The TALE homeodomain of PBX1 is involved in human primary testis-determination

Hum Mutat. 2019 Aug;40(8):1071-1076. doi: 10.1002/humu.23780. Epub 2019 May 21.

Abstract

Human sex-determination is a poorly understood genetic process, where gonad development depends on a cell fate decision that occurs in a somatic cell to commit to Sertoli (male) or granulosa (female) cells. A lack of testis-determination in the human results in 46,XY gonadal dysgenesis. A minority of these cases is explained by mutations in genes known to be involved in sex-determination. Here, we identified a de novo missense mutation, p.Arg235Gln in the highly conserved TALE homeodomain of the transcription factor Pre-B-Cell Leukemia Transcription Factor 1 (PBX1) in a child with 46,XY gonadal dysgenesis and radiocubital synostosis. This mutation, within the nuclear localization signal of the protein, modifies the ability of the PBX1 protein to localize to the nucleus. The mutation abolishes the physical interaction of PBX1 with two proteins known to be involved in testis-determination, CBX2 and EMX2. These results provide a mechanism whereby this mutation results specifically in the absence of testis-determination.

Keywords: TALE homeodomain; disorders of sex-development; gonadal dysgenesis; pre-B-cell leukemia transcription factor 1 (PBX1); sex-determination.

Publication types

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

MeSH terms

  • Female
  • Gonadal Dysgenesis, 46,XY / genetics*
  • HEK293 Cells
  • Homeodomain Proteins / metabolism
  • Humans
  • Models, Molecular
  • Mutation, Missense*
  • Nuclear Localization Signals
  • Polycomb Repressive Complex 1 / metabolism
  • Pre-B-Cell Leukemia Transcription Factor 1 / chemistry
  • Pre-B-Cell Leukemia Transcription Factor 1 / genetics*
  • Pre-B-Cell Leukemia Transcription Factor 1 / metabolism
  • Sex Determination Processes
  • Synostosis / genetics*
  • Transcription Factors / metabolism

Substances

  • CBX2 protein, human
  • HOXB8 protein, human
  • Homeodomain Proteins
  • Nuclear Localization Signals
  • Pre-B-Cell Leukemia Transcription Factor 1
  • Transcription Factors
  • empty spiracles homeobox proteins
  • PBX1 protein, human
  • Polycomb Repressive Complex 1