GENOMIC SEQUENCE OF THE DAX1 GENE - AN ORPHAN NUCLEAR RECEPTOR RESPONSIBLE FOR X-LINKED ADRENAL HYPOPLASIA CONGENITA AND HYPOGONADOTROPIC HYPOGONADISM

The gene responsible for X-linked adrenal hypoplasia congenita, DAX1, encodes a member of the nuclear hormone receptor superfamily. We seque nced 8851 bp that contained the DAX1 genomic region. The DAX gene was composed of two exons and one 3.4-kilobase intron. Putative TATA and G C boxes and a putative steroidogenic factor 1 response element were pr esent in the 5'-flanking region. Two potentially polymorphic short tan dem repeats were identified. The first exon encoded two putative novel zinc finger motifs within a putative DNA binding domain and part of t he ligand binding domain, and the second exon encoded the remainder of the ligand binding domain. Although the putative DNA binding domain o f DAX1 does not contain substantial sequence similarity to other nucle ar hormone receptor superfamily members, the putative ligand binding d omain had remarkable similarity to other family members. Single-strand conformational polymorphism analysis permitted identification of thre e new mutations in DAX1. In conclusion, single-strand conformational p olymorphism analysis facilitates identification of mutations in the DA X1 gene, and the short tandem repeats may permit linkage analysis in f amilies in which mutations are not yet identified. We speculate that D AX1 may be the most primitive member of the nuclear hormone receptor s uperfamily identified in mammals.