title: Molecular genetic analysis of a de novo balanced translocation t(6;17)(p21.31;q11.2) associated with hypospadias and anorectal malformation.
abstract: We report a young boy with penoscrotal hypospadias, anal atresia (AA) with a recto-urethral fistula, a hypoplastic kidney and a balanced translocation t(6;17)(p21.31;q11.2). Physical mapping of the breakpoints localized the chromosome 6 breakpoint within an intron of the gene lipoma HMGIC fusion partner-like 5 (LHFPL5) whereas the chromosome 17 breakpoint was mapped to the first intron of the 182-FIP gene encoding the Fragile X Mental Retardation Protein Interacting Protein. Sequence analysis across the breakpoints revealed an almost perfectly balanced translocation with a 2 bp deletion on the derivative chromosome 6 and a 7 bp duplication on the derivative chromosome 17. We identified a fusion transcript consisting of the first exon of 182-FIP and the last exon of LHFPL5 in patient-derived cells. Quantitative expression analysis of the genes flanking the breakpoints, revealed increased transcript levels for SFRS protein kinase 1 (SRPK1) and TAO kinase 1 (TAOK1) which suggests a positional effect due to the translocation. We hypothesize that the urogenital and anorectal malformations in the patient result from one or several mechanisms including disruption of the genes 182-FIP and LHFPL5, altered expression of the genes flanking the translocation breakpoints and, a gain of function mechanism mediated by the 182-FIP-LHFPL5 fusion transcript.
authors.affiliation: Department of genetics and pathology, Section of Clinical Genetics The Rudbeck laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Mahmoud Reza
authors.initials: MR
authors.lastname: Mansouri
authors.forename: Birgit
authors.initials: B
authors.lastname: Carlsson
authors.forename: Edward
authors.initials: E
authors.lastname: Davey
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordenskjöld
authors.forename: Tomas
authors.initials: T
authors.lastname: Wester
authors.forename: Göran
authors.initials: G
authors.lastname: Annerén
authors.forename: Göran
authors.initials: G
authors.lastname: Läckgren
authors.forename: Niklas
authors.initials: N
authors.lastname: Dahl
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology; D001003:Anal Canal / Q000002:abnormalities*; D001483:Base Sequence; D002648:Child; D019457:Chromosome Breakage; D002886:Chromosomes, Human, Pair 17; D002896:Chromosomes, Human, Pair 6; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007021:Hypospadias / Q000473:pathology*; D008297:Male; D050506:Mutant Chimeric Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012007:Rectum / Q000002:abnormalities*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: D050506:Mutant Chimeric Proteins; D012333:RNA, Messenger