title: Huntington's disease-like phenotype due to trinucleotide repeat expansions in the TBP and JPH3 genes.
abstract: We report a group of 252 patients with a Huntington's disease-like (HDL) phenotype, including 60 with typical Huntington's disease, who had tested negative for pathological expansions in the IT15 gene, the major mutation in Huntington's disease. They were screened for repeat expansions in two other genes involved in HDL phenotypes: those encoding the junctophilin-3 (JPH3/HDL2) and prion (PRNP/HDL1) proteins. In addition, because of the clinical overlap between patients with HDL disease and autosomal dominant cerebellar ataxia or dentatorubral and pallidoluysian atrophy (DRPLA), we investigated trinucleotide repeat expansions in genes encoding the TATA-binding protein (TBP/SCA17) and atrophin-1 (DRPLA). Two patients carried 43 and 50 uninterrupted CTG repeats in the JPH3 gene. Two other patients had 44 and 46 CAA/CAG repeats in the TBP gene. Patients with expansions in the TBP or JPH3 genes had HDL phenotypes indistinguishable from Huntington's disease. Taking into account patients with typical Huntington's disease, their frequencies were evaluated as 3% each in our series of typical HDL patients. Interestingly, incomplete penetrance of the 46 CAA/CAG repeat in the TBP gene was observed in a 59-year-old transmitting, but healthy, parent. Furthermore, we report a new configuration of the expanded TBP allele, with 11 repeats on the first polymorphic stretch of CAGs. Expansions in the DRPLA gene and insertions in the PRNP gene were not found in our group of patients. Further genetic heterogeneity of the HDL phenotype therefore exists.
authors.affiliation: INSERM U289, Hôpital de la Salpêtrière, 47 Bd de l'Hôpital, 75013 Paris, France. brice@ccr.jussieu.fr
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.forename: Hiroto
authors.initials: H
authors.lastname: Fujigasaki
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Lebre
authors.forename: Agnes
authors.initials: A
authors.lastname: Camuzat
authors.forename: Cecile
authors.initials: C
authors.lastname: Jeannequin
authors.forename: Catherine
authors.initials: C
authors.lastname: Dode
authors.forename: Junko
authors.initials: J
authors.lastname: Takahashi
authors.forename: Chankranira
authors.initials: C
authors.lastname: San
authors.forename: Robert
authors.initials: R
authors.lastname: Bellance
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D010641:Phenotype; D016133:Polymerase Chain Reaction / Q000379:methods; D011328:Prions / Q000235:genetics; D035181:TATA-Box Binding Protein / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011328:Prions; D035181:TATA-Box Binding Protein; C095278:atrophin-1; C412507:junctophilin