A novel synonymous mutation in the MPZ gene causing an aberrant splicing pattern and Charcot-Marie-Tooth disease type...

Area of Science:

• Genetics
• Molecular Biology
• Neurology

Background:

• Charcot-Marie-Tooth disease (CMT) is a group of inherited peripheral neuropathies with diverse genetic causes.
• The MPZ gene encodes the P0 protein, crucial for myelin sheath formation in peripheral nerves.
• Mutations in MPZ are a known cause of CMT, particularly CMT type 1B.

Observation:

• Two families with mild sensory-motor neuropathy were identified with a novel synonymous variant (c.309G>T, p.G103G) in exon 3 of the MPZ gene.
• Next-generation sequencing excluded mutations in other known CMT-associated genes.
• In vitro splicing assays revealed that the c.309T variant enhances a cryptic donor splice site, leading to increased expression of an alternative transcript.

Findings:

• The alternative transcript (r.304_448del) is predicted to produce a truncated P0 protein lacking its transmembrane domain.
• This suggests a potential haploinsufficiency mechanism underlying the neuropathy in affected individuals.
• This is the third reported synonymous MPZ variant linked to CMT1 and impacting RNA splicing.

Implications:

• Synonymous variants, previously often overlooked, can functionally impact gene splicing and lead to disease.
• These findings underscore the importance of considering splicing alterations in the genetic diagnosis of CMT.
• The study expands the known mechanisms by which MPZ gene variations cause peripheral neuropathies.