1. Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy.
- Author
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Strømme P, Mangelsdorf ME, Shaw MA, Lower KM, Lewis SM, Bruyere H, Lütcherath V, Gedeon AK, Wallace RH, Scheffer IE, Turner G, Partington M, Frints SG, Fryns JP, Sutherland GR, Mulley JC, and Gécz J
- Subjects
- Amino Acid Sequence, Animals, Family Health, Female, Haplotypes, Humans, Male, Mice, Models, Genetic, Molecular Sequence Data, Mutation, Missense, Nucleic Acid Hybridization, Pedigree, Poly A genetics, Sequence Homology, Amino Acid, Tissue Distribution, Transcription, Genetic, Drosophila Proteins genetics, Epilepsy genetics, Intellectual Disability genetics, Mutation, X Chromosome
- Abstract
Mental retardation and epilepsy often occur together. They are both heterogeneous conditions with acquired and genetic causes. Where causes are primarily genetic, major advances have been made in unraveling their molecular basis. The human X chromosome alone is estimated to harbor more than 100 genes that, when mutated, cause mental retardation. At least eight autosomal genes involved in idiopathic epilepsy have been identified, and many more have been implicated in conditions where epilepsy is a feature. We have identified mutations in an X chromosome-linked, Aristaless-related, homeobox gene (ARX), in nine families with mental retardation (syndromic and nonspecific), various forms of epilepsy, including infantile spasms and myoclonic seizures, and dystonia. Two recurrent mutations, present in seven families, result in expansion of polyalanine tracts of the ARX protein. These probably cause protein aggregation, similar to other polyalanine and polyglutamine disorders. In addition, we have identified a missense mutation within the ARX homeodomain and a truncation mutation. Thus, it would seem that mutation of ARX is a major contributor to X-linked mental retardation and epilepsy.
- Published
- 2002
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