BAG3 – Distal Hereditary Motor Neuropathy

Bcl2-associated athanogene 3 (BAG3) has been implicated in various neuromuscular disorders, including Charcot-Marie-Tooth disease type 2 and myofibrillar myopathy. In a cohort of 435 Chinese patients with CMT and related neuropathies, heterozygous missense variants in BAG3 were identified in two sporadic CMT2 cases, but no familial segregation or recurrence of BAG3 variants has been documented in distal hereditary motor neuropathy (Distal hereditary motor neuropathy) (PMID:34255403). Thus, clinical validity for BAG3 in dHMN is currently limited.

Functionally, BAG3 forms a stable complex with HSPB8 to stimulate macroautophagy and prevent aggregation of misfolded proteins, supporting a mechanistic link to axonal maintenance (PMID:18006506). However, no in vitro or in vivo assays have directly assessed the impact of BAG3 deficiency or variants on motor neuron function or peripheral nerve pathology specific to dHMN.

Key Take-home: While BAG3-mediated autophagy provides biological plausibility for a role in motor neuron integrity, only two unsegregated cases link BAG3 variants to distal hereditary motor neuropathy; additional familial and disease-specific functional studies are required to establish causality.

References

• Human Genetics | 2021 | Overview of CMT Genotypes and Phenotypes in Central South China PMID:34255403
• The Journal of Biological Chemistry | 2008 | HspB8 chaperone activity toward poly(Q)-containing proteins depends on its association with Bag3, a stimulator of macroautophagy PMID:18006506

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