Spectrum of Clinical Variability with SEPT9 Gene Mutation in Hereditary Neuralgic Amyotrophy: Understanding the...

Area of Science:

• Genetics
• Molecular Biology
• Neurology

Background:

• Hereditary Neuralgic Amyotrophy (HNA) is an autosomal dominant disorder causing severe pain and muscle wasting.
• Mutations in the SEPTIN9 gene are associated with HNA, but the exact disease mechanism remains unclear.

Purpose of the Study:

• To investigate the phenotypic and genetic characteristics of HNA in a large Indian family.
• To identify the specific genetic mutation responsible for HNA in the studied pedigree.

Main Methods:

• Clinical evaluation of 9 affected family members.
• Genetic analysis of 6 affected and 4 unaffected individuals to identify SEPTIN9 gene mutations.
• Molecular simulation to assess the impact of the identified mutation on protein structure and function.

Main Results:

• A recurrent NM_001113491.2:p.Arg106Trp mutation in the SEPTIN9 gene was identified in 6 affected family members.
• Molecular simulations showed the mutation alters septin-9 protein conformation, impairing microtubule binding and bundling.
• Significant clinical variability was observed among affected individuals despite the shared mutation.

Conclusions:

• The identified SEPTIN9 mutation is causative for HNA in this family.
• Clinical heterogeneity in HNA may result from variable gene penetrance and epigenetic factors.
• This represents the first genetically confirmed HNA case series from India, contributing to understanding HNA pathogenesis.