Functional confirmation that the R1488* variant in SCN9A results in complete loss-of-function of Na_v1.7

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Congenital Insensitivity to Pain (CIP) is an extremely rare inherited disorder characterized by the inability to perceive pain.
• Genetic variants in the SCN9A gene, encoding the Na_v1.7 sodium channel, are associated with CIP, often presenting with anosmia and inherited recessively.
• Previous studies indicated that certain SCN9A mutations lead to a complete loss-of-function of the Na_v1.7 channel.

Purpose of the Study:

• To investigate the genetic basis of Congenital Insensitivity to Pain (CIP) in a consanguineous family.
• To functionally characterize a novel SCN9A variant identified in CIP patients.

Main Methods:

• Whole exome sequencing was performed on three affected and one unaffected family member.
• Patch clamp electrophysiology was utilized to assess the functional impact of the identified SCN9A variant.
• Human embryonic kidney (HEK) 293 cells were transfected with the variant for functional analysis.

Main Results:

• A homozygous nonsense variant, R1488*, in the SCN9A gene was identified in all individuals with CIP.
• Electrophysiological analysis confirmed that the R1488* variant leads to a complete loss-of-function of the Na_v1.7 sodium channel.
• This finding corroborates previous reports linking SCN9A variants to CIP.

Conclusions:

• The R1488* variant in the SCN9A gene causes a complete loss-of-function of the Na_v1.7 channel.
• This loss-of-function is the underlying mechanism for Congenital Insensitivity to Pain (CIP) in the studied family.
• The study validates the role of SCN9A in pain perception and provides functional evidence for a specific causative variant.