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P Humphries

Publications and source records attributed to P Humphries.

At least 73 records · Page 4Linked to original sources
PubMed1991

A three-base-pair deletion in the peripherin-RDS gene in one form of retinitis pigmentosa.

The group of retinopathies termed retinitis pigmentosa (RP) greatly contribute to visual dysfunction in man with a frequency of roughly 1 in 4,000. We mapped the first autosomal dominant RP (adRP) gene to chromosome 3q, close to the gene encoding rhodopsin, a rod photoreceptor pigment protein. Subsequently, mutations in this gene have been implicated as responsible for some forms of adRP. Another adRP gene has been mapped to chromosome 8p. A third adRP gene in a large Irish pedigree has been mapped to chromosome 6p, showing tight linkage with the gene for peripherin, a photoreceptor cell-specific glycoprotein, which is thus a strong candidate for the defective gene. We have now identified a three-base-pair deletion which results in the loss of one of a pair of highly conserved cysteine residues in the predicted third transmembrane domain of peripherin. This deletion segregates with the disease phenotype but is not present in unaffected controls, and suggests that mutant peripherin gives rise to retinitis pigmentosa.

Amino Acid Sequence↗
PubMed1991

Evaluation of mixed chimerism by in vitro amplification of dinucleotide repeat sequences using the polymerase chain reaction.

The influence of mixed hematopoietic chimerism (MC) after allogeneic bone marrow transplantation remains unknown. Increasingly sensitive detection methods have shown that MC occurs frequently. We report a highly sensitive novel method to assess MC based on the polymerase chain reaction (PCR). Simple dinucleotide repeat sequences called microsatellites have been found to vary in their repeat number between individuals. We use this variation to type donor-recipient pairs following allogeneic BMT. A panel of seven microsatellites was used to distinguish between donor and recipient cells of 32 transplants. Informative microsatellites were subsequently used to assess MC after BMT in this group of patients. Seventeen of the 32 transplants involved a donor of opposite sex; hence, cytogenetics and Y chromosome-specific PCR were also used as an index of chimerism in these patients. MC was detected in bone marrow aspirates and peripheral blood in 18 of 32 patients (56%) by PCR. In several cases, only stored slide material was available for analysis but PCR of microsatellites or Y chromosomal material could be used successfully to assess the origin of cells in this archival material. Cytogenetic analysis was possible in 17 patients and MC was detected in three patients. Twelve patients received T-cell-depleted marrow and showed a high incidence of MC as revealed by PCR (greater than 80%). Twenty patients received unmanipulated marrow, and while the incidence of MC was lower (44%), this was a high percentage when compared with other studies. Once MC was detected, the percentages of recipient cells tended to increase. However, in patients exhibiting MC who subsequently relapsed, this increase was relatively sudden. The overall level of recipient cells in the group of MC patients who subsequently relapsed was higher than in those who exhibited stable MC. Thus, while the occurrence of MC was not indicative of a poor prognosis per se, sudden increases in the proportions of recipient cells may be a prelude to graft rejection or relapse.

Anemia, Aplastic↗
PubMed1991

Autosomal dominant retinitis pigmentosa: a new multi-allelic marker (D3S621) genetically linked to the disease locus (RP4).

We report the characterization of a new eight-allele microsatellite (D3S621) isolated from a human chromosome 3 library. Two-point and multi-locus genetic linkage analysis have shown D3S621 to co-segregate with the previously mapped RP4 (theta m = 0.12, Zm = 4.34) and with other genetic markers on the long arm of the chromosome, including D3S14 (R208) (theta m = 0.00, Zm = 15.10), D3S47 (C17) (theta m = 0.11, Zm = 4.95), Rho (theta m = 0.07, Zm = 1.37), D3S21 (L182) (theta m = 0.07, Zm = 2.40) and D3S19 (U1) (theta m = 0.13, Zm = 2.78). This highly informative marker, with a polymorphic information content of 0.78, should be of considerable value in the extension of linkage data for autosomal dominant retinitis pigmentosa with respect to locii on the long arm of chromosome 3.

