Knockout of the trcp3 gene causes a recessive neuromotor disease in mice.

Delta202 mice carry a transgene encoding the SV40 T antigen. Mice homozygous for the transgene develop paralysis and atrophy starting at week 4 and die around week 12. To determine the molecular basis of the neurological syndrome, we identified the transgene insertion site by sequencing two successive nested PCR products amplified with reverse primers from circularized Delta202 mouse DNA fragments generated through XbaI digestion. From the cloned products a consensus 542 bp sequence was obtained, with 409 bp corresponding to the transgene ends surrounding a 133 bp sequence formed by a left 128 bp segment and a right 8 bp segment. The 128 bp sequence matched the chr3:36811347-364811421 sequence corresponding to the promoter region of the trpc3 gene between nucleotides -54 and -53 from the transcriptional start point (+1). Complementary DNA amplification from total brain RNA demonstrated a lack of TRPC3 transcripts in Delta202 mouse brain. The neurologic syndrome of Delta202 mice thus appears to be a monogenic recessive neuromotor disease caused by interruption of the trpc3 gene promoter due to the transgene insertion which in turn blocks the transcription and knocks out TRPC3 calcium channels leading to a failure in the postnatal development of the central nervous system.