A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation.
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Higgins JJ, Pucilowska J, Lombardi RQ, Rooney JP
A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation.
Neurology. 2004 Nov 23;63(10):1927-31.
- PubMed ID
- 15557513 [ View in PubMed]
- Abstract
BACKGROUND: Identifying the genetic factors that contribute to memory and learning is limited by the complexity of brain development and the lack of suitable human models for mild disorders of cognition. METHODS: Previously, a disease locus 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. The genes and transcripts within the candidate region were systematically analyzed for mutations by single-strand polymorphism analysis and DNA sequencing. RESULTS: A nonsense mutation causing a premature stop codon in a novel gene (cereblon; CRBN) was identified that encodes for an ATP-dependent Lon protease. The predicted protein sequence is highly conserved across species, and it belongs to a family of proteins that selectively degrade short-lived polypeptides and regulate mitochondrial replication and transcription. One member of the Lon-containing protein family is regionally expressed in the human hippocampus, an important neuroanatomic region that is involved in long-term potentiation and learning. The mutation in the CRBN gene described interrupts an N-myristoylation site and eliminates a casein kinase II phosphorylation site at the C terminus. CONCLUSIONS: 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-dependent degradation of proteins in memory and learning.