The Rogdi Knockout Mouse is a Model for Kohlschütter–Tönz Syndrome

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Abstract Kohlschütter–Tönz syndrome (KTS) is a rare autosomal recessive disorder characterized by severe intellectual disability, early-onset epileptic seizures, and amelogenesis imperfecta. Loss of ROGDI expression likely produces these severe patient defects. Here, we present a novel Rogdi mutant mouse demonstrating that Rogdi-/- loss of function recapitulates most KTS patient symptoms. Mutants displayed pronounced 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 is highly pH-dependent, as an acidic pH is required to accelerate matrix protein degradation and to promote mineralization. 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.

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