A cryptic splicing mutation in the INF2 gene causing Charcot-Marie-Tooth disease with minimal glomerular dysfunction

Area of Science:

• Genetics
• Neurology
• Nephrology

Background:

• Mutations in the inverted formin-2 (INF2) gene are known to cause focal segmental glomerulosclerosis (FSGS) and Charcot-Marie-Tooth (CMT) disease.
• Previous research linked INF2 mutations to combined neuropathy and kidney dysfunction.

Observation:

• A three-generation family presented with autosomal dominant intermediate CMT, characterized by sensorimotor polyneuropathy, pes cavus, and kyphoscoliosis.
• Patients exhibited minimal to mild glomerular dysfunction, with normal plasma albumin and creatinine levels in most cases.

Findings:

• A novel cryptic splicing mutation in the INF2 gene (c.271C>G, p.Arg91Gly) was identified.
• In vitro assays confirmed the mutation causes an in-frame deletion of 40 amino acids in INF2 (p.Arg91_p.Gln130del).
• This mutation resulted in intermediate CMT with only mild renal impairment.

Implications:

• The genetic spectrum of INF2-associated disorders is expanded.
• INF2 mutations can cause isolated CMT without clinically relevant kidney disease.
• Genetic analysis for INF2 mutations should be considered even in patients without concurrent kidney issues.