Background: Identifying the genetic factors that contribute to memory and lea rning is limited by the complexity of brain development and the lack of suitable human models for mild disorders of cognition. Methods: Pre...Background: Identifying the genetic factors that contribute to memory and lea rning is limited by the complexity of brain development and the lack of suitable human models for mild disorders of cognition. Methods: Previously, a disease lo cus was mapped for a mild type of nonsyndromic mental retardation (IQ between 50 and 70) to a 4.2-MB interval on chromosome 3p25-pter in a large kindred. Th e genes and transcripts within the candidate region were systematically analyzed for mutations by single-strand polymorphism analysis and DNA sequencing. Resu lts: A nonsense mutation causing a premature stop codon in a novel gene (cereblo n; CRBN) was identified that encodes for an ATP-dependent Lon protease. The pr edicted protein sequence is highly conserved across species, and it belongs to a family of proteins that selectively degrade short-lived polypeptides and regu late mitochondrial replication and transcription. One member of the Lon-contai ning protein family is regionally expressed in the human hippocampus, an importa nt neuroanatomic region that is involved in long-term potentiation and learnin g. The mutation in the CRBN gene described interrupts an N-myristoylation site and eliminates a casein kinase II phosphorylation site at the C terminus. Concl usions: A gene on chromosome 3p that is associated with mild mental retardation in a large kindred is reported. This finding implicates a role for the ATP-dep endent degradation of proteins in memory and learning.展开更多
文摘Background: Identifying the genetic factors that contribute to memory and lea rning is limited by the complexity of brain development and the lack of suitable human models for mild disorders of cognition. Methods: Previously, a disease lo cus was mapped for a mild type of nonsyndromic mental retardation (IQ between 50 and 70) to a 4.2-MB interval on chromosome 3p25-pter in a large kindred. Th e genes and transcripts within the candidate region were systematically analyzed for mutations by single-strand polymorphism analysis and DNA sequencing. Resu lts: A nonsense mutation causing a premature stop codon in a novel gene (cereblo n; CRBN) was identified that encodes for an ATP-dependent Lon protease. The pr edicted protein sequence is highly conserved across species, and it belongs to a family of proteins that selectively degrade short-lived polypeptides and regu late mitochondrial replication and transcription. One member of the Lon-contai ning protein family is regionally expressed in the human hippocampus, an importa nt neuroanatomic region that is involved in long-term potentiation and learnin g. The mutation in the CRBN gene described interrupts an N-myristoylation site and eliminates a casein kinase II phosphorylation site at the C terminus. Concl usions: A gene on chromosome 3p that is associated with mild mental retardation in a large kindred is reported. This finding implicates a role for the ATP-dep endent degradation of proteins in memory and learning.
