A novel GDAP1 Q218E mutation in autosomal dominant Charcot-Marie-Tooth disease

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene are typically associated with autosomal recessive (AR) Charcot-Marie-Tooth disease (CMT), presenting diverse phenotypes.
• Reports of GDAP1 mutations in autosomal dominant (AD) CMT are rare, limiting the understanding of its role in dominant inheritance patterns.

Purpose of the Study:

• To investigate the genetic basis of AD CMT in a family with a suspected novel mutation.
• To characterize the phenotype and molecular pathology associated with a new GDAP1 mutation in AD CMT.

Main Methods:

• Genetic analysis of affected family members to identify mutations.
• Segregation analysis within the pedigree to confirm co-inheritance of the mutation.
• Clinical and histopathological examination of affected individuals.

Main Results:

• A novel Q218E mutation in the GDAP1 gene was identified and co-segregated with AD CMT in the family.
• The mutation is located within the conserved glutathione S-transferase (GST) domain of GDAP1.
• Affected individuals exhibited later onset and milder phenotypes compared to AR CMT patients, with evidence of both axonal degeneration and demyelination.

Conclusions:

• This study reports the first identified mutation in the GDAP1 gene associated with autosomal dominant CMT.
• The Q218E mutation in GDAP1 leads to a distinct clinical presentation in AD CMT, differing from AR forms.
• GDAP1 mutations can cause both recessive and dominant forms of Charcot-Marie-Tooth disease, highlighting its critical role in peripheral nerve function.