Changes in primary DNA sequence complexity influence the phenotypic consequences of mutations in human gene regulatory regions.

No general rules have been proposed to account for the functional consequences of gene regulatory mutations. In a first attempt to establish the nature of such rules, an analysis was performed of the DNA sequence context of 153 different single base-pair substitutions in the regulatory regions of 65 different human genes underlying inherited disease. Use of a recently proposed measure of DNA sequence complexity (taking into account the level of structural repetitiveness of a DNA sequence, rather than simply the oligonucleotide composition) has served to demonstrate that the concomitant change in local DNA sequence complexity surrounding a substituted nucleotide is related to the likelihood of a regulatory mutation coming to clinical attention. Mutations that led to an increase in complexity exhibited higher odds ratios in favour of pathological consequences than mutations that led to a decrease or left complexity unchanged. This relationship, however, was discernible only for pyrimidine-to-purine transversions. Odds ratios for other types of substitution were not found to be significantly associated with local changes in sequence complexity, even though a trend similar to that observed for Y-->R transversions was also apparent for transitions. These findings suggest that the maintenance of a defined level of DNA sequence complexity, or at least the avoidance of an increase in sequence complexity, is a critical prerequisite for the function of gene regulatory regions.

Human gene mutation database-a biomedical information and research resource.

Although 20 years have elapsed since the first single basepair substitution underlying an inherited disease in humans was characterised at the DNA level, the initiative has only recently been taken to establish central database resources for pathological genetic variants. Disease-associated gene lesions are currently collected and publicised by the Human Gene Mutation Database (HGMD) in Cardiff, locus-specific mutation databases, and to some extent also by the Genome Database (GDB) and Online Mendelian Inheritance in Man (OMIM). To date, HGMD represents the only comprehensive and publicly available database of gene lesions underlying human inherited disease. By July 1999, HGMD contained over 18,000 different mutations from some 900 human genes, the majority being single basepair substitutions. In addition to its potential as an information resource for clinicians and genetic counsellors, HGMD has allowed molecular geneticists to address a variety of biological questions through meta-analysis of the collated data. HGMD also promises to assist research workers in optimising mutation search strategies for a given gene. A questionnaire sent out to, and answered by, the editors of 20 key journals revealed that human genetics journals are increasingly reluctant to publish mutation reports. Electronic data submission and publication facilities are therefore urgently required. The World Wide Web (WWW) provides an excellent medium within which to combine the centralised management of basic mutation data, including rigorous quality control, with the possibility of publishing additional mutation-related information. In response to these needs, HGMD has both instituted a collaboration with Springer-Verlag GmbH, Heidelberg, to potentiate free online submission and electronic publication of human gene mutation data and developed links with the curators of locus-specific mutation databases.

Gout: beyond the stereotype.

Not all gout presents with involvement of the big toe, and not all gout patients are middle-aged men. Chronic gout may mimic rheumatoid arthritis; hyperuricemia may develop in postmenopausal women and in organ transplant recipients who are being treated with immunosuppressive agents. Both classic and nonclassic cases may benefit from new therapeutic agents.

Neighboring-nucleotide effects on the rates of germ-line single-base-pair substitution in human genes.

The spectrum of single-base-pair substitutions logged in The Human Gene Mutation Database (HGMD), comprising 7,271 different lesions in the coding regions of 547 different human genes, was analyzed for nearest-neighbor effects on relative mutation rates. Owing to its retrospective nature, HGMD allows mutation rates to be estimated only in relative terms. Therefore, a novel methodology was devised in order to obtain these estimates in iterative fashion, correcting, at the same time, for the confounding effects of differential codon usage and for the fact that different types of amino acid replacement come to clinical attention with different probabilities. Over and above the hypermutability of CpG dinucleotides, reflected in transition rates five times the base mutation rate, only a subtle and locally confined influence of the surrounding DNA sequence on relative single-base-pair substitution rates was observed, which extended no farther than 2 bp from the substitution site. A disparity between the two DNA strands was evidenced by the fact that, when substitution rates were estimated conditional on the 5' and 3' flanking nucleotides, a significant rate difference emerged for 10 of 96 possible pairs of complementary substitutional events. Mutational bias, favoring substitutions toward flanking bases, a phenomenon reminiscent of misalignment mutagenesis, was apparent and exhibited both directionality and reading-frame sensitivity. No specific preponderance of repeat-sequence motifs was observed in the vicinity of nucleotide substitutions, but a moderate correlation between the relative mutability and thermodynamic stability of DNA triplets emerged, suggesting either inefficient DNA replication in regions of high stability or the transient stabilization of misaligned intermediates.

