Mice that are heterozygous for the targeted mutation are viable and fertile. No gene product (protein) is detected by immunohistochemical analysis of homozygotes. Homozygous females are subfertile, 15-20% of homozygous females can have litters. Homozygotes exhibit impaired circadian rhythm generation, muscle weakness, increased motor activity and increased induced airway hyperresponsiveness and inflammation. In constant darkness, homozygotes initially display shortened circadian period. Some homozygotes develop arrhythmic circadian periods after extended darkness. Heterozygotes also display abnormal circadian rhythm. Homozygotes have both gross and microscopic anatomical abnormalities of the gastrointestinal tract. 10-15% of homozygotes die of stenosis of the gut before one year of age. Male homozygotes exhibit moderate right ventricular (RV) hypertension, RV hypertrophy, thickened and remodeled pulmonary arteries, perivascular inflammation of smaller pulmonary vessels and airways, reduced serum testosterone levels, and reduced serum follicle-stimulating hormone (FSH) levels. Although male homozygotes had early testicular degeneration, age-dependent degeneration is slowed. All offspring of heterozygous females exhibit developmental delays such as reduced body weight and impaired social behavior. This mutant mouse strain may be useful in studies of embryonic and neonatal development, circadian rhythm, airway hyperresponsiveness and inflammation (asthma), gastrointestinal innervation and motility and idiopathic pulmonary arterial hypertension.
