Molecular genetic analysis of a de novo balanced translocation t(6;17)(p21.31;q11.2) associated with hypospadias and anorectal malformation

Hum Genet. 2006 Mar;119(1-2):162-8. doi: 10.1007/s00439-005-0122-9. Epub 2006 Jan 3.

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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics
  • Abnormalities, Multiple / pathology
  • Anal Canal / abnormalities*
  • Base Sequence
  • Child
  • Chromosome Breakage
  • Chromosomes, Human, Pair 17*
  • Chromosomes, Human, Pair 6*
  • Female
  • Gene Expression Profiling
  • Humans
  • Hypospadias / pathology*
  • Male
  • Mutant Chimeric Proteins / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rectum / abnormalities*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Translocation, Genetic / genetics*

Substances

  • Mutant Chimeric Proteins
  • RNA, Messenger