The human gene mutation database.

The Human Gene Mutation Database (HGMD) represents a comprehensive core collection of data on published germline mutations in nuclear genes underlying human inherited disease. By September 1997, the database contained nearly 12 000 different lesions in a total of 636 different genes, with new entries currently accumulating at a rate of over 2000 per annum. Although originally established for the scientific study of mutational mechanisms in human genes, HGMD has acquired a much broader utility to researchers, physicians and genetic counsellors so that it was made publicly available at http://uwcm.ac.uk/uwcm/mg/hgmd0.html in April 1996. Mutation data in HGMD are accessible on the basis of every gene being allocated one web page per mutation type, if data of that type are present. Meaningful integration with phenotypic, structural and mapping information has been accomplished through bi-directional links between HGMD and both the Genome Database (GDB) and Online Mendelian Inheritance in Man (OMIM), Baltimore, USA. Hypertext links have also been established to Medline abstracts through Entrez , and to a collection of 458 reference cDNA sequences also used for data checking. Being both comprehensive and fully integrated into the existing bioinformatics structures relevant to human genetics, HGMD has established itself as the central core database of inherited human gene mutations.

Calciphylaxis mimicking skin lesions of connective tissue diseases.

Calciphylaxis is a rare condition found in patients with end-stage renal disease and secondary hyperparathyroidism. We describe two cases of prominent cutaneous manifestations of calciphylaxis in which skin lesions were refractory to topical treatments. We also include a brief description of calciphylaxis.

Performance of four computer-based diagnostic systems.

BACKGROUND: Computer-based diagnostic systems are available commercially, but there has been limited evaluation of their performance. We assessed the diagnostic capabilities of four internal medicine diagnostic systems: Dxplain, Iliad, Meditel, and QMR. METHODS: Ten expert clinicians created a set of 105 diagnostically challenging clinical case summaries involving actual patients. Clinical data were entered into each program with the vocabulary provided by the program's developer. Each of the systems produced a ranked list of possible diagnoses for each patient, as did the group of experts. We calculated scores on several performance measures for each computer program. RESULTS: No single computer program scored better than the others on all performance measures. Among all cases and all programs, the proportion of correct diagnoses ranged from 0.52 to 0.71, and the mean proportion of relevant diagnoses ranged from 0.19 to 0.37. On average, less than half the diagnoses on the experts' original list of reasonable diagnoses were suggested by any of the programs. However, each program suggested an average of approximately two additional diagnoses per case that the experts found relevant but had not originally considered. CONCLUSIONS: The results provide a profile of the strengths and limitations of these computer programs. The programs should be used by physicians who can identify and use the relevant information and ignore the irrelevant information that can be produced.

Stimulus repetition rate effect on the auditory brainstem response in systemic lupus erythematosus.

Neuropsychiatric involvement is common in systemic lupus erythematosus (SLE), but, in early half of cases, indications are not present on examination. Auditory brainstem response (ABR) measures using differential stimulus repetition rates have been reported as sensitive indicators of subclinical central nervous system (CNS) disorders associated with SLE. In the present study, ABRs were measured in a group of normal-hearing subjects with SLE, as well as in a group of subject controls. Differences in interpeak latency (IPL) measures obtained using low- and high-stimulus repetition rates did not reach statistical significance (P greater than .05). Clinical utility of ABRs using high- and low-stimulus repetition rates for the identification of occult CNS disorder in patients with SLE was not demonstrated.