Disruption of a Novel Gene (IMMP2L) by a Breakpoint in 7q31 Associated with Tourette Syndrome

Abstract

Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder characterized by multiple motor and phonic tics. We identified a male patient with GTS and other anomalies. It was determined that he carried a de novo 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 D7S515 and D7S522, which define a region previously shown to be disrupted in a familiar case of GTS. Yeast and bacterial artificial chromosome clones spanning the breakpoints were identified by means of FISH analysis. To further characterize the distal breakpoint for a role in GTS, we performed Southern blot hybridization analysis and identified a 6.5-kb SacI junction fragment in the patient's genomic DNA. The DNA sequence of this fragment revealed two different breaks in 7q31 within a region of approximately 500 kb. IMMP2L, a novel gene coding for the apparent human homologue of the yeast mitochondrial inner membrane peptidase subunit 2, was found to be disrupted by both the breakpoint in the duplicated fragment and the insertion site in 7q31. The 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 region of chromosomal rearrangement, including NRCAM, Leu-Rch Rep, and Reelin, is discussed. The 7q31 breakpoint interval has also been implicated in other neuropsychiatric diseases that demonstrate some clinical overlap with GTS, including autism and speech-language disorder.

Intragenic deletions affecting two alternative transcripts of the IMMP2L gene in patients with Tourette syndrome

“…7 On the other hand, we could amplify the entire NM_001244606.1 transcript and we showed that this transcript had two 5 0 non-coding exons of 54 and 74 bp (designated exon 1a and 1b, respectively). Throughout the text we use NM_001244606.1 as the long IMMP2L transcript.…”

“…6 In 2001, a boy with a de novo inverted duplication, dup(7)(pter-q31.1::q31.1-q22.1::q31.1-qter), presenting with vocal and motor tics was reported. 7,8 The 7q31 breakpoint was within the region described by Boghosian-Sell and colleagues 6 and disrupted a novel gene, IMMP2L. 7 These two studies implicated 7q31 as a candidate TS region.…”

“…7,8 The 7q31 breakpoint was within the region described by Boghosian-Sell and colleagues 6 and disrupted a novel gene, IMMP2L. 7 These two studies implicated 7q31 as a candidate TS region. Subsequently, a familybased association study was performed in a cohort of FrenchCanadian patients from Quebec, and a biased transmission of alleles from heterozygote parents to their TS offspring was found for markers D7S522, D7S523 and D7S1516 (located within IMMP2L).…”

“…IMMP2L is expressed in a wide range of tissues including the fetal and adult brain, but not in the adult liver and lung. 7 Mammalian IMMP1L and IMMP2L constitute, like the yeast Imp1 and Imp2, the subunits in the inner membrane peptidase complex, which catalyze the removal of the signal peptides required for the targeting of proteins from the mitochondrial matrix into the intermembrane space across the inner membrane. 12 The two subunits share a conserved core and they are both catalytically active, but process different substrates.…”

Translocation breakpoint at 7q31 associated with tics: further evidence for IMMP2L as a candidate gene for Tourette syndrome

“…Further studies identified that a novel gene, IMMP2L (MIM 605977), was interrupted by both the breakpoint in the duplicated fragment and the insertion site in 7q31. 7 We describe the detailed molecular genetic analysis of an 18-yearold boy with a de novo translocation t(2;7)(p24.2;q31) who developed motor tics at the age of 13 years and has significant speech and language impairment. The breakpoints are further characterised and the IMMP2L gene is found to be disrupted and partially deleted by the translocation, along with a cryptic 7.2-Mb deletion involving a number of genes.…”