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Expanding the Molecular and Pathologic Spectrum of HSPB8 Myopathy and Distal Motor Neuropathy
Brendan Nicholas Putko1, Eric J Sorenson1, Gaofeng Cui2
1Department of Neurology, Mayo Clinic, Rochester, MN.
Objectives:
HSPB8 variants cause myopathy, distal motor neuropathy, and Charcot-Marie-Tooth disease. We describe 2 patients who expand the molecular and pathologic spectrum of HSPB8 disorder.
Methods:
We reviewed clinical and laboratory data and performed molecular dynamics simulations to explore variant effect.
Results:
Patient 1 is an adult man presenting with childhood-onset, distal lower limb weakness, followed by proximal weakness. EMG detected predominant myopathic and neurogenic changes in upper and lower limbs, respectively. Biopsy revealed myopathy with rimmed vacuoles in the supraspinatus and neurogenic changes in the tibialis anterior. He carries a novel, predicted deleterious HSPB8 heterozygous variant, c.185G>A (p. Gly62Asp). Patient 2 is an adult man presenting with distal, asymmetric, progressive lower limb weakness that extended to proximal and neck muscles. Quadriceps biopsy showed myopathy with rimmed vacuoles and protein aggregates, especially TIA1, p62, and TDP-43. TIA1 aggregates were more prominent than Z-disk protein accumulation. He carries a known HSPB8 pathogenic variant, c.421 A>G (p.Lys141Glu). Molecular dynamics simulations suggested that p.Gly62Asp may exert its effects through post-translation modifications while p.Lys141Glu may disrupt dimerization.
Discussion:
HSPB8 p.Gly62Asp is the first N-terminal variant associated with myopathy. TIA1 aggregates, more prominent than Z-disk myofibril aggregates, suggest that p.Lys141Glu may affect stress granule dynamics more than Z-disk integrity.
Insights
Two patients with HSPB8-related disorders expand the known spectrum of myopathy and neuropathy. Novel variants and protein aggregation patterns offer new insights into disease mechanisms.
Area of Science:
- Neurology
- Genetics
- Molecular Biology
Background:
- Mutations in the Heat Shock Protein Family B Member 8 (HSPB8) gene are associated with neuromuscular disorders, including distal myopathy, distal motor neuropathy, and Charcot-Marie-Tooth disease.
- The full spectrum of clinical presentations and underlying molecular mechanisms of HSPB8-related disorders are not yet fully understood.
Purpose of the Study:
- To expand the molecular and pathological spectrum of HSPB8-related disorders.
- To investigate the effects of novel and known HSPB8 variants using clinical data and molecular dynamics simulations.
Main Methods:
- Review of clinical and laboratory data from two patients with HSPB8 variants.
- Performance of molecular dynamics simulations to explore the functional impact of identified variants.
- Histopathological examination of muscle biopsies.
Main Results:
- Patient 1 presented with childhood-onset distal weakness and myopathic/neurogenic changes, carrying a novel HSPB8 variant (c.185G>A, p.Gly62Asp).
- Patient 2 exhibited progressive distal and proximal weakness with myopathy and prominent TIA1 aggregates, carrying a known HSPB8 variant (c.421A>G, p.Lys141Glu).
- Molecular simulations suggested p.Gly62Asp may affect post-translational modifications and p.Lys141Glu may disrupt protein dimerization.
Conclusions:
- The p.Gly62Asp variant represents the first identified N-terminal HSPB8 variant associated with myopathy.
- Prominent TIA1 aggregates in Patient 2 suggest that the p.Lys141Glu variant may primarily impact stress granule dynamics over Z-disk integrity.
- These findings broaden the understanding of HSPB8-related neuromuscular conditions and their molecular pathology.
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