A point mutation at the X-chromosomal proteolipid protein locus in Pelizaeus-Merzbacher disease leads to disruption of myelinogenesis.
A group of inherited neurological disorders are the X-chromosome linked dysmyelinoses, in which myelin membranes of the CNS are missing or perturbed due to a strongly reduced number of differentiated oligodendrocytes. In animal dysmyelinoses (jimpy mouse, msd-mouse, md rat, shaking pup) mutations of the main integral myelin membrane protein, proteolipid protein, have been identified. Pelizaeus-Merzbacher disease (PMD) or sudanophilic leucodystrophy is an X-linked dysmyelinosis in humans. We report here on the molecular basis of the defect of affected males of a PMD kindred. Rearrangements of the PLP gene were excluded by Southern blot hybridisation analysis and PCR amplification of overlapping domains of the PLP gene. Sequence analysis revealed one single C----T transition in exon IV, which leads to a threonine----isoleucine substitution within a hydrophobic intramembrane domain. The impact of this amino-acid exchange on the structure of PLP in the affected cis membrane domain is discussed. A space filling model of this domain suggests a tight packing of the alpha-helices of the loop which is perturbed by the amino-acid substitution in this PMD exon IV mutant. The C----T transition in exon IV abolishes a Hph I restriction site. This mutation at the recognition site for Hph I (RFLP) and allele-specific primers have been used for mutation screening the PMD kindred.
Weimbs
T
T
Institut für Biochemie, Medizinische Fakultät, Universität zu Köln.
Dick
T
T
Stoffel
W
W
Boltshauser
E
E
D001483:Base Sequence; D015139:Blotting, Southern; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000175:diagnosis* / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009185:Myelin Proteins / Q000235:genetics*; D018991:Myelin Proteolipid Protein; D015345:Oligonucleotide Probes; D010375:Pedigree; D016133:Polymerase Chain Reaction / Q000379:methods; D015183:Restriction Mapping; D012729:Sex Chromosome Aberrations; D014960:X Chromosome
D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein; D015345:Oligonucleotide Probes