Palatal cytosol cortisol-binding protein associated with cleft palate susceptibility and H–2 genotype

Abstract

GENETICALLY different inbred strains of mice have different susceptibilities to the production of cleft palate by a standard dose regimen of corticoids at the critical period during palatal organogenesis¹. Because in target tissues corticoids form a specific cytoplasmic cortisol–receptor complex which interacts with the genome, resulting in activation or depression of transcription^2,3, we have postulated that susceptibility to corticoid-induced cleft palate is mediated by genetic differences in a cytosolic corticoid receptor protein(s) in palatal anlagen⁴. Other studies have suggested that susceptibility to cortisone-induced cleft palate is regulated by genes closely linked to the H–2 locus⁵. We report here that the total level of cytosolic protein binders of ³H-cortisol in maternal and foetal palates on day 11 of gestation correlates with susceptibility to cleft palate and with the H–2 genotype. After separation of macromolecular bound hormone from free hormone on columns of Sephadex G-25 and further separation by microelectrofocusing⁶, only one maternal and foetal palatal cytosol binder for ³H-cortisol (pI 6.9–7.0) was found to correlate with susceptibility to cleft palate and the H–2 genotype. Thus, a product of a gene in or near the H–2 locus seems to be the glucocorticoid receptor, the level of which must be increased for a congenital malformation to occur.