SOXopathies: Growing Family of Developmental Disorders Due to SOX Mutations

Abstract

The SRY-related (SOX) transcription factor family pivotally contributes to determining cell fate and identity in many lineages. Since the original discovery that SRY deletions cause sex reversal, mutations in half of the 20 human SOX genes have been associated with rare congenital disorders, henceforward called SOXopathies. Mutations are generally de novo, heterozygous, and inactivating, revealing gene haploinsufficiency, but other types, including duplications, have been reported too. Missense variants primarily target the HMG domain, the SOX hallmark that mediates DNA binding and bending, nuclear trafficking, and protein-protein interactions. We here review key clinical and molecular features of SOXopathies and discuss the prospect that the disease family likely involves more SOX genes and larger clinical and genetic spectrums than currently appreciated.

Keywords: SOX; SRY; developmental disorder; genetic variant; human disease; mutation.

Figure 1.

Timeline of SOXopathy discovery. Cumulative graph showing the numbers of distinct pathogenic alterations identified within and around SOX genes over time. Closed symbols and plain lines represent validated gene-disease associations, whereas open symbols and dotted lines represent suggested associations. Links made through GWAS are not included because of undefined variants and numbers.

Figure 2.

Shared and distinctive features of SOX proteins and genes. A. Alignment of the HMG domain sequences (including 3 flanking residues on each side) of the human HMGB and TCF/LEF proteins with those of a few SOX proteins (top) and all human SOX proteins (bottom) highlights full conservation (greyish blue) and semi-conservation (cyan blue) of specific residues. Residues involved in DNA binding, DNA bending, α-helices, nuclear localization signals (NLS), and nuclear export signal (NES) are indicated. B. 3D solution NMR structure of the human SRY HMG domain complexed to DNA shows that the HMG domain is characterized by three α-helices (H1 to H3 from the N- to the C-terminus) that position themselves into an L-shape, contact DNA exclusively in the minor groove, and force bending of the DNA helix. This schematic was generated by SWISS-MODEL according to [94]. C. Domain structure organization of the human SOX proteins. HMG, HMG domain; TAD, transactivation domain; TRD, transrepression domain; DIM, homodimerization domain; cc, coiled coil; TAM, middle transactivation domain; TAC, C-terminal transactivation domain; PQA, PQA-rich domain. D. Chromosomal distribution of the human SOX genes.

Figure 3.

Examples of key roles of SOX genes in development derived primarily from experiments in vitro and in animal models. Drawings were created using BioRender.

Figure I.

Types and distributions of pathogenic mutations in the SOX9 locus. A) SOX9 locus and flanking genes on 17q24.3, including enhancers primarily active in chondrocytes (Ch^Enh, green bars), Sertoli cells (Tes^Enh, blue bars), embryonic mandibular region (PRS^Enh, light green bars) and other cell types/tissues (brown bars); microdeletions causing Pierre Robin sequence (PRS^Δ) and XY sex reversal (XYSR^Δ); a duplication causing XX sex reversal (RevSex^Δ); and translocations causing campomelic dysplasia (dark green arrows), acampomelic dysplasia (lighter green arrows), Pierre Robin sequence (light green arrows), XY or XX sex reversal (blue arrows), or skeletal dysplasia and XY sex reversal (teal arrows). B) SOX9 exon/intron and protein structures, including pathogenic microdeletions (del) and nonsense variants (*), frameshift variants (fs) and missense and splice variants (Δ).