Position effect at the SOX3 locus by an interchromosomal insertion causes hereditary spastic paraplegia

Area of Science:

• Genomics
• Molecular Biology
• Neurogenetics

Background:

• Pathogenic rewiring of 3D genome architecture causes genetic diseases.
• Recognizing cis-regulatory effects of structural variation is challenging.
• The Xq27.1 region is a hotspot for disease-causing insertions.

Purpose of the Study:

• Investigate the disease mechanism of X-linked recessive complex spastic paraplegia.
• Understand the role of a 149-kb interchromosomal insertion at Xq27.1.
• Identify the cis-regulatory effects and transcriptional dysregulation caused by the insertion.

Main Methods:

• Generated induced pluripotent stem cells (iPSCs) from affected individuals.
• Utilized CRISPR perturbation, neural differentiation, Hi-C, and transcriptomic analyses.
• Examined the regulatory effects on the SOX3 locus and its targets.

Main Results:

• Identified 3D regulatory rewiring of SOX3 and dysregulation of its targets in iPSC-derived neurons.
• Observed regulatory partitioning of the SOX3 topologically associating domain (TAD).
• Demonstrated reduced activation of SOX3 expression by upstream cis-regulatory elements, dependent on CTCF-binding sites within the insertion.

Conclusions:

• The interchromosomal insertion at Xq27.1 causes X-linked spastic paraplegia through a position effect at the SOX3 locus.
• This study provides mechanistic evidence linking 3D genome alterations to hereditary spastic paraplegia.
• Highlights the importance of investigating structural variations in genetic disease etiology.