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The TALE homeodomain of PBX1 is involved in human primary testis‐determination
Author(s) -
Eozenou Caroline,
Bashamboo Anu,
BigTopalovic Joelle,
Merel Tiphanie,
Zwermann Oliver,
Lourenco Diana,
Lottmann Henri,
Lichtenauer Urs,
Rojo Sandra,
Beuschlein Felix,
McElreavey Ken,
Brauner Raja
Publication year - 2019
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23780
Subject(s) - biology , emx2 , gonadal dysgenesis , missense mutation , steroidogenic factor 1 , transcription factor , homeobox , somatic cell , mutation , genetics , testis determining factor , gonad , sertoli cell , nuclear protein , gene , microbiology and biotechnology , endocrinology , nuclear receptor , y chromosome , spermatogenesis
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.