A novel mutation in the proteolipid protein gene leading to Pelizaeus-Merzbacher disease.

Point mutations of the gene of human proteolipid protein (PLP) have been recognized as the molecular basis of one form of leukodystrophy, the X-chromosome-linked Pelizaeus-Merzbacher disease (PMD). We report the molecular analysis of four PMD patients in three unrelated families and describe a point mutation (G-->A transition) in exon V which leads to the substitution of Gly216 by a serine residue in a highly conserved extracytosolic domain and a Mae I RFLP. Molecular modelling with energy minimization indicates that this seemingly minor alteration of the amino-acid sequence induces a considerable conformational change and tight packing of the polypeptide chain apparently not compatible with the regular PLP function in oligodendrocytes. This mutation has been detected and characterized by PCR amplification of genomic DNA using intron and exon primers and the complete sequence analysis of the seven exons and a 300 bp promoter region of the PLP gene of two affected brothers. The sequence analysis of a PCR fragment representing exon V amplified from genomic DNA of different kindreds of the pedigree revealed the mother as the only carrier indicating that the mutation has occurred de novo in the mother's germline. PLP gene (including the 8.8 kb intron I) rearrangements have been excluded by Southern blot hybridization and overlapping PCR amplification of genomic DNA

Genetic linkage studies in Alzheimer's disease families

Alzheimer's disease is a devastating neurological disorder and the leading cause of dementia among the elderly. Recent studies have localized the gene for familial Alzheimer's disease to chromosome 21 in a series of early onset AD families (mean age of onset 60) is a more common clinical form of the disorder. Thirteen families with multiply affected Alzheimer's disease family members were identified and sampled. Ten of these families were of the late onset Alzheimer's disease type. Simulation studies were used to evaluate the usefulness of these pedigrees in linkage studies in familial Alzheimer's disease. Linkage studies undertaken to test the localization of both early onset and late onset Alzheimer's disease families to chromosome 21 failed to establish linkage and excluded linkage from a large portion of the region where the early onset Alzheimer's disease gene was localized. These findings suggest that more than one etiology may exist for familial Alzheimer's disease and indicate the need for continued screening of the genome in familial Alzheimer's disease families