Dominance and homozygosity.
Because of the high consanguinity rates in many communities in Israel we had the opportunity to study homozygosity for some dominant disorders. This experience and a review confirmed that in most cases homozygotes of dominant disorders are more severely affected than heterozygotes. In some cases molecular analysis allowed an understanding of the mechanisms involved. While heterozygosity for point mutations or deletions of PAX3 lead to similar manifestations (Waardenburg syndrome), in homozygotes the phenotype is much more severe, probably in direct relation to the loss of function. Charcot-Marie-Tooth 1A is caused by a duplication of PMP22 and further over-expression lead to a more severe disorder. In diseases in which the mutation leads to an abnormal structural protein, the homozygote may be as severely affected as the heterozygote (epidermolysis bullosa simplex) or more severely (achondroplasia, Marfan syndrome). The polyglutamine tract is translated in disorders caused by CAG triplet expansions. In homozygotes for Machado-Joseph disease the onset is earlier and the symptoms are more severe than in heterozygotes, while in Huntington disease homozygotes are affected like heterozygotes.
Zlotogora
J
J
Rosa and David Orzen Human Genetics Clinic, Department of Human Genetics, Hadassah Medical Center, Hebrew University, Jerusalem, Israel.
D000130:Achondroplasia / Q000235:genetics; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D016110:Epidermolysis Bullosa Simplex / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006816:Huntington Disease / Q000235:genetics; D017827:Machado-Joseph Disease / Q000235:genetics; D008297:Male; D008382:Marfan Syndrome / Q000235:genetics; D005810:Multigene Family; D009154:Mutation; D009223:Myotonic Dystrophy / Q000235:genetics; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D014157:Transcription Factors; D014849:Waardenburg Syndrome / Q000235:genetics
D004268:DNA-Binding Proteins; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D014157:Transcription Factors; C068686:Pax3 protein, mouse