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Biomedical subjects

E Healy

Publications and source records attributed to E Healy.

At least 19 recordsLinked to original sources
PubMed2004

Expression and glycosylation of MUC1 in epidermolysis bullosa-associated and sporadic cutaneous squamous cell carcinomas.

BACKGROUND: Cutaneous squamous cell carcinoma (SCC) is particularly problematic in certain patient groups, including patients with dystrophic or junctional epidermolysis bullosa (DEB/JEB). Theoretically, vaccination against a cell surface antigen which is expressed on this type of tumour could prevent SCC development, as well as treat primary and metastatic disease in this patient group. Preliminary studies have suggested that MUC1, a transmembrane glycoprotein, is overexpressed in sporadic cutaneous SCCs, and MUC1 has been used with some success as a target antigen for vaccine development in breast cancer, where it is expressed on > 50% of neoplastic cells in approximately 50-80% of tumours. Furthermore, aberrant glycosylation of MUC1 has been detected in this and other cancer types; however, the glycosylation status of MUC1 in cutaneous SCC is not known. OBJECTIVES: To investigate the expression and glycosylation status of MUC1 in SCCs arising in patients with DEB and JEB, and for comparison in sporadic SCCs and sporadic Bowen's disease. METHODS: Immunohistochemical analysis of MUC1 in 30 SCCs from subjects with DEB/JEB, 55 sporadic SCCs and 30 sporadic lesions of Bowen's disease was carried out using four separate monoclonal antibodies which recognize different isoforms of MUC1. RESULTS: Expression of MUC1 was detected in 100% of SCCs arising in patients with DEB and JEB; > 50% of neoplastic cells stained positive for MUC1 in 57% of DEB/JEB SCCs, with over 95% of tumour cells immunopositive in 33% of cases. MUC1 expression was also observed in 95% of sporadic SCCs and 97% of Bowen's disease, with 36% of sporadic SCCs immunopositive for MUC1 in > 50% of tumour cells. Investigation of the glycosylation status showed that MUC1 was predominantly hyperglycosylated in the DEB/JEB and sporadic tumours. CONCLUSIONS: The results demonstrate that a significant proportion of DEB/JEB and sporadic SCCs express MUC1 in > 50% of tumour cells. Therefore, MUC1 may be a suitable candidate antigen against which to develop a tumour vaccine for these patient groups.

Bowen's Disease↗
PubMed2001

Functional variation of MC1R alleles from red-haired individuals.

Red hair in humans is associated with variant alleles of the alphaMSH receptor gene, MC1R. Loss of MC1R function in other mammals results in red or yellow hair pigmentation. We show that a mouse bacterial artificial chromosome (BAC) which contains Mc1r will efficiently rescue loss of Mc1r in transgenic mice, and that overexpression of the receptor suppresses the effect of the endogenous antagonist, agouti protein. We engineered the BAC to replace the mouse coding region with the human MC1R sequence and used this in the transgenic assay. The human receptor also efficiently rescued Mc1r deficiency, and in addition, appeared to be completely resistant to the effects of agouti, suggesting agouti protein may not play a role in human pigmentary variation. Three human variant alleles account for 60% of all cases of red hair. We engineered each of these in turn into the BAC and find that they have reduced, but not completely absent, function in transgenic mice. Comparison of the phenotypes of alphaMSH-deficient mice and humans in conjunction with this data suggests that red hair may not be the null phenotype of MC1R.

Alleles↗
PubMed2001

Localization of a gene (MCUL1) for multiple cutaneous leiomyomata and uterine fibroids to chromosome 1q42.3-q43.

Dominant transmission of multiple uterine and cutaneous smooth-muscle tumors is seen in the disorder multiple leiomyomatosis (ML). We undertook a genomewide screen of 11 families segregating ML and found evidence for linkage to chromosome 1q42.3-q43 (maximum multipoint LOD score 5.40). Haplotype construction and analysis of recombinations permitted the minimal interval containing the locus, which we have designated "MCUL1," to be refined to an approximately 14-cM region flanked by markers D1S517 and D1S2842. Allelic-loss studies of tumors indicated that MCUL1 may act as a tumor suppressor. Identification of MCUL1 should have wide interest, since this gene may harbor low-penetrance variants predisposing to the common form of uterine fibroids and/or may undergo somatic mutation in sporadic leiomyomata.

Chromosome Mapping↗
PubMed2000

Pleiotropic effects of the melanocortin 1 receptor (MC1R) gene on human pigmentation.

