The TALE homeodomain of PBX1 is involved in human primary 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.

Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1‐related syndrome

“…Interestingly, the second affected sibling (II‐5; 46, XY) presented here showed complete sex reversal of both internal and external organs, without any signs of male gonad development (no streak gonad). In line with earlier reports (Eozenou et al, ; Slavotinek et al, ), the phenotypic heterogeneity among patients carrying the same mutation indicates a limited genotype–phenotype correlation, possibly influenced by factors such as gender, genetic modifiers, or skewed gene expression.…”

“…Genital abnormalities are commonly reported in male patients with PBX1 mutations (10/14), with the phenotypic spectrum ranging from cryptorchidism to partial development of female internal and/or external genitalia (Alankarage et al, ; Eozenou et al, ; Kia et al, ; Riedhammer et al, ; Slavotinek et al, ; Le Tanno et al, ). Interestingly, the second affected sibling (II‐5; 46, XY) presented here showed complete sex reversal of both internal and external organs, without any signs of male gonad development (no streak gonad).…”

“…These include facial dysmorphism, and anatomic abnormalities of the ear, genitalia, heart, and lung. Developmental delay/intellectual disability is common, and growth restriction and hearing loss have also been reported (Table S1; Alankarage et al, ; Eozenou et al, ; Heidet et al, ; Kia, Sarafoglou, Mooganayakanakote Siddappa, & Roberts, ; Riedhammer et al, ; Slavotinek et al, ; Sun et al, ; Le Tanno et al, ). We present two cases of perinatal death, from independent pregnancies in one family, with a recurrent disease‐causing mutation in PBX1 due to paternal mosaicism for the mutation.…”

Disorders of Sex Development—Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation

“…This variant is located in a highly conserved TALE homeodomain of the protein, as opposed to previously described variants that are located in the consensus splice site, potentially explaining the different phenotype [72,73]. In vitro studies of cellular location showed that the mutated p.Arg235Gln PBX1 protein was unable to correctly localize into the nucleus and also had an impaired biological activity, as its physical interaction with two proteins known to be involved in testis determination (EMX2 and CBX2) were abolished [74]. This data suggests that specific variants located in the TALE homeodomain of PBX1 are a novel cause of human 46,XY DSD.…”

“…In humans, deleterious variants involving PBX1 were previously associated with congenital anomalies of the kidney and urinary tract, but not with DSD [72,73]. PBX1 has been implicated in human testicular development after the identification of a single de novo heterozygous variant (p.Arg235Gln) in a 46,XY GD patient with normal kidneys and radiocubital synostosis [74]. This variant is located in a highly conserved TALE homeodomain of the protein, as opposed to previously described variants that are located in the consensus splice site, potentially explaining the different phenotype [72,73].…”