GNB4 – Charcot-Marie-Tooth Disease

This summary describes the association between GNB4 and Charcot-Marie-Tooth disease based on multiple independent lines of evidence. Several studies have identified pathogenic missense variants in GNB4 that clearly segregate with the CMT phenotype, establishing a robust link between the gene and the disease (PMID:27908631). The clinical presentations across studies include features such as pes cavus, scoliosis, and distal muscle weakness, which are hallmarks of the CMT phenotype.

In a seminal case report, a Czech patient was found to carry a de novo missense variant, c.169A>G (p.Lys57Glu), identified through whole exome sequencing (PMID:27908631). This patient presented at 35 years of age with severe neuropathy, marked by a high CMT neuropathy score, pes cavus, and scoliosis. The absence of the variant in the parents and an unaffected sibling provides strong evidence for de novo occurrence and pathogenicity.

Further supporting evidence comes from multi-patient studies in which autosomal dominant inheritance was observed. One Japanese family presented with a heterozygous variant, c.659A>G (p.Gln220Arg), in addition to other recurrent variants reported in independent cohorts (PMID:28642160). In a separate Korean study involving three families, additional variants including c.229G>C (p.Gly77Arg) and c.265A>G (p.Lys89Glu) were detected, and segregation analysis in these families indicated that these mutations are causative for both intermediate and demyelinating subtypes of CMT (PMID:34071515).

The genetic evidence is further bolstered by clear segregation patterns; affected relatives in familial cases have consistently harbored the pathogenic variants, reinforcing the autosomal dominant mode of inheritance. The detection of these variants by robust sequencing methods, coupled with absence in control cohorts, underlines the specificity of GNB4 alterations in CMT cases. Notably, the recurrent nature of variants such as p.Lys57Glu, identified initially in a de novo context, emphasizes their clinical relevance.

Functional studies have provided moderate but compelling evidence in support of the genetic findings. Investigations using in vitro assays and immunohistochemistry have demonstrated that mutations in GNB4 result in impaired GPCR signaling and reduced expression in peripheral nerve tissues (PMID:23434117). These experiments not only replicate the expected biochemical deficits but also mirror the neuropathological features observed in patients, thereby closing the loop between molecular dysfunction and clinical phenotype.

In conclusion, the combined genetic and functional evidence supports a strong association between GNB4 and Charcot-Marie-Tooth disease. Multiple independent case reports and cohort studies have established both the pathogenicity of de novo and familial variants as well as the biological mechanism underlying the disease. Key take‑home message: GNB4 mutations are a critical diagnostic marker in CMT, underscoring their clinical utility in both genetic testing and tailored treatment strategies.

References

• Neuromuscular disorders : NMD • 2017 • Confirmation of the GNB4 gene as causal for Charcot-Marie-Tooth disease by a novel de novo mutation in a Czech patient PMID:27908631
• European journal of medical genetics • 2017 • A novel missense variant of GNB4 in a Japanese family with autosomal dominant motor and sensory neuropathy PMID:28642160
• Life (Basel, Switzerland) • 2021 • Clinical and Neuroimaging Features in Charcot-Marie-Tooth Patients with GNB4 Mutations PMID:34071515
• American journal of human genetics • 2013 • Exome sequencing identifies GNB4 mutations as a cause of dominant intermediate Charcot-Marie-Tooth disease PMID:23434117

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