Disruption of a novel gene (IMMP2L) by a breakpoint in 7q31 associated with Tourette syndrome

Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder characterized by multiple motor and phonic tics. We identified a male pati ent with GTS and other anomalies. It was determined that he carried a de no vo duplication of the long arm of chromosome 7 [46,XY,dup(7)(q22.1-q31.1)]. Further molecular analysis revealed that the duplication was inverted. The distal chromosomal breakpoint occurred between the two genetic markers D7S 515 and D7S522, which define a region previously shown to be disrupted in a familiar case of GTS. Yeast and bacterial artificial chromosome clones spa nning the breakpoints were identified by means of FISH analysis. To further characterize the distal breakpoint for a role in GTS, we performed Souther n blot hybridization analysis and identified a 6.5-kb SacI junction fragmen t in the patient's genomic DNA. The DNA sequence of this fragment revealed two different breaks in 7q31 within a region of similar to 500 kb. IMMP2L, a novel gene coding for the apparent human homologue of the yeast mitochond rial inner membrane peptidase subunit 2, was found to be disrupted by both the breakpoint in the duplicated fragment and the insertion site in 7q31. T he cDNA of the human IMMP2L gene was cloned, and analysis of the complete 1 ,522-bp transcript revealed that it encompassed six exons spanning 860 kb. The possible role of IMMP2L and several other candidate genes within the re gion of chromosomal rearrangement, including NRCAM, Leu-Rch Rep, and Reelin , is discussed. The 7q31 breakpoint interval has also been implicated in ot her neuropsychiatric diseases that demonstrate some clinical overlap with G TS, including autism and speech-language disorder.