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P Humphries

Publications and source records attributed to P Humphries.

At least 37 records · Page 2Linked to original sources
PubMed1996

Three keratin gene mutations account for the majority of dominant simplex epidermolysis bullosa cases within the population of Ireland.

We have located three extended families in Ireland (population 3.5 million) with autosomal dominant simplex forms of Epidermolysis Bullosa (EBS). A mutation within the keratin type I (K14) gene (Met-->272-->Arg) in one family suffering from the generalized simplex (Koebner) form of the disease has been previously described (Humphries et al., Hum Mutat 2:37-42, 1993). Here we report on the identification of mutations within the remaining two families, both of whom suffer from the Weber-Cockayne form of the disease. These mutations, within the type II keratin (K5) gene, are Asn-->193-->Lys and Met-->327-->Thr. They have been shown in each case to co-segregate with the disease and are not present in the normal population. Within the three families, a total of 44 living persons with such mutations have been identified, providing a minimum prevalence estimate for the disease in the Irish population of approximately 1 in 80,000, compared to an overall estimated global incidence at birth for all forms of EB of 1 in 50,000. Therefore, these three mutations probably account for the majority of cases of EBS within this population.

Amino Acid Sequence↗
PubMed1996

Mapping the RP10 locus for autosomal dominant retinitis pigmentosa on 7q: refined genetic positioning and localization within a well-defined YAC contig.

Retinitis pigmentosa is a genetically heterogeneous disease that has autosomal dominant, autosomal recessive and X-linked forms. Autosomal dominant retinitis pigmentosa (adRP) has thus far been associated with eight distinct loci, including the rhodopsin and peripherin/RDS genes as well as unidentified genes on chromosomes 7p, 7q, 8q, 17p, 17q, and 19q. The RP10 locus for adRP on chromosome 7q was first mapped in a Spanish family; later, an unrelated American family was identified that also showed linkage to 7q. By combining the linkage results from both families, we are able to assign the disease gene to a 5-cM interval on 7q. Based on extensive physical mapping of this region, the genetic interval is now fully contained within a approximately 5-Mb segment on a well-defined YAC contig. These studies significantly reduce the size of the RP10 critical region, exclude a number of possible candidate genes, and provide the necessary cloned DNA for the positional cloning of the RP10 gene.

Base Sequence↗
PubMed1994

Assignment of a gene for autosomal recessive retinitis pigmentosa (RP12) to chromosome 1q31-q32.1 in an inbred and genetically heterogeneous disease population.

Linkage analysis was carried out in a large family segregating for autosomal recessive retinitis pigmentosa (arRP), originating from a genetically isolated population in The Netherlands. Within the family, clinical heterogeneity was observed, with a major section of the family segregating arRP with characteristic para-arteriolar preservation of the retinal pigment epithelium (PPRPE). In the remainder of the ar-RP-patients no PPRPE was found. Initially, all branches of the family were analyzed jointly, and linkage was found between the marker F13B, located on 1q31-q32.1, and RP12 (zmax = 4.99 at 8% recombination). Analysis of linkage heterogeneity between five branches of the family yielded significant evidence for nonallelic genetic heterogeneity within this family, coinciding with the observed clinical differences. Multipoint analysis, carried out in the branches that showed linkage, favored the locus order 1cen-D1S158-(F13B, RP12)-D1S53-1qter (zmax = 9.17). The finding of a single founder allele associated with the disease phenotype supports this localization. This study reveals that even in a large family, apparently segregating for a single disease entity, genetic heterogeneity can be detected and resolved successfully.

Adult↗
PubMed1994

Adenovirus 12 E1A gene detection by polymerase chain reaction in both the normal and coeliac duodenum.

A 12 amino acid sequence from the adenovirus 12 E1B protein is homologous at the protein level with a similar 12-mer derived from the wheat protein A-gliadin. It has been suggested that exposure to Ad 12 could sensitise individuals to gliadins with resultant gluten sensitive enteropathy. In this study, the polymerase chain reaction (PCR) was used to analyse duodenal biopsy tissue from patients with coeliac disease for the presence of Ad 12. The sensitivity of the assay system was at least 1 in 10(5) cells and specificity was confirmed both by probing with an internal oligonucleotide and by direct sequencing. Ad 12 sequences were detected in three of 17 patients with adult coeliac disease and in five of 16 adult controls with normal duodenal biopsies. Since exposure to the virus would be predicted to occur in infancy we also studied patients with childhood coeliac disease diagnosed at less than 1 year of age. Ad 12 was positive in three of 10 childhood coeliac patients and one of seven controls. In addition, we studied a cohort of patients who presented with a diarrhoeal illness and associated anti alpha gliadin antibodies in 1983. These patients had duodenal biopsies performed at this time. One of three patients with abnormal histology had detectable Ad 12 while two of 14 with normal findings were positive for Ad 12. Finally, the potential oncogenic nature of Ad 12 prompted examination of a group of patients with intestinal tumours. Ad 12 DNA was, however, in only two of 19 tumour samples tested. These data indicate that Ad 12 can be successfully detected using PCR on paraffin embedded tissue. Furthermore, Ad 12 was detected at a relatively high level in normal duodenum. The results do not, however, support the hypothesis that prior exposure to Ad 12 is implicated in the pathogenesis of coeliac disease.

Adenocarcinoma↗
PubMed1994

Donor leukemia following allogeneic bone marrow transplantation.

