This report describes neuronopathy, distal hereditary motor, autosomal dominant 4 (HMND4), a subtype of autosomal dominant distal hereditary motor neuropathy. The human gene implicated is HSPB3, which encodes a small heat shock protein; mutations in this gene are also associated with Charcot-Marie-Tooth disease type 2. There is no high-scoring fly ortholog, but several low- to moderate-scoring orthologs.
Multiple UAS constructs of Hsap\HSPB3 have been introduced into flies, including wild-type and variants implicated in disease. See the 'Disease-Implicated Variants' table below.
Pan-neuronal or motor neuron-specific expression of mutant, but not wild-type, isoforms of Hsap\HSPB3 result in a decrease in motor activity in adult flies that is more pronounced in older flies. Larvae neuronally expressing mutant Hsap\HSPB3 exhibit decreased mitochondrial membrane potential in the ventral nerve cord, and decreases in mitophagy when expressed in larval motorneurons, suggesting impaired mitochondrial function. Transgenic expression Dmel\Pink1 or Dmel\park were sufficient to rescue mitochondrial and motor activity phenotypes in larvae or adult flies expressing mutant Hsap\HSPB3.
[updated Jan. 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 4; HMND4](https://omim.org/entry/613376)
[HEAT-SHOCK 27-KD PROTEIN 3; HSPB3](https://omim.org/entry/604624)
Autosomal dominant distal hereditary motor neuronopathy-4 (HMND4) is caused by heterozygous mutation in the HSPB3 gene on chromosome 5q11. [from MIM:613376; 2023.11.08]
The HSPB3 gene encodes a small heat-shock protein. Small heat-shock proteins are characterized by a conserved sequence of 80 to 100 amino acids, often called the alpha-crystallin domain, and range in size from 12 to 43 kD in the monomeric state; as multimeric complexes, they range from 150 to 800 kD (Lam et al., 1996; pmid:8972725). [from MIM:604624; 2023.11.08]
Many to many; HSPB3 has multiple low- to moderate-scoring Drosophila orthologs.