Variants of the melanocortin 1 receptor (MC1R) gene are common in individuals with red hair and fair skin, but the relative contribution to these pigmentary traits in heterozygotes, homozygotes and compound heterozygotes for variants at this locus from the multiple alleles present in Caucasian populations is unclear. We have investigated 174 individuals from 11 large kindreds with a preponderance of red hair and an additional 99 unrelated redheads, for MC1R variants and have confirmed that red hair is usually inherited as a recessive characteristic with the R151C, R160W, D294H, R142H, 86insA and 537insC alleles at this locus. The V60L variant, which is common in the population may act as a partially penetrant recessive allele. These individuals plus 167 randomly ascertained Caucasians demonstrate that heterozygotes for two alleles, R151C and 537insC, have a significantly elevated risk of red hair. The shade of red hair frequently differs in heterozygotes from that in homozygotes/compound heterozygotes and there is also evidence for a heterozygote effect on beard hair colour, skin type and freckling. The data provide evidence for a dosage effect of MC1R variants on hair as well as skin colour.

Alleles↗
PubMed2000

Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca(2+) pump.

Hailey-Hailey disease (HHD) is an autosomal dominant skin disorder characterized by suprabasal cell separation (acantholysis) of the epidermis. Previous genetic linkage studies localized the gene to a 5 cM interval on human chromosome 3q21. After reducing the disease critical region to <1 cM, we used a positional cloning strategy to identify the gene ATP2C1, which is mutated in HHD. ATP2C1 encodes a new class of P-type Ca(2+)-transport ATPase, which is the homologue for the rat SPLA and the yeast PMR1 medial Golgi Ca(2+)pumps and is related to the sarco(endo)plasmic calcium ATPase (SERCA) and plasma membrane calcium ATPase (PCMA) families of Ca(2+)pumps. The predicted protein has the same apparent transmembrane organization and contains all of the conserved domains present in other P-type ATPases. ATP2C1 produces two alternative splice variants of approximately 4.5 kb encoding predicted proteins of 903 and 923 amino acids. We identified 13 different mutations, including nonsense, frameshift insertion and deletions, splice-site mutations, and non-conservative missense mutations. This study demonstrates that defects in ATP2C1 cause HHD and together with the recent identification of ATP2A2 as the defective gene in Darier's disease, provide further evidence of the critical role of Ca(2+)signaling in maintaining epidermal integrity.

Amino Acid Sequence↗
PubMed2000

Melanocortin-1-receptor gene and sun sensitivity in individuals without red hair.

Susceptibility to sunburn, photoageing, and skin cancer is inversely related to an individual's ability to tan after sun exposure. We examined variants in the melanocortin-1-receptor (MC1R) gene in individuals from Ireland and the UK. We found evidence of an association between the degree of tanning after repeated sun exposure, and the number of variant alleles present. Heterozygotes were intermediate between wild-type individuals and those with two variant alleles. We suggest that MC1R gene status therefore determines sun sensitivity in people without red hair.

Adult↗
PubMed2000

Evidence for variable selective pressures at MC1R.

It is widely assumed that genes that influence variation in skin and hair pigmentation are under selection. To date, the melanocortin 1 receptor (MC1R) is the only gene identified that explains substantial phenotypic variance in human pigmentation. Here we investigate MC1R polymorphism in several populations, for evidence of selection. We conclude that MC1R is under strong functional constraint in Africa, where any diversion from eumelanin production (black pigmentation) appears to be evolutionarily deleterious. Although many of the MC1R amino acid variants observed in non-African populations do affect MC1R function and contribute to high levels of MC1R diversity in Europeans, we found no evidence, in either the magnitude or the patterns of diversity, for its enhancement by selection; rather, our analyses show that levels of MC1R polymorphism simply reflect neutral expectations under relaxation of strong functional constraint outside Africa.

Africa↗
PubMed2000

A 16-year follow-up of a child inpatient population.

The purpose of this study was to evaluate long-term outcomes of children who had been inpatients in a child psychiatry unit. Fifty children, who were consecutive admissions to a Dublin inpatient child psychiatry unit between November 1978 and July 1980, were followed up 16 years later. We obtained some direct information on 33 subjects; of these, 4 subjects had died and 11 subjects (33%) were living abroad. A poor outcome as defined by death, imprisonment, adult psychiatric disorder or unemployment was present in 18 of the 24 subjects (79%) on whom this information was available. We conclude that more support and increased availability of services post discharge are needed.

Adolescent↗
PubMed2000

Novel keratin 16 mutations and protein expression studies in pachyonychia congenita type 1 and focal palmoplantar keratoderma.

