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.
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Acknowledgments
We would like to thank the patient and his family for their contribution to this study. This work was supported by grants from the Swedish Research Council, the Swedish Cancer Society, The Sävstaholm Society, Torsten and Ragnar Söderbergs Fund, the Borgström Foundation and Uppsala University. We would also like to thank Mats Gustafsson, Department of Genetics and Pathology at Uppsala University, for his help with the statistics. The study was approved by the appropriate Swedish review board and an informed consent was obtained.
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Mansouri, M.R., Carlsson, B., Davey, E. et al. Molecular genetic analysis of a de novo balanced translocation t(6;17)(p21.31;q11.2) associated with hypospadias and anorectal malformation. Hum Genet 119, 162–168 (2006). https://doi.org/10.1007/s00439-005-0122-9
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DOI: https://doi.org/10.1007/s00439-005-0122-9