INTS13 variants causing a recessive developmental ciliopathy disrupt assembly of the Integrator complex

Area of Science:

• Genetics
• Developmental Biology
• Molecular Biology

Background:

• Oral-facial-digital (OFD) syndromes are congenital disorders with facial, oral, and digit malformations.
• OFDs are increasingly recognized as developmental ciliopathies, linked to mutations in cilia-related genes.
• The Integrator complex's role in gene expression modulation is known, but its direct link to OFD syndromes was unclear.

Purpose of the Study:

• To identify the genetic cause of variable OFD type 2 in two families.
• To investigate the function of INTS13, a subunit of the Integrator complex, in ciliogenesis and gene regulation.
• To establish INTS13 as a causative gene for a specific type of OFD syndrome and ciliopathy.

Main Methods:

• Homozygosity mapping and exome sequencing were used to identify genetic variants.
• Functional studies involved depletion of INTS13 in human cultured cells and Xenopus embryos.
• Analysis of INTS13 protein interactions and its effect on ciliogenesis and ciliary gene expression.

Main Results:

• Distinct germline variants (p.S652L and p.K668Nfs*9) in the INTS13 gene were identified in affected families.
• INTS13 depletion was shown to disrupt ciliogenesis in human cells.
• Knockdown of INTS13 in Xenopus embryos resulted in motile cilia anomalies and dysregulation of ciliary genes.

Conclusions:

• Mutations in INTS13 cause an autosomal recessive ciliopathy, leading to OFD syndromes.
• INTS13 is essential for proper ciliogenesis and the regulation of ciliary gene expression.
• This study highlights critical interactions within the Integrator complex and its role in human development.