Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans

Nat Genet. 2002 Nov;32(3):359-69. doi: 10.1038/ng1009. Epub 2002 Oct 15.

Abstract

Male embryonic mice with mutations in the X-linked aristaless-related homeobox gene (Arx) developed with small brains due to suppressed proliferation and regional deficiencies in the forebrain. These mice also showed aberrant migration and differentiation of interneurons containing gamma-aminobutyric acid (GABAergic interneurons) in the ganglionic eminence and neocortex as well as abnormal testicular differentiation. These characteristics recapitulate some of the clinical features of X-linked lissencephaly with abnormal genitalia (XLAG) in humans. We found multiple loss-of-function mutations in ARX in individuals affected with XLAG and in some female relatives, and conclude that mutation of ARX causes XLAG. The present report is, to our knowledge, the first to use phenotypic analysis of a knockout mouse to identify a gene associated with an X-linked human brain malformation.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • Base Sequence
  • Brain / abnormalities
  • Brain / pathology
  • Bromodeoxyuridine / pharmacology
  • Cell Differentiation
  • Cell Division
  • Cell Movement
  • DNA, Complementary / metabolism
  • Epithelial Cells / metabolism
  • Genetic Linkage*
  • Genetic Vectors
  • Genitalia / abnormalities*
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / physiology*
  • Humans
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Knockout
  • Microscopy, Fluorescence
  • Models, Genetic
  • Molecular Sequence Data
  • Mutation*
  • Neurons / metabolism
  • Neurons / pathology
  • Phenotype
  • Prosencephalon / abnormalities*
  • Syndrome
  • Testis / abnormalities*
  • Testis / pathology
  • Transcription Factors / genetics*
  • Transcription Factors / physiology*
  • Transfection
  • X Chromosome / genetics*

Substances

  • ARX protein, human
  • ARX protein, mouse
  • DNA, Complementary
  • Homeodomain Proteins
  • Transcription Factors
  • Bromodeoxyuridine

Associated data

  • GENBANK/AB006103
  • GENBANK/AC002504
  • GENBANK/AY038071