Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy.
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.
Strømme
Petter
P
Department of Cytogenetics and Molecular Genetics, Women's and Children's Hospital, North Adelaide, South Australia 5006, Australia.
Mangelsdorf
Marie E
ME
Shaw
Marie A
MA
Lower
Karen M
KM
Lewis
Suzanne M E
SM
Bruyere
Helene
H
Lütcherath
Viggo
V
Gedeon
Agi K
AK
Wallace
Robyn H
RH
Scheffer
Ingrid E
IE
Turner
Gillian
G
Partington
Michael
M
Frints
Suzanna G M
SG
Fryns
Jean-Pierre
JP
Sutherland
Grant R
GR
Mulley
John C
JC
Gécz
Jozef
J
D000595:Amino Acid Sequence; D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics*; D005192:Family Health; D005260:Female; D006239:Haplotypes; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D009693:Nucleic Acid Hybridization; D010375:Pedigree; D011061:Poly A / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D014018:Tissue Distribution; D014158:Transcription, Genetic; D014960:X Chromosome
D029721:Drosophila Proteins; C079410:al protein, Drosophila; D011061:Poly A