Alleles↗
PubMed1991

Autosomal dominant retinitis pigmentosa: localization of a disease gene (RP6) to the short arm of chromosome 6.

DNA from members of an Irish pedigree presenting with late onset autosomal dominant retinitis pigmentosa (ADRP) have been typed with a series of genetic markers from chromosome 6p. Positive two-point lod scores have been obtained with five markers (D6S89: theta = 0.10, Z = 3.338; D6S109: theta = 0.10, Z = 3.932; D6S105: theta = 0.00, Z = 6.081; HLA-DRA: theta = 0.00, Z = 4.364; and RDS: theta = 0.00, Z = 5.376). In a series of overlapping multipoint analyses a lod score of 6.6 was obtained, maximizing at HLA-DRA and hence localizing the ADRP gene (RP5) segregating in this pedigree to 6p. These data provide direct evidence for an additional autosomal dominant RP locus and strongly implicate the human equivalent of the mouse retinal degeneration slow (rds) gene, peripherin-rds, as a candidate for autosomal dominant retinitis pigmentosa.

Base Sequence↗
PubMed1991

Mixed chimaerism.

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Anemia, Aplastic↗
PubMed1991

Early detection of leukaemic relapse after bone marrow transplantation using the polymerase chain reaction.

We report a case of acute lymphoblastic leukaemia relapsing after allogeneic bone marrow transplantation in which the polymerase chain reaction (PCR) was used to assess chimeric status. This technique demonstrated the progressive reappearance of host cells prior to clinical relapse. The relapse was of host cell origin as shown by the presence of female (recipient) metaphases containing an abnormal chromosomal marker (iso 9q) which had also been present at initial diagnosis. The emergence of host cells in this case, detected only by PCR techniques but not by cytogenetic methods, appeared to herald overt relapse. PCR analysis provides a sensitive tool for detecting a progressive rise in host cell numbers which may predict clinical relapse.

Adult↗
PubMed1990

Frequency of deletion 508 among Irish cystic fibrosis patients.

We estimate the incidence of cystic fibrosis in Ireland to be at least 1 case per 1838 live births. We have analysed DNA from 44 Irish CF patients for the presence of deletion 508, using the polymerase chain reaction. The deletion was found in 76% of their chromosomes, and approximately 58% of the patients are homozygous for this deletion. Our results are not significantly different from those found in Canadian or UK patient populations, in which frequencies are higher than those found in Southern European countries.

Chromosome Deletion↗
PubMed1990

Further evidence of exclusion of linkage between type II autosomal dominant retinitis pigmentosa (ADRP) and D3S47 on 3q.

Linkage of the anonymous DNA marker D3S47 (CRI-C17) and autosomal dominant retinitis pigmentosa (ADRP) was tested in a large, extended family with type II (late onset) ADRP. D3S47 has been shown previously to be tightly linked to the RP locus in one family with type I (early onset) ADRP (McWilliams et al., 1989, Genomics 5: 619-622). Linkage between ADRP type II and D3S47 has recently been excluded in a single family (Ingelhearn et al., 1990, Genomics 6: 168-173). Results of our linkage analysis clearly establish that type II ADRP in our family is unlinked to D3S47. These findings support the hypothesis that type II ADRP is genetically distinct from type I ADRP.

Chromosomes, Human, Pair 3↗
PubMed1990

Human nidogen gene: identification of multiple RFLP and exclusion as candidate gene in a family with epidermolysis bullosa (EBS2) with evidence for linkage to chromosome 1.

Epidermolysis bullosa (EB) is a group of heritable blistering diseases affecting the dermal-epidermal basement membrane zone. We have recently provided evidence for genetic linkage of the molecular defect in a large family with dominant simplex, generalized (Koebner) type of EB (EBS2) to the long arm of chromosome 1. Because human nidogen gene has been mapped to chromosomal locus 1q43 in the human genome, we examined the possibility that nidogen, an integral component of all basement membranes, would be the candidate gene in this family of EBS2. Restriction fragment-length polymorphism, which was shown with several restriction endonucleases to be present within the nidogen gene, was utilized for linkage analyses. The results using an informative PvuII polymorphism as a marker of allelic inheritance supported exclusion of the EBS2 locus from approximately 10 cM in either side of the nidogen locus, when Lod score of -2.0 was taken as the limit of exclusion. This study demonstrates the feasibility of examining other families with EB for possible linkage to the nidogen locus.

