Biomedical subjects
A F Wright
Publications and source records attributed to A F Wright.
Retinitis pigmentosa families showing apparent X linked inheritance but unlinked to the RP2 or RP3 loci.
Three families with retinitis pigmentosa (RP) are described in which the disorder shows apparent X linked inheritance but does not show linkage to the RP2 and RP3 regions of the short arm of the X chromosome. The families are also inconsistent with a localisation of the disease gene between DXS164 and DXS28. In one case, reassessment of the family in the light of these results suggested that the family may have an autosomal dominant form of RP. The remaining two families are consistent with X linkage and suggest the possibility of a new X linked RP (XLRP) locus. These families highlight the difficulties in determining the mode of inheritance on the basis of pedigree structure and clinical data alone. Molecular genetics plays an important role in confirming the mode of inheritance and in detecting potential misclassifications, particularly in a group of disorders as heterogeneous as RP. They emphasise that caution is required in genetic counselling of RP families, particularly in the absence of any molecular genetic analysis.
The EUROGEM map of human chromosome 18.
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Linkage disequilibrium in the region of the autosomal dominant polycystic kidney disease gene (PKD1).
The gene for autosomal dominant polycystic kidney disease (PKD1) is located on chromosome 16p, between the flanking markers D16S84 and D16S125 (26.6prox). This region is 750 kb long and has been cloned. We have looked at the association of 10 polymorphic markers from the region, with the disease and with each other. This was done in a set of Scottish families that had previously shown association with D16S94, a marker proximal to the PKD1 region. We report significant association between two CA repeat markers and the disease but have not found evidence for a single founder haplotype in these families, indicating the presence of several mutations in this population. Our results favor a location of the PKD1 gene in the proximal part of the candidate region.
Modular continuing medical education: our flexible friend?
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Should general practitioners be testing for depression?
While most patients with recognized depressive illness are treated by general practitioners without referral, there is evidence that many patients classifiable as depressed after psychiatric interview are not diagnosed as such. Missing depression is of great importance since it is now eminently treatable. This paper explores the use in primary care of questionnaire tests for depression and also their role in case finding in vulnerable groups of patients. The potential of existing validated questionnaires in clinical work and audit is largely unexploited. As yet, however, there is no gold standard for the diagnosis of depression seen in primary care. Clusters of symptoms do not yet accurately predict the course of the illness or response to treatment. More research is needed on the natural history of depression seen in the community, as well as on treatment and outcome.
A study of genetic linkage heterogeneity in 35 adult-onset polycystic kidney disease families.
A genetic heterogeneity analysis of 35 kindreds with adult-onset polycystic kidney disease (ADPKD) was carried out using the D16S85, D16S84, D16S125 and D16S94 loci that are closely linked to the PKD1 locus on chromosome 16. The results show that the likelihood of two ADPKD loci is 2,514.9 times greater than for a single locus (P < 0.0001). The maximum likelihood lod score is 27.38 under heterogeneity with PKD1 lying 4.9 cM proximal to D16S85 (in males). At least 3% of kindreds are unlinked to PKD1, since the 95% confidence limits of alpha, the proportion of families linked to PKD1, are 0.54-0.97. Only 2 out of 35 kindreds (5.7%) show statistically significant evidence of non-linkage to PKD1, with conditional probabilities of 0.987 and 0.993 that the disease locus is unlinked. This confirms the existence of a small subgroup of ADPKD kindreds that are unlinked to PKD1 and provides a firm basis for genetic counselling of this population on the basis of DNA probes.
Pharmacokinetic studies in mice with ICI D0490, a novel recombinant ricin A-chain immunotoxin.
A colorectal tumour-directed immunotoxin, ICI D0490, has been constructed by linking recombinant ricin A-chain to C242, a mouse monoclonal antibody, by means of a methyl-hindered disulphide bond. Recombinant ricin A-chain and a hindered disulphide linker were anticipated to confer favourable pharmacokinetic properties on the immunotoxin. The pharmacokinetics of ICI D0490 have been studied in mice following single and repeated i.v. administration. The concentrations of intact immunotoxin in mouse plasma at various time intervals after injection for up to 96 h were measured by a solid-phase enzyme-linked immunosorbent assay (ELISA) and the data analysed by both model-dependent (two compartment) and model-independent methods. Following a single i.v. bolus dose of 2.5 mg kg-1 (50% of the LD10 in mice), the clearance of ICI D0490 from the plasma was extremely slow; 34 microliters min-1 kg-1, t1/2 beta = 33 h. Model-dependent and model-independent analyses gave comparable results with steady state volumes of distribution of 93 and 69 ml kg-1, respectively. The two compartment analysis gave an initial volume of distribution (63 ml kg-1) which is consistent with the predicted plasma volume. Over the dose range 0.05-5 mg ICI D0490 kg-1, plasma levels at 2 and 24 h were linearly related to dose (r > or = 0.98) indicating that at doses up to 5 mg ICI D0490 kg-1 clearance does not appear to have a saturable component. Repeated doses of ICI D0490 (1 mg kg-1 day x 5) did not lead to drug accumulation. These studies demonstrate that ICI D0490 has excellent in vivo stability and persistence which, in conjunction with activity and toxicity data, identify ICI D0490 as a promising candidate for clinical evaluation in the treatment of colorectal cancer.
