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


Eozenou, Caroline; Bashamboo, Anu; Bignon-Topalovic, Joelle; Merel, Tiphanie; Zwermann, Oliver; Lourenco, Diana; Lottmann, Henri; Lichtenauer, Urs; Rojo, Sandra; Beuschlein, Felix; McElreavey, Ken; Brauner, Raja (2019). The TALE homeodomain of PBX1 is involved in human primary testis-determination. Human Mutation, 40(8):1071-1076.

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.

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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Endocrinology and Diabetology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:August 2019
Deposited On:05 Jul 2019 11:57
Last Modified:25 Sep 2019 00:37
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1059-7794
OA Status:Closed
Publisher DOI:https://doi.org/10.1002/humu.23780
PubMed ID:31058389

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