DeCure for Neuronopathy, distal hereditary motor, type 5B
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for neuronopathy, distal hereditary motor, type 5B — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleNeuronopathy, distal hereditary motor, type 5B maps to a 2-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for neuronopathy, distal hereditary motor, type 5b is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
BICD cargo adaptor 2 (BICD2) — BICD2 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6PSE · 2.404 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Distal hereditary motor neuropathy type 5B is one subtype within a group of disorders that share a length-dependent, predominantly motor neuropathy. By 2011, eleven causative genes and four loci had been identified across all forms of distal hereditary motor neuropathy, but 80% of patients still had a mutation in an undiscovered gene. A 2007 study of 112 families found disease-causing mutations in only 17 patients, in the genes HSPB8, HSPB1, BSCL2 and SETX; no mutations were found in GARS, DCTN1 or VAPB. That study confirmed both genetic and phenotypic heterogeneity and provided evidence of genetic mosaicism in transmitting an HSPB1 mutation.
In 2017, exome sequencing of a Taiwanese family with autosomal dominant distal hereditary motor neuropathy, after excluding mutations in common implicated genes, identified a heterozygous mutation in the cytoplasmic tryptophanyl-tRNA synthetase gene WARS (c.770A>G, p.His257Arg). The same mutation was found in one additional Taiwanese pedigree and one Belgian family of Caucasian origin, out of 79 Taiwanese pedigrees and 163 index cases from Australian, European and Korean families. Cell transfection studies showed a dominant-negative effect on aminoacylation activity, compromising protein synthesis and reducing cell viability; the mutant protein also inhibited neurite outgrowth and caused neurite degeneration in neuronal cell lines and rat motor neurons, and potentiated angiostatic activities by enhancing interaction with vascular endothelial-cadherin.
A 2020 report described a third family with lower motor neuron disease due to mutations in PLEKHG5, the first nonconsanguineous family, with two previously unreported mutations. PLEKHG5 encodes a protein that activates the NFκB signalling pathway, and mutations had previously been associated with distal spinal muscular atrophy IV and intermediate axonal neuropathy C, both autosomal recessive. The proteins implicated across distal hereditary motor neuropathies have diverse functions including protein misfolding, RNA metabolism, axonal transport and cation-channel dysfunction.
What remains missing is a clear understanding of the genetic cause for the majority of patients, as 80% of cases still lack a known mutation. No clinical trials of any drug for distal hereditary motor neuropathy type 5B are reported in these abstracts, and no treatment data exist. The field lacks the patient stratification and funding needed to move from gene discovery to therapy development.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
AbstractThe distal hereditary motor neuropathies (dHMN) comprise a heterogeneous group of diseases that share the common feature of a length-dependent predominantly motor neuropathy. Many forms of dHMN have minor sensory abnormalities and/or a significant upper-motor-neuron component, and there is often an overlap with the axonal forms of Charcot-Marie-Tooth disease (CMT2) and with juvenile forms of amyotrophic lateral sclerosis and hereditary spastic paraplegia. Eleven causative genes and four loci have been identified with autosomal dominant, recessive and X-linked patterns of inheritance. Despite advances in the identification of novel gene mutations, 80% of patients with dHMN have a mutation in an as-yet undiscovered gene. The causative genes have implicated proteins with diverse functions such as protein misfolding (HSPB1, HSPB8, BSCL2), RNA metabolism (IGHMBP2, SETX, GARS), axonal transport (HSPB1, DYNC1H1, DCTN1) and cation-channel dysfunction (ATP7A and TRPV4) in motor-nerve disease. This review will summarise the clinical features of the different subtypes of dHMN to help focus genetic testing for the practising clinician. It will also review the neuroscience that underpins our current understanding of how these mutations lead to a motor-specific neuropathy and highlight potential therapeutic strategies. An understanding of the functional consequences of gene mutations will become increasingly important with the advent of next-generation sequencing and the need to determine the pathogenicity of large amounts of individual genetic data.
Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study
AbstractDistal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; glycyl-tRNA synthetase (GARS), dynactin 1 (DCTN1), small heat shock 27 kDa protein 1 (HSPB1), small heat shock 22 kDa protein 8 (HSPB8), Berardinelli-Seip congenital lipodystrophy (BSCL2) and senataxin (SETX). In addition a mutation in the (VAMP)-associated protein B and C (VAPB) was found in several Brazilian families with complex and atypical forms of autosomal dominantly inherited motor neuron disease. We have investigated the distribution of mutations in these seven genes in a cohort of 112 familial and isolated patients with a diagnosis of distal motor neuropathy and found nine different disease-causing mutations in HSPB8, HSPB1, BSCL2 and SETX in 17 patients of whom 10 have been previously reported. No mutations were found in GARS, DCTN1 and VAPB. The phenotypic features of patients with mutations in HSPB8, HSPB1, BSCL2 and SETX fit within the distal HMN classification, with only one exception; a C-terminal HSPB1-mutation was associated with upper motor neuron signs. Furthermore, we provide evidence for a genetic mosaicism in transmitting an HSPB1 mutation. This study, performed in a large cohort of familial and isolated distal HMN patients, clearly confirms the genetic and phenotypic heterogeneity of distal HMN and provides a basis for the development of algorithms for diagnostic mutation screening in this group of disorders.
A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy
AbstractDistal hereditary motor neuropathy is a heterogeneous group of inherited neuropathies characterized by distal limb muscle weakness and atrophy. Although at least 15 genes have been implicated in distal hereditary motor neuropathy, the genetic causes remain elusive in many families. To identify an additional causal gene for distal hereditary motor neuropathy, we performed exome sequencing for two affected individuals and two unaffected members in a Taiwanese family with an autosomal dominant distal hereditary motor neuropathy in which mutations in common distal hereditary motor neuropathy-implicated genes had been excluded. The exome sequencing revealed a heterozygous mutation, c.770A > G (p.His257Arg), in the cytoplasmic tryptophanyl-tRNA synthetase (TrpRS) gene (WARS) that co-segregates with the neuropathy in the family. Further analyses of WARS in an additional 79 Taiwanese pedigrees with inherited neuropathies and 163 index cases from Australian, European, and Korean distal hereditary motor neuropathy families identified the same mutation in another Taiwanese distal hereditary motor neuropathy pedigree with different ancestries and one additional Belgian distal hereditary motor neuropathy family of Caucasian origin. Cell transfection studies demonstrated a dominant-negative effect of the p.His257Arg mutation on aminoacylation activity of TrpRS, which subsequently compromised protein synthesis and reduced cell viability. His257Arg TrpRS also inhibited neurite outgrowth and led to neurite degeneration in the neuronal cell lines and rat motor neurons. Further in vitro analyses showed that the WARS mutation could potentiate the angiostatic activities of TrpRS by enhancing its interaction with vascular endothelial-cadherin. Taken together, these findings establish WARS as a gene whose mutations may cause distal hereditary motor neuropathy and alter canonical and non-canonical functions of TrpRS.
Annals of Clinical and Translational Neurology · 2020 · 6 citations · open access
Novel <i>PLEKHG5</i> mutations in a patient with childhood‐onset lower motor neuron disease
AbstractThe PLEKHG5 gene encodes a protein that activates the nuclear factor kappa B (NFκB) signaling pathway. Mutations in this gene have been associated with distal spinal muscular atrophy IV and intermediate axonal neuropathy C, both with an autosomal recessive mode of inheritance. Two families with low motor neuron disease (LMND) caused by mutations in PLEKHG5 have been reported to date. We present a third LMND family, the first nonconsanguineous, due to two not previously reported PLEKHG5 mutations. Our results confirm and extend previous findings linking PLEKHG5 mutations to lower motor neuron diseases.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
