Chaperonopathies: Spotlight on Hereditary Motor Neuropathies

Area of Science:

• Genetics and Molecular Biology
• Neurology
• Biochemistry

Background:

• Distal hereditary motor neuropathies (dHMN) are rare neuromuscular disorders impacting peroneal muscles without sensory loss.
• Twenty-three genes are implicated in dHMN, with four encoding chaperones: DNAJB2 (HSP40/DNAJ family) and HSPB1, HSPB3, HSPB8 (small heat shock proteins).
• Mutations in HSPB1 are more frequent, while DNAJB2, HSPB3, and HSPB8 mutations are rare, complicating mechanistic studies.

Approach:

• This review synthesizes current knowledge on dHMN genetics.
• It focuses on four specific chaperone-encoding genes: DNAJB2, HSPB1, HSPB3, and HSPB8.
• The review examines shared disease mechanisms underlying these genetic forms of dHMN.

Key Points:

• Chaperones are crucial for protein folding, localization, and managing misfolded proteins within a cellular network.
• Mutations in DNAJB2, HSPB1, HSPB3, and HSPB8 can lead to dHMN, despite the varied frequencies of identified mutations.
• Specific mutations, like c.352+1G>A in DNAJB2 and K141 alterations in HSPB8, are notable.

Conclusions:

• Despite diverse mutation frequencies, chaperone gene mutations in dHMN may converge on common pathological pathways.
• Understanding these shared mechanisms is vital for deciphering the pathophysiology of these rare neuropathies.
• Further research into the integrated chaperone network's role in dHMN is warranted.