The Rogdi knockout mouse is a model for Kohlschütter–Tönz syndrome

Kohlschütter–Tönz syndrome (KTS) is a rare autosomal recessive disorder characterized by severe intellectual disability, early-onset epileptic seizures, and amelogenesis imperfecta. Here, we present a novel Rogdi mutant mouse deleting exons 6–11- a mutation found in KTS patients disabling ROGDI function. This Rogdi −/− mutant model recapitulates most KTS symptoms. Mutants displayed pentylenetetrazol-induced seizures, confirming epilepsy susceptibility. Spontaneous locomotion and circadian activity tests demonstrate Rogdi mutant hyperactivity mirroring patient spasticity. Object recognition impairment indicates memory deficits. Rogdi −/− mutant enamel was markedly less mature. Scanning electron microscopy confirmed its hypomineralized/hypomature crystallization, as well as its low mineral content. Transcriptomic RNA sequencing of postnatal day 5 lower incisors showed downregulated enamel matrix proteins Enam, Amelx, and Ambn . Enamel crystallization appears highly pH-dependent, cycling between an acidic and neutral pH during enamel maturation. Rogdi −/− teeth exhibit no signs of cyclic dental acidification. Additionally, expression changes in Wdr72 , Slc9a3r2 , and Atp6v0c were identified as potential contributors to these tooth acidification abnormalities. These proteins interact through the acidifying V-ATPase complex. Here, we present the Rogdi −/− mutant as a novel model to partially decipher KTS pathophysiology. Rogdi −/− mutant defects in acidification might explain the unusual combination of enamel and rare neurological disease symptoms.