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 a nd a milder syndrome consisting of congenital cataracts and late onset corneal dystrophy. The nonsense mutations, at codons 103 and 353, tru ncate PAX6 within the N-terminal paired and C-terminal PST domains, re spectively. The wild-type PST domain activates transcription autonomou sly 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 mi ce and suggests a critical role for PAX6 in controlling the migration and differentiation of specific neuronal progenitor cells in the brain .