Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion.
Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a CAG repeat expansion that lengthens a glutamine segment in the novel huntingtin protein. To elucidate the molecular basis of HD, we extended the polyglutamine tract of the mouse homologue, Hdh, by targetted introduction of an expanded human HD CAG repeat, creating mutant HdhneoQ50 and HdhQ50 alleles that express reduced and wild-type levels of altered huntingtin, respectively. Mice homozygous for reduced levels displayed characteristic aberrant brain development and perinatal lethality, indicating a critical function for Hdh in neurogenesis. However, mice with normal levels of mutant huntingtin did not display these abnormalities, indicating that the expanded CAG repeat does not eliminate or detectably impair huntingtin's neurogenic function. Thus, the HD defect in man does not mimic complete or partial Hdh inactivation and appears to cause neurodegenerative disease by a gain-of-function mechanism.
White
J K
JK
Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown 02129, USA.
Auerbach
W
W
Duyao
M P
MP
Vonsattel
J P
JP
Gusella
J F
JF
Joyner
A L
AL
MacDonald
M E
ME
D000483:Alleles; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D005314:Embryonic and Fetal Development / Q000235:genetics; D017353:Gene Deletion; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins