This report describes neuronopathy, distal hereditary motor, autosomal dominant 2 (HMND2). The human gene implicated in this disease is HSPB8, which encodes a small heat-shock protein that plays roles in stress tolerance and regulation of autophagy-mediated protein degradation. HSPB8 is also implicated in a similar disease, Charcot-Marie-Tooth disease, axonal, type 2L (FBhh0000946).
Multiple UAS constructs of the human Hsap\HSPB8 gene have been introduced into flies, including wild-type and variants implicated in disease. See the 'Disease-Implicated Variants' table below. Variant(s) implicated in human disease tested (as transgenic human gene, HSPB8): the K141E and K141N variant forms have been introduced into flies; these variants are implicated in both CMT2L and HMND2. See the report for neuronopathy, HSPB8-related (FBhh0000945) for information on experimental results using Drosophila models of these diseases.
[updated Feb. 2024 by FlyBase; FBrf0222196]
Distal hereditary motor neuronopathy (dHMN or HMN) is a heterogeneous group of neuromuscular disorders caused by anterior horn cell degeneration and characterized by progressive distal motor weakness and muscular atrophy of the peripheral nervous system without sensory impairment. Distal HMN is also referred to as spinal Charcot-Marie-Tooth disease (spinal CMT). Distal HMN is often referred to as a 'neuronopathy' instead of a 'neuropathy' based on the hypothesis that the primary pathologic process resides in the neuron cell body and not in the axons (Irobi et al., 2006, pubmed:16775372). [From MIM:607641, 2016.01.11]
[NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 2; HMND2](https://omim.org/entry/158590)
[HEAT-SHOCK 22-KD PROTEIN 8; HSPB8](https://omim.org/entry/608014)
Distal autosomal dominant distal hereditary motor neuronopathy-2 (HMND2) is caused by heterozygous mutation in the gene encoding heat-shock 22-kD protein-8. [from MIM:158590; 2024.02.20]
HSPB8 modulates autophagy-mediated protein degradation in a mouse ALS1 model using SOD1 (Crippa et al., 2010; PMID:20570967).
HSPB8 encodes a protein that belongs to the superfamily of small heat-shock proteins containing a conservative alpha-crystallin domain at the C-terminal part of the molecule. [Gene Cards, HSPB8; 2019.02.14]
As a family, the small heat-shock proteins are important in stress tolerance; many exhibit chaperone-like activity in preventing aggregation of target proteins, keeping them in a folding-competent state and refolding them by themselves or in concert with other ATP-dependent chaperones (Bakthisaran et al., 2015; pubmed:25556000).
Many to many: multiple members of this gene family in both species. Human genes include HSPB1, HSPB2, HSPB3, CRYAA, CRYAB, HSPB6, HSPB7, HSPB8, HSPB9, CRYAA2.
Low-scoring ortholog of multiple human small heat-shock genes (many to many). Dmel\Hsp67Bc shares 33% identity and 54% similarity with human HSPB8. Dmel\Hsp67Bc meets multiple criteria for functional similarity specifically to HSPB8 (FBrf0212431).
