Heterozygous Seryl-tRNA Synthetase 1 Variants Cause Charcot-Marie-Tooth Disease

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Charcot-Marie-Tooth (CMT) is a group of inherited neurological disorders affecting peripheral nerves.
• Genetic diagnosis remains elusive for many CMT patients.
• Autosomal dominant mutations in aminoacyl-tRNA synthetases (ARSs) are known contributors to CMT.

Purpose of the Study:

• To identify the genetic cause of CMT in three families.
• To investigate the functional consequences of identified mutations in seryl-tRNA synthetase 1 (SerRS).
• To elucidate the molecular mechanisms underlying ARS-related CMT.

Main Methods:

• Whole-exome sequencing in affected individuals and unaffected family members.
• Linkage analysis to identify the disease-associated genomic region.
• Bioinformatic predictions, cellular assays, and biochemical analyses to assess variant impact.

Main Results:

• Heterozygous missense mutations in the SerRS gene were identified and segregated with CMT in three families.
• Mutant SerRS proteins showed reduced aminoacylation activity and abnormal dimerization.
• These molecular defects suggest impaired protein synthesis and induced eIF2α phosphorylation.

Conclusions:

• Heterozygous SerRS variants represent a novel cause of autosomal dominant CMT.
• Understanding the impact of mutant SerRS on cellular functions advances knowledge of ARS-related CMT.
• These findings contribute to improved genetic diagnosis and understanding of CMT pathogenesis.