An STR polymorphism at the CYBB locus.
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Linkage analysis in a family with complete type congenital stationary night blindness with and without myopia.
A family is described with X-linked congenital stationary night blindness of the complete type (CSNB1) in which clinical variation between affected males resulted in diagnostic difficulties. In two affected male cousins, one had congenital nystagmus and myopia, while the other was initially thought to have retinitis pigmentosa with optic atrophy and was hyperopic. The diagnosis of X-linked congenital stationary night blindness was established by clinical, psychophysical and electrophysiological criteria, and DNA markers flanking the CSNB1 locus were analysed in the family. The results show that both affected males have inherited the same haplotype from their carrier mothers, excluding the possibility that a myopia gene in linkage disequilibrium with CSNB1 has recombined with this locus.
A blueprint for shared psychiatric care in the community.
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A family with RP3 type of X-linked retinitis pigmentosa: an association with ciliary abnormalities.
The results of linkage analysis in a family with X-linked retinitis pigmentosa (XLRP) are presented. Probe M27B (DXS255), localized to Xp11.22, was only loosely linked to XLRP, whereas pHOC3 (OTC), in the more distal Xp21.1 region, was tightly linked. In this family, the conditional probability of an RP3 locus (in Xp21.1-p11.4) was found to be 0.978 compared with 0.021 for an RP2 locus (in Xp11.4-p11.2). Risk assessment showed that 2 out of 4 "at risk" females showing no clinical abnormality have a high probability of being genetic carriers of XLRP. Some affected males have recurrent respiratory infections as a result of a condition indistinguishable from the immotile cilia syndrome; indeed, there is an association between XLRP and susceptibility to respiratory infections in the majority of affected males. The possibility that previously observed ciliary abnormalities in XLRP patients might be associated specifically with an RP3 locus abnormality is discussed.
New insights into genetic eye disease.
Most human genetic abnormalities affecting the eye are clinically detectable but, until recently, our knowledge of the genes concerned was sparse. Several genes capable of causing progressive degeneration of the mammalian retina have now been identified by a combination of 'positional cloning' and 'candidate gene' approaches. One of these genes codes for the visual pigment rhodopsin. The identification of two genes (rd and rds) capable of causing retinal degeneration in the mouse has provided candidate genes for similar human disorders.
Effects of angiotensin converting enzyme inhibition in adult polycystic kidney disease.
The pathogenesis of hypertension in autosomal-dominant polycystic kidney disease (ADPKD) is unclear, but increased activity of the renin-angiotension system may contribute. The renal and systemic hemodynamic response to lisinopril, an angiotension converting enzyme (ACE) inhibitor, in patients with ADPKD without renal failure was compared with the response in matched unaffected family members. Mean blood pressure and renal vascular resistance decreased in the affected group after lisinopril, with no significant change in the unaffected group. Glomerular filtration rate (GFR) was unchanged and therefore filtration fraction fell significantly. Changes in urinary excretion of 6-keto-PGF1 alpha and kallikrein suggested that increased renal synthesis of PGI2 or activation of the renal kallikrein-kinin system were not likely to be responsible for the hemodynamic effects. The acute decrease in renal vascular resistance without change in GFR suggests that ACE inhibition may have a particular value in the treatment of hypertension associated with ADPKD which should be assessed by further long-term studies.
The effect of mutation on linkage disequilibrium.
The standard formula for the approach to linkage equilibrium between two diallelic loci, initially at disequilibrium, is expressed in terms of their probability of recombination (Li, 1955). By a simple extension, we show how to incorporate the effects of mutation at one or both loci. It can thereby be inferred that in general these effects are unlikely to be of major importance, contrary to some recent suggestions.
Evidence for linkage disequilibrium between D16S94 and the adult onset polycystic kidney disease (PKD1) gene.
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Multipoint mapping of adult onset polycystic kidney disease (PKD1) on chromosome 16.
Analysis of genetic linkage data in 33 adult onset polycystic kidney (ADPKD) families was carried out using probes for the D16S85, D16S84, and D16S94 loci. The data set of 33 families shows no evidence of genetic heterogeneity since one unlinked family was previously excluded. Two point linkage analysis showed maximum likelihood values of the recombination fraction of 0.07 for ADPKD and D16S85 (lod score 18.78), 0.02 for ADPKD and D16S84 (lod score 7.55), and 0.00 for ADPKD and D16S94 (lod score 6.73). Multipoint analysis showed a maximum likelihood order of tel-D16S85-0.06-D16S84-0.02-(PKD1, D16S94)-cen with a multipoint lod score of 32.16. Analysis of rare recombinants lying close to PKD1 gave results consistent with this order.
Frequency of rhodopsin codon 23 mutation and retinitis pigmentosa.
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