Two siblings with spondylothoracic dysostosis, and two siblings and three unrelated children with spondylocostal dysostosis are described. Both conditions are inherited and characterised by malformed thoracic and lumbar vertebrae. Spondylothoracic dysostosis produces "crab-like" deformities of the ribs, and is usually fatal during early infancy due to respiratory failure. Spondylocostal dysostosis causes short-trunked dwarfism but does not usually reduce life expectancy. These clinical features are distinct from congenital scoliosis, although all three conditions are associated with a particular group of malformations.

Neurofibromatosis type-1 (NF-1) is an autosomal dominant disorder, caused by mutations in the NF-1 gene. Mutation analysis in the NF-1 gene is complicated by the large size of the gene, the high mutation rate, and the presence of pseudogenes. By means of the polymerase chain reaction, we have amplified 70% of the NF-1 coding sequence using reverse transcribed mRNA and genomic DNA from 25 unrelated Scottish Caucasian patients. We have used chemical mismatch cleavage analysis and direct sequencing of asymmetrically amplifed PCR products to characterise mutations within the NF-1 gene. Using the above strategy, we detected 10 novel mutations and an intragenic polymorphism with a heterozygosity of approximately 47% in the Scottish population. Of the 10 mutations, 7 are potentially disease causing. They include splice site errors responsible for exon skipping (1721 + 3A to G) and (5749 + 2T to G), small insertions (7485insGG) and (6519insG), a nonsense mutation (R2496X), and missense and silent mutations (G1166D, K1419R, G1404G, S1311S, N1776N). A correlation of the phenotype with the genotype is presented. Thus, in this study we have identified a heterogeneous group of germline mutations, the majority of which are predicted to cause disruption of the protein product, neurofibromin. This approach has therefore proved to be useful for the detection of mutations in the gene for neurofibromatosis type-1, and can be applied to detection of molecular pathologies in general.

We have studied the porphobilinogen deaminase gene transcripts from seven unrelated patients from the West of Scotland, all suffering from acute intermittent porphyria. This was achieved by reverse transcription and PCR amplification of mRNA followed by asymmetric amplification and direct sequencing. Five novel and two previously described mutations were identified and found to be single base substitutions. Of the five novel mutations, three were missense (R116Q, T2691, G274R) and two were nonsense (Q204 Stop, W283 Stop). Using Escherichia coli PBGD as a model, it is possible to predict and explain the deleterious effects that these mutations might have on the function and structure of the enzyme.

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The gene for human mineralocorticoid receptor (hMR), previously mapped to chromosome 4, has been further localized to 4q31.1 by in situ hybridization using a biotinylated 3.75 kb human cDNA clone encoding the primary amino acid sequence of hMR as a probe. Preliminary comparative mapping studies in orangutan (Pongo pygmaeus) suggest localization of the probe to the long arm of chromosome 3.