide repeat causes HD. Taken together, these observations suggest that the dominant HD mutation either confers a new property on the mRNA or, more likely, alters an interaction at the protein level.

Adult↗