Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support...

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Transfer RNA (tRNA) synthetases are crucial for protein synthesis.
• Emerging research highlights their nuclear and extracellular functions beyond translation.
• Dominant gain-of-function mutations in tRNA synthetases are linked to diseases like Charcot-Marie-Tooth.

Purpose of the Study:

• To investigate the role of recessive loss-of-function mutations in tRNA synthetases.
• To identify the genetic basis and clinical manifestations of bi-allelic mutations in FARSB.
• To elucidate the disease mechanism associated with phenylalanine-tRNA synthetase (FARS) deficiency.

Main Methods:

• Clinical evaluation of five individuals from four families with a multi-system disease.
• Genetic analysis to identify bi-allelic mutations in the FARSB gene.
• Functional studies including assessment of exon skipping, frameshift, and protein synthesis activity.

Main Results:

• Identified five individuals with bi-allelic FARSB mutations, including a splice junction variant (SJV) and missense variants.
• Clinical presentation included interstitial lung disease, cerebral aneurysms, brain calcifications, and cirrhosis.
• Mutations led to noncatalytic activity and frameshift, but did not impair protein synthesis in affected individuals or carriers.

Conclusions:

• Bi-allelic loss-of-function mutations in FARSB cause a multi-system disease.
• The disease mechanism is independent of the canonical tRNA synthetase activity in protein translation.
• This study suggests a critical, non-translational role for phenylalanine-tRNA synthetase (FARS) in maintaining normal organ function.