Biomedical subjects
Publications and source records attributed to P Humphries.
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The human retina carries specialized neurons, the rod and cone photoreceptors, which absorb and transduce light energy and transmit impulses through the optic nerve to the brain. The most prevalent group of inherited retinopathies, affecting approximately 1.5 million people, is collectively termed retinitis pigmentosa (RP). Mutations responsible for RP have now been found in two genes encoding transmembrane proteins of the rod photoreceptor outer segment disc, and a number of additional causative genes have been localized. It is likely that characterization of the majority of such genes over the next few years will lead to a substantial elucidation of the molecular pathology of this debilitating group of hereditary conditions.
The human RDS gene, previously mapped to chromosome 6p, encodes a protein found in the outer disc membrane of the photoreceptor cells of the retina. The cDNA sequence of the human gene shows 85% identity with the bovine peripherin gene and the rds (retinal degeneration slow) genes from mouse and rat. Mutations in the RDS gene have recently been implicated in autosomal dominant retinitis pigmentosa (adRP) in some families. Here we present evidence that the third exon of this gene is subject to polymorphic variation in humans. The three sequence alterations described in this paper give rise to amino acid substitutions. However, as these missense mutations also occur in the normal population they are not implicated as causing adRP. Interestingly such sequence variation is not found within other species examined including mouse and bovine. These intragenic polymorphisms will be of future potential value in studies to locate further disease causing mutations in adRP patients in the RDS gene.
By screening patients with autosomal dominant retinitis pigmentosa for mutations in the rhodopsin gene, two deletions (8 bp and 1 bp) have been identified in exon 5; these deletions cause a shift in the reading frame. The predicted proteins should be radically altered with translation continuing past the normal stop signal and resulting in a rhodopsin molecule that is, respectively, 1 and 10 amino acids longer. The clinical phenotype of the patients is described and is compared with that associated with other mutations in the same region of the gene.
Using single-strand conformation polymorphism electrophoresis, heteroduplex analysis, and direct sequencing, we have searched for possible disease-causing mutations in the adRP family in which we originally found tight linkage of the disease to 6p. We have now identified a single base change in exon 2, which results in the replacement of a serine residue at codon 212 for a glycine residue. The mutation cosegregates with the disease with a lod score of 12.1 at theta = 0.0.
Recent evidence suggesting the involvement of mutant rhodopsin proteins in the pathogenesis of autosomal recessive retinitis pigmentosa has prompted us to investigate whether this form of the disease shows non-allelic genetic heterogeneity, as has previously been shown to be the case in autosomal dominant retinitis pigmentosa. The availability of a unique inbred Dutch pedigree has enabled us to address this question. We have used an intragenic polymorphism to exclude the possibility that a mutation in the rhodopsin gene is responsible for the disease in this patient population. These data provide evidence for the involvement of at least two loci in autosomal recessively inherited retinitis pigmentosa.
We have analyzed DNA from 13 bovine reference pedigrees using primers specific for microsatellite markers derived from the 21-steroid hydroxylase (CYP21) and prolactin (PRL) genes and the leukocyte antigen (BOLA DRBP1) pseudogene. Linkage was demonstrated between PRL and BOLA DRBP1 (theta = 0.05; Z = 19.6), cyp21 and PRL (theta = 0.13; Z = 6.8), and BOLA DRBP1 and CYP21 (theta = 0.17; Z = 10.4). These results suggest an order BOLA DRBP1-PRL-CYP21, although in a multilocus analysis the alternative order PRL-BOLA DRBP1-CYP21 was also possible. The data confirm and extend the previously established syntenic relationship between these markers on bovine chromosome 23 and provide points of anchorage for further linkage studies in the reference pedigrees described.
Retinitis Pigmentosa (RP) is a group of inherited retinopathies which affect approximately 1 in 4,000 individuals. The disorder can be classified on the basis of inheritance; dominant, recessive and X-linked forms have been well documented. The existence of genetic heterogeneity within autosomal dominant RP (adRP) had been previously demonstrated. As a result of extensive linkage studies in 2 large Irish families and 1 American pedigree three adRP genes have been mapped. adRP genes have been localised to chromosome 3q close to the rod photoreceptor gene, rhodopsin; to chromosome 6p close to another transmembrane photoreceptor gene, peripherin/RDS and to the pericentric region of chromosome 8, although the causative gene in this region has not yet been identified. Here we report the results of a linkage study in a Spanish family, who exhibit an early-onset form of adRP. The adRP gene segregating in this family has been excluded from the three known adRP loci on chromosomes 3q, 6p and 8 using a series of both intragenic microsatellite markers from the rhodopsin and peripherin/RDS genes and markers flanking the three known loci. These results provide definitive evidence for the existence of a fourth adRP locus, further emphasising the genetic heterogeneity that exists within adRP.
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An 8-year-old girl with some features of Turner syndrome and karyotype 45X/46XY had developed a bilateral gonadoblastoma in her rudimentary ovaries. Her normal Y chromosome showed the characteristic distal fluorescence, as seen in her father's. Another mosaic, this time 45X/46XidicY, and also with some Turner features had rudimentary ovaries, but no gonadoblastoma had developed at age 14. The nature of her idicY, which showed no fluorescent distal Yq and had one of the centromeres inactivated, was confirmed by in situ hybridisation with a Yp-specific probe. Using primers from a human Yp-specific sequence, we amplified DNA extracted from paraffin-embedded ovarian tissue from both cases, and from a normal testicle and a normal ovary as controls. The finding of the expected Y-derived PCR product in the rudimentary gonads from these mosaic patients indicates the presence of their Y chromosome in both. We discuss the validity of the findings, and the possible role of sequences in or near the fluorescent part of Yq in the origin of gonadoblastoma in Y-bearing mosaic Turner syndrome.
Autosomal dominant familial exudative vitreoretinopathy (adFEVR) is a hereditary disorder characterized by the incomplete vascularization of the peripheral retina. The primary biochemical defect in adFEVR is unknown. The adFEVR locus has tentatively been assigned to 11q by linkage studies. We report the results of an extended multipoint linkage analysis of two families with adFEVR by using five markers (INT2, D11S533, D11S527, D11S35, and CD3D) from 11q13-q23. Pairwise linkage data obtained in the two families were rather similar and hence have not provided evidence for genetic heterogeneity. The highest complied two-point lod score (3.67, at a recombination fraction of .07) was obtained for the disease locus versus D11S533. Multipoint analyses showed that the adFEVR locus maps most likely, with a maximum location score of over 20, between D11S533/D11S527 and D11S35, at recombination rates of .147 and .104, respectively. Close linkage without recombination (maximum lod score 11.26) has been found between D11S533 and D11S527.
We recently reported the localization of a gene for late-onset autosomal dominant retinitis pigmentosa (adRP; RP6), on the short arm of chromosome 6, by linkage analysis in a large family of Irish origin. It is notable that the gene encoding peripherin-RDS, a photoreceptor-specific protein, recently has been physically mapped on 6p. In our own analysis, an intrageneic marker derived from this gene cosegregated with the adRP disease locus with zero recombination (lod score 5.46 at q = .00). Using the CEPH reference panel, we now report the mapping of the peripherin-RDS gene relative to other 6p markers in the CEPH data base. Incorporation of these data into a multipoint analysis produced a lod score for adRP of 8.21, maximizing at the peripherin-RDS locus. This study provides strong evidence suggesting a role for peripherin-RDS in the etiology of one form of adRP.
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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.
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