Genetic investigations of four neurological disorders : From phenotype to mutation

Abstract: More than 5000, more or less rare, genetic diseases are known in man. A genetic disease is in most casesinherited from one generation to the next, and is caused by a change in the genetic code, a mutation.Once a disease gene is identified, the function of the gene and the mechanism underlying the diseasewill be better understood, allowing development of better therapeutic strategies (pharmacology andgene therapy).Hyperkalaemic periodic paralysis (hyperPP) is an autosomal dominant disorder characterised bytransient attacks of muscle weakness or paralysis. Two Swedish pedigrees with hyperPP showedlinkage to the gene encoding the adult skeletal muscle sodium alpha subunit channel (SCN4A). Anexchange of C2188 to T was found in the two pedigrees, resulting in a substitution of methionine forthreonine.Hypokalaemic periodic paralysis (hypoPP) is more common than the phenotypically relatedhyperPP. Thirteen families of Scandinavian origin were analysed and linkage was established to thegene for skeletal muscle calcium alpha subunit gene (CACNL1A3). Mutations were subsequentlyidentified in the patients. In all nine Danish families and in one Finnish family, a base pair substitutionwas observed, resulting in an amino acid change from arginine to histidine at position 528 in theprotein. In the remaining families, two Finnish and one Norwegian, a mutation causing replacementof arginine 1239 by histidine was found.Sjögren-Larsson syndrome (SLS) is an autosomal recessive disorder characterised by mentalretardation, spastic di- or tetraplegia and congenital ichthyosis. By linkage analysis the SLS gene wasmapped to chromosome 17. A better genetic map of the region was established through three differentmethods: 1) by analysis of new microsatellite markers, 2) by analysis of a radiation hybrid panel to getan inter-marker order and 3) by analysis of YAC clones. Because of a founder effect, SLS is morecommon in the northern part of Sweden than in the rest of the world. The majority of Swedish SLSpatients were found to have a mutation in the seventh exon of the FALDH gene, the C943T mutation.This base pair substitution results in an amino acid change. Further mutations found in the remainingSwedish patients and in non-Swedish patients were four more amino acid changes, five mutationsresulting in a prematurely terminated protein and one combined deletion and insertion of bases,resulting in an insertion of six amino acids.A boy with multiple anomalies, including severe mental retardation, stenosis of the left bronchi,hirsutism and epilepsy, was analysed for chromosomal rearrangements. His karyotype showed additionof chromosomal material on one of his chromosome 1. Using fluorescence in situ hybridisation (FISH)with a chromosome 1 specific probe it was demonstrated that the extra material originated fromchromosome 1. Cosmids distributed over the long arm of chromosome 1 were used as probes toidentify the duplicated regions. It was shown that the mutation giving the boy his phenotype was aduplication of the chromosome bands 1q31 -q41.