PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects.
The human eye malformation aniridia results from haploinsufficiency of PAX6, a paired box DNA-binding protein. To study this dosage effect, we characterized two PAX6 mutations in a family segregating aniridia and a milder syndrome consisting of congenital cataracts and late onset corneal dystrophy. The nonsense mutations, at codons 103 and 353, truncate PAX6 within the N-terminal paired and C-terminal PST domains, respectively. The wild-type PST domain activates transcription autonomously and the mutant form has partial activity. A compound heterozygote had severe craniofacial and central nervous system defects and no eyes. The pattern of malformations is similar to that in homozygous Sey mice and suggests a critical role for PAX6 in controlling the migration and differentiation of specific neuronal progenitor cells in the brain.
Glaser
T
T
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Jepeal
L
L
Edwards
J G
JG
Young
S R
SR
Favor
J
J
Maas
R L
RL
D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D015783:Aniridia / Q000235:genetics; D000853:Anophthalmos / Q000235:genetics; D001483:Base Sequence; D001921:Brain / Q000002:abnormalities*; D002386:Cataract / Q000151:congenital / Q000235:genetics; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005124:Eye Abnormalities / Q000235:genetics*; D005136:Eye Proteins; D005260:Female; D018398:Homeodomain Proteins; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D010375:Pedigree; D017354:Point Mutation; D012097:Repressor Proteins
D017931:DNA Primers; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D004247:DNA