Chromosomes, Human, Pair 1↗
PubMed1990

Inhibition of enzyme function by human autoantibodies to an autoantigen pyruvate dehydrogenase E2: different epitope for spontaneous human and induced rabbit autoantibodies.

Antibodies to the mitochondrial autoantigen M2, characteristic of the autoimmune liver disease primary biliary cirrhosis (PBC), react with the E2 subunit of the pyruvate dehydrogenase enzyme (PDH-E2). We examined the effect of disease sera on the enzyme activation catalysed by the PDH complex. Inhibition of enzyme activity was observed in 19 of 24 sera of patients with PBC with a level of greater than 90% inhibition in 14 at a serum dilution of 1/50. The onset of inhibition by serum was rapid, within the time of mixing, and the inhibitory activity was shown to reside in the immunoglobulin fraction of the serum. The immunoglobulin fraction of control sera from patients with other liver diseases (n = 26) and healthy persons (n = 8) failed to produce inhibitory activity. In addition sera from four rabbits, intensively immunized with a recombinant human M2 autoantigen, gave anti-M2 reactions by fluorescence, ELISA and immunoblotting, but did not inhibit the activity of PDH. The failure of experimentally induced M2 antibodies in rabbits to inhibit is interesting in view of the reactivity of the natural M2 autoantibodies of PBC with the highly conserved site on the enzyme which carries the essential lipoic acid cofactor.

Animals↗
PubMed1990

Retinitis pigmentosa: genetic mapping in X-linked and autosomal forms of the disease.

Retinitis pigmentosa (RP) is an hereditary degenerative disease of the retina and a major cause of visual impairment, prevalence estimates ranging from 1 in 3000 to 1 in 7000. The condition may segregate as an autosomal dominant, autosomal recessive or an X-linked recessive trait and it may also occur on a sporadic basis in up to 50% of cases. In the autosomal dominant form, close linkage to the DNA marker C17 (D3S47) was recently established in a large family of Irish origin displaying early-onset disease (McWilliam et al. 1989), multipoint analysis indicating the gene for rhodopsin as a likely candidate (Farrar et al. 1990). In that gene, a C----A transversion in codon 23, resulting in a proline----histidine substitution has now been identified in 17 of 148 unrelated ADRP patients in the United States (Dryja et al. 1990). This mutation is absent however in the original Irish pedigree (it is also absent in 21 other dominant Irish pedigrees, representing approximately 70% of the estimated ADRP population) indicating that another mutation, either in rhodopsin itself, or in a gene very closely linked to rhodopsin is responsible for the disease in that family. Analysis of other dominant pedigrees using the C17 and/or rhodopsin probes has indicated either tight linkage (Bhattacharya, Personal Communication), looser linkage, possibly indicative of a second locus on 3q (Olsson et al. 1990) or no linkage (Farrar et al. 1990, Blanton et al. 1990, Inglehearn et al. 1990). Extensive genetic heterogeneity thus exists in the autosomal dominant form of this disease, and in the light of these new observations, earlier tentative evidence for linkage of ADRP to the Rhesus locus on chromosome 1 will be re-evaluated. A locus for type II Usher syndrome (classical RP combined with congenital pedial deafness, and normal vestibular function) has now been established on the long arm of chromosome 1 (Kimberling et al. 1990). Type I Usher families, in which hearing loss is more profound and vestibular function absent, do not segregate with the same chromosome 1q markers, indicating the existence of another, as yet unlocated gene. In the X-linked form of the disease, two genes, XLRP2 and XLRP3, have been located on the proximal short arm of the X chromosome using a combination of physical and linkage mapping techniques, and there is some evidence to suggest a possible third locus more distally located.(ABSTRACT TRUNCATED AT 400 WORDS)

Chromosome Deletion↗