Pachyonychia congenita type 1 (PC-1) is an autosomal dominant ectodermal dysplasia characterized by nail dystrophy, focal non-epidermolytic palmoplantar keratoderma (FNEPPK) and oral lesions. We have previously shown that mutations in keratin 16 (K16) cause fragility of specific epithelia resulting in phenotypes of PC-1 or FNEPPK alone. Here, we report 2 novel mutations in K16 causing distinct phenotypes. A heterozygous missense mutation (L124R) was detected in a kindred with PC-1. In a family where mild FNEPPK was the only phenotype, a 23 bp deletion and a separate 1 bp deletion downstream were found in exon 6: [1244-1266del; 1270delG]. At the protein level, these mutations remove 8 residues and substitute 2 residues in the helix termination motif (HTM) of the K16 polypeptide. The HTM sequence is conserved in all known intermediate filament proteins and for convenience, this complex mutation was designated deltaHTM. Transient expression of K16 cDNAs carrying either the L124R or the deltaHTM mutation in epithelial cell line PtK2 produced aggregation of the keratin cytoskeleton. However, the aggregates observed with the deltaHTM mutation were morphologically different and appeared to be less disruptive to the endogenous cytoskeleton. Therefore, loss of the HTM sequence may render this mutant K16 less capable of contributing to filament assembly and decrease its dominant-negative effect, resulting in the milder FNEPPK phenotype.

Base Sequence↗
PubMed2000

Dopaminergic sensitivity and prediction of antidepressant response.

This study was designed to examine neuroendocrine predictors of antidepressant response to the selective serotonin reuptake inhibitor (SSRI) paroxetine. We assessed the prognostic utility of the apomorphine stimulation test by examining the relationship between pretreatment change in growth hormone (GH) following apomorphine and acute response to paroxetine treatment. We hypothesized that those subjects with most marked pretreatment dopaminergic supersensitivity, as manifested by greatest change in GH, would be most likely to show an early antidepressant response and would also be more likely to develop manic or hypomanic symptoms on paroxetine. Contrary to our hypothesis, greater dopamine postsynaptic sensitivity was associated with greater resistance to paroxetine treatment. In our sample of 13 subjects with a major depressive episode, pretreatment GH response to apomorphine per unit weight was inversely correlated with change in Hamilton depression rating scale following 6 weeks of paroxetine. Within the group of subjects who showed mood elevation on paroxetine, there was a trend towards greater GH response being associated with slower antidepressant response. With regard to the development of manic or hypomanic symptoms on paroxetine, change in GH per unit weight not did distinguish the two subjects who subsequently developed paroxetine-induced hypomania from other subjects. The seven subjects with previous antidepressant-induced hypomania did not differ from the other subjects in change in GH response per unit weight. The finding that subjects who had low dopamine receptor responsivity pretreatment were more likely to have an antidepressant response with paroxetine is consistent with recent suggestions that the therapeutic effect of SSRIs may be mediated through increased dopamine receptor sensitivity in the mesolimbic system. Further work assessing pretreatment and post-treatment GH response to apomorphine will help to test the hypothesis that low dopamine receptor responsivity predicts antidepressant response to SSRIs.

Adult↗
PubMed1999

Genetic studies of the human melanocortin-1 receptor.

Genetic approaches have suggested a critical role for the melanocortin-1 receptor in the control of pigmentation. We showed that this gene is unusually polymorphic in European populations and that, of the many variants, three in particular appear to be associated with red hair or fair skin. Family studies suggest these are inherited as an autosomal recessive trait (or at least approximate to this in many families). To date all individuals with two of these three changes (homozygote or compound heterozygote) have red hair. Early functional studies are in keeping with defective signalling through MC1R. An interested and perhaps unexpected question relates to the evolutionary factors that have given rise to such variants. Two models can be proposed, that are based on multiple alleles with minor changes in function or genetic hitch-hicking.

Animals↗
PubMed1999

Somatic mutations in the Peutz-Jeghers (LKB1/STKII) gene in sporadic malignant melanomas.

Germline mutations in the LKB1/STK11 gene cause characteristic hamartomas and freckling to develop in patients with Peutz-Jeghers syndrome (PJS). The hamartomas arise as a result of somatic "second hits" at LKB1/STK11 and therefore contain a neoplastic element. The origin of the pigmented lesions in PJS is unknown and difficult to test, as these are hardly ever biopsied. PJS patients are at increased risk of benign and malignant tumors, particularly of the colon, breast, pancreas, testis, and ovary, although the increased risk for any one of these sites may be quite modest. Somatic LKB1/STK11 mutations have been found, albeit at a low frequency, in sporadic tumors of the colon, stomach, ovary, and testis. Although PJS patients are not known to have an excess of skin tumors, if the freckles of PJS patients are actually small, benign tumors, LKB1/STK11 mutations must provide these lesions with a selective advantage, and similar mutations might also give a selective advantage to related malignant tumors, such as melanomas. We have therefore screened 16 melanoma cell lines, 15 primary melanomas, and 19 metastases for LKB1/STK11 mutations. Two LKB1/STK11 mutations were found: a missense change (Y49D) accompanied by allele loss in a cell line; and a missense change (G135R), without a detected mutation in the other allele, in a primary tumor. Both these mutations are highly likely to be pathogenic. Novel polymorphisms, including an unusual heptanucleotide repeat, were also found in introns 2 and 3. LKB1/STK11 mutations occur in a significant minority of tumors of several sites, including malignant melanomas.

AMP-Activated Protein Kinase Kinases↗