Although allogeneic bone marrow transplantation has been shown to be a highly effective treatment for acute and chronic leukemia, leukemic relapse remains a significant problem. Leukemic relapse occurs in recipient cells in the majority of cases, but the paucity of donor cell leukemias may reflect the sensitivity of the investigative technique. We have developed a highly sensitive technique to identify the origin of all hematopoietic cells in the post transplant state which is based on PCR amplification of microsatellites, polymorphic tandem repetitive elements. We have identified donor leukemia (AML M5) following a sex matched BMT for severe aplastic anemia, verified a previously reported case of donor leukemia following BMT for chronic granulocytic leukemia and recently identified an acquired cytogenetic abnormality(del 11q23) in donor cells four years following an apparently successful BMT for AML. In all cases the donors have remained healthy. Postulated mechanisms include transfer to the transplanted marrow of a dormant oncogene residing in the DNA of either a virus, the chromosomes of degenerating irradiation damaged host leukemic cells or in the marrow stroma which is radioresistant and host in origin following BMT. Using sensitive techniques donor leukemia has been shown to be a more common event than was previously thought and an understanding of its pathogenesis may allow us to elucidate leukemogenic mechanisms in man.

Adolescent↗
PubMed1993

A mutation (Met-->Arg) in the type I keratin (K14) gene responsible for autosomal dominant epidermolysis bullosa simplex.

We have identified a single base change in exon 4 of the type I keratin gene which results in the replacement of a methionine for an arginine residue at codon 272 in an Irish family displaying an autosomal dominant simplex (Koebner) form of epidermolysis bullosa (EB). This family had previously provided tentative evidence for linkage to genetic markers on chromosome 1q. The mutation cosegregates with the disease, producing a lod score of 4.8 at theta = 0.

Amino Acid Sequence↗
PubMed1993

Evidence for further genetic heterogeneity in autosomal dominant retinitis pigmentosa.

We have investigated the possible involvement of further genetic heterogeneity in autosomal dominant retinitis pigmentosa using a previously unreported large Irish family with the disease. We have utilized polymorphic microsatellite markers to exclude the disease gene segregating in this family from 3q, 6p, and the pericentric region of 8, that is, each of the three chromosomal regions to which adRP loci are known to map. Hence, we provide definitive evidence for the involvement of a fourth locus in autosomal dominant retinitis pigmentosa.

Chromosome Mapping↗
PubMed1993

Isolation and genetic mapping of four microsatellite repeats from chromosome 3p21 using 40 CEPH pedigrees.

We have isolated and characterized the microsatellite markers D3S1447, D3S1448, D3S1449, and D3S1450, with PIC values of 0.771, 0.644, 0.633, and 0.552, respectively, from a hamster/human chromosome 3 library. By typing 40 CEPH pedigrees with each of these novel markers, we have sublocalized each microsatellite to 3p21 and with multipoint analyses have shown that the likelihood of the order centromere-D3S13-24.24 cM-D3S1450-9.41 cM-D3S1447-7.05 cM-D3F15S2-3 cM-[D3S1448-2.2 cM-D3S1449]-6.13 cM-D3S1100- telomere significantly exceeds any other order (8.0 x 10(3):1). These finely mapped markers will be extremely useful in aiding in the physical characterization of 3p21, which has been implicated in a range of tumor tissues.

Animals↗
PubMed1993

Polymorphisms and rare sequence variants at the ROM1 locus.

Rom-1 is an integral membrane protein of the rod photoreceptor outer segment. The ROM1 gene is located on human chromosome 11q13, a region to which the loci of four degenerative retinopathies have been mapped. To identify alleles of ROM1, we have screened the DNA of 57 controls and 180 patients with inherited retinopathies. Six ROM1 polymorphisms were identified: two in non-coding sequences (C-7T, T insertion 966/967), two substitutions (Ala118Gly, Arg223Arg), and two RFLPs outside the transcription unit, detected with BcII and Hind III. One rare sequence variant (Arg229His) was found in two adRP probands; in the one family studied the allele was discordant with the disease. A second rare variant (Ala265Thr) was found in both an adRP family and a control; a third rare variant (Met271Thr) was present only in a control family. These polymorphisms will be useful in the evaluation of ROM1 as a candidate gene in inherited retinal diseases. The recognition of the rare variants will prevent their misassignment as disease-causing mutations.

Alleles↗
PubMed1993

Exclusion of the involvement of all known retinitis pigmentosa loci in the disease present in a family of Irish origin provides evidence for a sixth autosomal dominant locus (RP8).

Retinitis Pigmentosa (RP) is the most prevalent degenerative retinal disease of mendelian origin, currently affecting approximately 1.5 million people worldwide. To date it has been established that a minimum of five different genes maybe involved in the pathogenesis of autosomal dominant forms of RP (adRP). The genes encoding two retinal specific proteins, rhodopsin and peripherin/RDS, have been implicated in causing adRP due to the observation of many different mutations in these genes in patients suffering from RP. The three remaining adRP genes have been mapped to specific regions of human chromosomes but as yet are uncharacterized. We have investigated if there is evidence for the presence of another locus in the genome which when mutated causes adRP. We have utilised polymorphic genetic markers which have previously been mapped to each of the regions known to harbour adRP genes, to test for the exclusion or linkage of the disease gene segregating in a pedigree of Irish origin and find no evidence for linkage. Hence we provide definitive evidence for the involvement of yet another locus. The implications of high levels of genetic heterogeneity inherent in adRP are discussed in relation to diagnosis, prognosis and future therapies.

Chromosome Mapping↗