Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia

Area of Science:

• Genetics
• Skeletal Dysplasias
• Molecular Biology

Background:

• SPONASTRIME dysplasia is a rare genetic disorder affecting skeletal development.
• The underlying genetic cause of SPONASTRIME dysplasia remained unknown.
• Previous research has not identified causative genetic alterations.

Purpose of the Study:

• To identify the genetic basis of SPONASTRIME dysplasia.
• To investigate the role of the TONSL gene in skeletal development and genome integrity.
• To understand the functional impact of identified TONSL mutations.

Main Methods:

• Whole-exome sequencing (WES) was performed on individuals with SPONASTRIME dysplasia.
• Functional studies using dermal fibroblasts from affected individuals.
• In vitro cell-based assays and in silico structural analyses of TONSL.
• Generation and analysis of a knock-in (KI) Tonsl mouse model.

Main Results:

• Bi-allelic mutations in the TONSL gene were identified in 10 out of 13 SPONASTRIME dysplasia cases.
• Cellular defects in patient-derived fibroblasts were rescued by wild-type TONSL expression.
• In vitro and in silico analyses supported the pathogenicity of identified TONSL variants.
• A Tonsl knock-in mouse model exhibited embryonic lethality, indicating physiological importance.

Conclusions:

• Genetic variants leading to reduced function of TONSL cause SPONASTRIME dysplasia.
• TONSL plays a critical role in embryonic development and postnatal growth.
• This study elucidates the molecular basis of SPONASTRIME dysplasia and highlights TONSL's function in genome maintenance.