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FB2026_02
,
released June 18, 2026
This report describes neuronopathy, distal hereditary motor, autosomal dominant 3 (HMND3). This disorder is described by OMIM as showing autosomal dominant inheritance, but autosomal recessive instances may also occur (MIM:608634). The human gene implicated in this disease is HSPB1, a small heat shock protein which functions as a molecular chaperone. There are several moderately-ranking orthologs of HSPB1 in Drosophila (for example, Hsp23), but all are more closely related to other members of the small heat shock protein (HSP20) family in human.
The human Hsap\HSPB1 gene has been introduced into flies, both as wild-type and as the HMN2B-associated variant p.Ser135Phe. See the 'Disease-Implicated Variants' table below.
Drosophila expressing mutant Hsap\HSPB1 in all neurons or specifically in motor neurons walk and climb more slowly than wild-type flies or those expressing wild-type Hsap\HSPB1. This phenotype is rescued by expressing HDAC6, similar to results seen in a mouse model.
[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 3; HMND3](https://omim.org/entry/608634)
[HEAT-SHOCK 27-KD PROTEIN 1; HSPB1](https://omim.org/entry/602195)
Distal hereditary motor neuropathies (dHMN) are a group of hereditary neuromuscular disorders characterized by length-dependent motor neuron weakness and subsequent muscle atrophy [1]. In the early stages, patients experience progressive weakness and atrophy in the lower limbs. As the disease progresses, the symptoms spread to the proximal muscles, and reach the upper limbs with foot deformities. (From Kang et al. 2020, FBrf0244341.)
Houlden et al. 2008 (pubmed:18832141) reported 5 families with HMND3. All patients had a similar slowly progressive disease course with a mean age at onset ranging from 21 to 54 years. Muscle weakness and atrophy started and predominated in the distal lower limb muscles. Muscle weakness and wasting progressed to the upper limbs approximately 5 to 10 years later along with proximal lower limb problems. Tendon reflexes were depressed or absent in all cases. [from MIM:608634; 2024.02.20]
Recently, over 20 genes have been reported to be associated with dHMN. These genes encode proteins with distinct functions such as protein folding (HSPB1, HSPB3, HSPB8, and DNAJB2), RNA metabolism (GARS, IGHMBP2, and STEX), axonal transport (HSPB1, DCTN1, and DYNC1H1), and cation channel activity (ATP7A and TRPV4). Among them, HSPB1 has received intensive attention because more than 30 different mutations causing dHMN or CMT2 have been described in this gene. Moreover, HSPB1 is also involved in various other human diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer disease, and heart disease. (From Kang et al. 2020 and references therein, FBrf0244341.)
Autosomal dominant distal hereditary motor neuronopathy-3 (HMND3) is caused by heterozygous mutation in the gene encoding heat-shock 27-kD protein-1 (HSPB1). [from MIM:608634; 2024.02.20]
Although the role of HSPB1 in muscle tissues is not fully understood, a few interesting observations may provide hints. For example, genetic deletion of HSPB1 in the mouse results in phenotypically normal animals but with ultrastructural irregularities in the Soleus muscle (altered sarcomere structure with Z-line deformation but without nuclei internalization). (From Adriaenssens et al. 2017, pubmed:28969372, citing Kammoun et al. 2016, pubmed:27512988).
Chaperones are proteins that, together with the protein degradation machinery (proteasomes, macroautophagy, etc.), contribute to the quality control apparatus and to the proteostasis of a cell. Typically, chaperones recognize other proteins (usually called their clients) to assist in their folding so that they attain their functional conformation at the sites where they must act. Most chaperones are promiscuous and they bind to many clients, although others (dedicated chaperones) restrict their associations to one or a few proteins. Chaperones can either be constitutively expressed, induced by stress (usually but not exclusively, heat shock) or both. Most chaperones induced by heat shock are frequently called heat shock proteins (HSPs). (From Lupo et al. 2016 and references therein, pubmed:28018906.)
One to many: 1 human gene to 2 Drosophila genes. Both potential orthologs are members of the small heat shock protein family (FBgg0000507).