Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2

Area of Science:

• Genetics
• Neuroscience
• Biochemistry

Background:

• Mutations in over 90 genes cause Charcot-Marie-Tooth disease (CMT), but the genetic cause remains unknown in over 50% of cases.
• Identifying novel CMT-causing genes requires global data sharing.

Purpose of the Study:

• To identify new genes responsible for autosomal-dominant CMT type 2 (CMT2).
• To investigate the role of the Na+,K+-ATPase alpha1 subunit (encoded by ATP1A1) in CMT2 pathogenesis.

Main Methods:

• Global collaborative sequencing data analysis from seven countries.
• Identification and segregation analysis of mutations within pedigrees.
• Immunostaining of peripheral nerve axons to localize ATP1A1.
• Two-electrode voltage clamp electrophysiology in Xenopus oocytes to assess Na+ current activity of ATP1A1 mutants.

Main Results:

• Seven missense mutations in ATP1A1 were identified as causative for autosomal-dominant CMT2.
• ATP1A1 was localized to the axolemma and Schmidt-Lanterman incisures in peripheral nerve axons.
• Some ATP1A1 mutants showed reduced Na+ current activity, indicating a loss-of-function defect.
• Five identified mutations clustered in a critical region of the ATP1A1 protein.

Conclusions:

• Mutations in ATP1A1 are a novel cause of autosomal-dominant CMT2.
• This finding implicates the Na+,K+-ATPase pump in peripheral nerve axon degeneration.
• ATP1A1 represents a potential therapeutic target for CMT and other neurodegenerative diseases.