title: Two Italian families with ITPR1 gene deletion presenting a broader phenotype of SCA15.
abstract: Spinocerebellar ataxia type15 (SCA15) is a pure ataxia characterized by very slow progression. Only seven families have been identified worldwide, in which partial deletions and a missense mutation of the inositol triphosphate receptor type I gene (ITPR1) have been reported. We examined a four-generation Italian family segregating an autosomal dominant cerebellar ataxia, in which linkage analysis was positive for the SCA15 locus. We performed a genomic real-time polymerase chain reaction to search for ITPR1 gene deletions in this family and in 60 SCA index cases negative for mutations in the SCA1-3, 6-8, 10, 12,and dentatorubral-pallidoluysian atrophy genes. The deleted segments were characterized using a custom array comparative genomic hybridization analysis. We have identified two families with an ITPR1 gene deletion: in one, the deletion involved ITPR1 only, while in the other both sulfatase-modifying factor 1 and ITPR1. Clinical data of ten patients and brain MRI (available for six) showed that the phenotype substantially overlapped known SCA15 cases,but we also noted buccolingual dyskinesias, facial myokymias,and pyramidal signs never reported in SCA15. ITPR1 expression analysis of two deleted cases showed a half dose. Our results further support ITPR1 gene as causative of SCA15. The families reported show that SCA15 is present in Italy and has a greater variability in the age at onset and clinical features than previously reported. We propose that the search for ITPR1 deletions is mandatory in the clinical hypothesis of SCA15 and that ITPR1-reduced expression in blood may be a useful marker to identify SCA15 patients harboring genomic deletions and possibly point mutations causing reduction of mRNA level.
authors.affiliation: A.O.U. San Giovanni Battista, S.C.D.U. Medical Genetics, Department of Genetics, Biology, and Biochemistry, University of Turin, Turin, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Di Gregorio
authors.forename: Laura
authors.initials: L
authors.lastname: Orsi
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Godani
authors.forename: Giovanna
authors.initials: G
authors.lastname: Vaula
authors.forename: Stella
authors.initials: S
authors.lastname: Jensen
authors.forename: Eric
authors.initials: E
authors.lastname: Salmon
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Ferrari
authors.forename: Stefania
authors.initials: S
authors.lastname: Squadrone
authors.forename: Maria Cesarina
authors.initials: MC
authors.lastname: Abete
authors.forename: Claudia
authors.initials: C
authors.lastname: Cagnoli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Brussino
authors.forename: Alfredo
authors.initials: A
authors.lastname: Brusco
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D004252:DNA Mutational Analysis; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics*; D007558:Italy; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology*; D055815:Young Adult
chemical_list: D005819:Genetic Markers; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger