Faculty Bibliography

The DAX1 protein is an orphan nuclear hormone receptor based on sequence similarity in the putative ligand-binding domain (LBD). DAX1 mutations result in X-linked adrenal hypoplasia congenita (AHC). Our objective was to identify DAX1 mutations in a series of families, to determine the types of mutations resulting in AHC and to locate single-amino-acid changes in a DAX1 structural model. The 14 new mutations identified among our 17 families with AHC brought the total number of families with AHC to 48 and the number of reported mutations to 42; 1 family showed gonadal mosaicism. These mutations included 23 frameshift, 12 nonsense, and six missense mutations and one single-codon deletion. We mapped the seven single-amino-acid changes to a homology model constructed by use of the three-dimensional crystal structures of the thyroid-hormone receptor and retinoid X receptor alpha. All single-amino-acid changes mapped to the C-terminal half of the DAX1 protein, in the conserved hydrophobic core of the putative LBD, and none affected residues expected to interact directly with a ligand. We conclude that most genetic alterations in DAX1 are frameshift or nonsense mutations and speculate that the codon deletion and missense mutations give insight into the structure and function of DAX1

A survey of 393 Puerto Rican and 354 non-Hispanic pediatric patients at Beth Israel Hospital, New York, revealed a significantly larger percentage of asthmatic subjects among Puerto Ricans, confirming findings of a study of Puerto Rican adults in New York. Assays of alpha 1-antitrypsin (AAT) concentration and phenotypes in 61 Puerto Rican asthmatic children revealed a significantly larger number with an S or Z variant in AAT phenotype. The AAT concentration was not a significant variable in this relationship, since four of five subjects with intermediate deficient AAT concentrations and a PiM phenotype were among control nonasthmatic Puerto Rican subjects. A family history of asthma was more common among asthmatic than control subjects and was most common for variant AAT phenotypes in either asthmatic or control subjects. We speculate that the S or Z variant of AAT affects the inflammatory response in such a way as to predispose to asthma