Gene of the Month - July: SOX3
Rather than a change in the protein‑coding sequence, it has been identified that an altered three‑dimensional genome architecture at the SOX3 locus, caused by an interchromosomal insertion, is responsible for an X‑linked recessive complex hereditary spastic paraplegia. The authors of a study published in the American Journal of Human Genetics describe a Danish family with six affected males who developed a spastic gait in early childhood and, over time, lost independent ambulation, in some cases accompanied by mild cognitive impairment, and they pinpoint a 149‑kb interchromosomal insertion originating from chromosome 4q24 and landing at Xq27.1 in these individuals.
SOX3 encodes a transcription factor that plays a key role in early nervous system development, in maintaining neural progenitor cells, and in controlling neuronal differentiation. The SOX3 gene lies in a regulatory hotspot at Xq27.1, a region particularly susceptible to structural variation. Using a combination of structural genome analyses and functional assays, the researchers show that the identified insertion causes a position effect: the SOX3 gene itself remains intact at the sequence level, but its spatial context within the genome and the way it connects to its regulatory elements are fundamentally altered.
In their functional analyses, the researchers studied patient‑derived induced pluripotent stem cells and neurons differentiated from these cells with CRISPR‑based perturbations, Hi‑C profiling and transcriptome analysis. Their experiments showed that the insertion reshapes the local 3D genome organization around SOX3 and disrupts the associated topologically associating domain (TAD) – the three‑dimensional neighborhood in which promoters and enhancers preferentially interact. As a consequence, SOX3 expression is reduced and activation of its downstream target genes is impaired in neuronal cells. The disease mechanism delineated in this study thus highlights the importance of structural variants in non‑coding regions.
Terkelsen T, Yumiceba V, Kim J, … Jensen UB. Position effect at the SOX3 locus by an interchromosomal insertion causes hereditary spastic paraplegia. Am J Hum Genet. 2026 Jul 24:S0002-9297(26)00267-3. doi: 10.1016/j.ajhg.2026.07.001. Epub ahead of print.