This report describes Charcot-Marie-Tooth disease, type 2L (CMT2L), which is a subtype of Charcot-Marie-Tooth disease; CMR2L exhibits autosomal dominant inheritance. 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, distal hereditary motor neuronopathy IIA (FBhh0000947).
Multiple UAS constructs of the human Hsap\HSPB8 gene have been introduced into flies, including wild-type and variants implicated in disease. 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 HMN2A. See the report for neuronopathy, HSPB8-related (FBhh0000945) for information on experimental results using Drosophila models of these diseases.
[updated Jan. 2020 by FlyBase; FBrf0222196]
Charcot-Marie-Tooth disease (CMT) constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. CMT is divided into several major types: Type 1 is characterized by demyelination and by a significantly slowed motor median nerve conduction velocity (NCV). Type 2 is characterized by axonal abnormalities and a normal or slightly reduced NCV. "Intermediate" types describe CMT families with nerve conduction velocities, in different affected individuals, that overlap the division between Type 1 and Type 2. Additional types are defined on the basis inheritance patterns. [from MIM:609260 and MIM:606482; 2015.12.15]
Symptoms typically include progressive distal muscle weakness and atrophy, often associated with mild to moderate sensory loss, depressed tendon reflexes, and high-arched feet. [from Gene Reviews, http://www.ncbi.nlm.nih.gov/books/NBK1358 2015.12.15]
[CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2L; CMT2L](https://omim.org/entry/608673)
[HEAT-SHOCK 22-KD PROTEIN 8; HSPB8](https://omim.org/entry/608014)
Axonal Charcot-Marie-Tooth disease type 2L (CMT2L) is caused by mutation in the HSPB8 gene; it exhibits autosomal dominant inheritance. Distal hereditary motor neuronopathy IIA (HMN2A) is an allelic disorder with an overlapping phenotype. [from MIM:608673; 2019.01.07]
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).
HSPB8 modulates autophagy-mediated protein degradation in a mouse ALS1 model using SOD1 (Crippa et al., 2010; PMID:20570967).
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).
