The Adrenocortical Dysplasia (acd) Mouse: Mutation in a Novel Gene Causes a Pleiotropic Phenotype of Urogenital Defects and Caudal Dysgenesis

Abstract

The adrenocortical dysplasia (DW/J‐acd/J) mouse is a spontaneous autosomal recessive mutant with developmental defects in organs derived from the urogenital ridge: the kidneys, gonads, and adrenals. Adrenocortical dysplasia and hypofunction are predominant features in surviving adult mice. Adult female mutant mice exhibit subnormal fertility secondary to an overall decrease in folliculogenesis in the ovary, and males are completely infertile due to germ cell degeneration in the testes. Fifty percent of adult acd mutant mice develop hydronephrosis due to ureteral hyperplasia. On the original genetic background, most mutants die within 1–2 days of life. Analysis of acd mutant embryos on this genetic background reveals variable, yet striking defects in caudal specification, limb patterning, and axial skeletal formation. We have identified a splice donor site mutation in a novel gene (Acd) in acd mutant mice. Characterization of Acd transcripts produced in acd mutant tissues reveals two abnormal transcripts and lack of any detectable normal transcript, consistent with a splicing defect. Expression of a beta‐actin‐driven Acd cDNA transgene rescues the mutant phenotype and provides genetic confirmation of the etiologic role of the Acd gene in the observed adrenal dysplasia. Surprisingly, the Acd gene is the mouse ortholog of a newly discovered telomeric regulator, which has recently been characterized by others as a novel component of the protein complex that controls telomere elongation by telomerase. Further studies are in progress to evaluate for evidence of genomic instability in acd mutant animals and to define the molecular mechanisms leading to urogenital and caudal dysgenesis in acd mutant embryos.

• Mouse
• Adrenal hypoplasia
• Infertility
• Caudal regression
• Telomere
• Genomic instability