Genomic cloning and characterization of the human homeobox gene SIX6 reveals a cluster of SIX genes in chromosome 14 and associates SIX6 hemizygositywith bilateral anophthalmia and pituitary anomalies

The Drosophila gene sine oculis (so), a nuclear homeoprotein that is requir ed for eye development, has several homologues in vertebrates (the SLY gene family). Among them, SIX3 is considered to be the functional orthologue of so because it is strongly expressed in the developing eye. However, embryo nic SIX3 expression is not Limited to the eye held, and SIX3 has been found to be mutated in some patients with holoprosencephaly type 2 (HPE2), sugge sting that SIX3 has wide implications in head development. We report here t he cloning and characterization of SIX6, a novel human SLP gene that is the homologue of the chick Six6(Optx2) gene. SIX6 is closely related to SIX3 a nd is expressed in the developing and adult human retina. Data from. chick and mouse suggest that the human SIX6 gene is also expressed in the hypotha lamic and the pituitary regions. SIX6 spans 2567 bp of genomic DNA and is s plit in two exons that are transcribed into a 1393-nucleotide-long mRNA. Ch romosomal mapping of SIX6 revealed that it is closely linked to SIX1 and SI X4 in human chromosome 14q22.3-q23, which provides clues about the origin a nd evolution of the vertebrate SIX family. Recently three independent repor ts have associated interstitial deletions at 14q22.3-q23 with bilateral ano phthalmia and pituitary anomalies. Genomic analyses of one of these cases d emonstrated SIX6 hemizygosity, strongly suggesting that SIX6 haploinsuffici ency is responsible for these developmental disorders. (C) 1999 Academic Pr ess.