Rare & Orphan Lab · DeCure for X
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for acromesomelic dysplasia 2A — 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.
No approved-drug candidate for acromesomelic dysplasia 2a 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.
growth differentiation factor 5 (GDF5) — GDF5 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.
RCSB Protein Data Bank · entry 2BHK · 2.4 Å · ligand ISOPROPYL ALCOHOL (IPA). Experimental structure, not a prediction.
Acromesomelic dysplasia 2A is an autosomal recessive skeletal disorder causing extremely short stature with acromelia and mesomelia of the limbs. A 1980 review states that radiographic features allow diagnosis in affected individuals over six months of age, but no treatment or intervention is described in that paper.
A 2018 study of a consanguineous Pakistani family with Hunter-Thompson subtype identified a novel homozygous missense variant in BMPR1B (c.1190T > G, p.Met397Arg) with a LOD score of 3.9. This was the first familial case of that subtype and the first report of BMPR1B underlying it. No therapy or drug is mentioned.
A 2023 study examined eight NPR2 missense variants classified as variants of uncertain significance, found in patients with acromesomelic dysplasia (homozygous) or short stature (heterozygous). Variants p.Leu51Pro, p.Gly123Val, p.Leu314Arg, and p.Arg388Gln showed defective cellular trafficking, retention in the endoplasmic reticulum, and impaired cGMP production. Variants p.Arg318Gly, p.Arg495Cys, and p.Arg557His behaved similarly to wild-type NPR2, while p.Arg932Cys had normal trafficking but defective cGMP activity. The authors note a genotype-phenotype relationship that may explain milder symptoms in short stature compared to acromesomelic dysplasia, but no drug or treatment is tested.
A 2020 study identified six patients with acromelic dysplasia carrying FBN1-TB5 mutations (p.Gly1762Ser, p.Tyr1699Cys, p.Gly1754Ser). A systematic review found that acromelic dysplasia is caused only by in-frame amino acid substitutions in this region, while truncating mutations cause Marfan syndrome. No therapy or drug is discussed.
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
AbstractThe radiographic features of acromesomelic dysplasia are presented, along with a summary of pertinent clinical features. They are thought to allow a diagnosis in affected individuals over six months of age. Since the condition has an autosomal recessive mode of genetic transmission and results in extremely short stature, the establishment of the diagnosis has practical importance.
https://doi.org/10.1148/radiology.137.2.7433666AbstractAcromesomelic dysplasia is genetically heterogeneous group of skeletal disorders characterized by short stature and acromelia and mesomelia of limbs. Acromesomelic dysplasia segregates in an autosomal recessive pattern and is caused by biallelic sequence variants in three genes (NPR2, GDF5, and BMPR1B). A consanguineous family of Pakistani origin segregating a subtype of acromesomelic dysplasia called Hunter-Thompson was clinically and genetically evaluated. Genotyping of microsatellite markers and linkage analysis revealed a 7.78 Mb homozygous region on chromosome 4q22.3, which harbors BMPR1B. Sequence analysis of the gene revealed a novel homozygous missense variant (c.1190T > G, p.Met397Arg) that segregates with the disease phenotype within the family and produced a Logarithm of odds (LOD) score of 3.9 with the disease phenotype. This study reports on the first familial case of acromesomelic dysplasia Hunter-Thompson type. It is also the first report of BMPR1B underlying the etiology of acromesomelic dysplasia Hunter-Thompson type.
https://doi.org/10.1111/ahg.12233AbstractIntroduction: Natriuretic peptide receptor 2 (NPR2 or NPR-B) plays a central role in growth development and bone morphogenesis and therefore loss-of-function variations in NPR2 gene have been reported to cause Acromesomelic Dysplasia, Maroteaux type 1 and short stature. While several hypotheses have been proposed to underlie the pathogenic mechanisms responsible for these conditions, the exact mechanisms, and functional characteristics of many of those variants and their correlations with the clinical manifestations have not been fully established. Methods: In this study, we examined eight NPR2 genetic missense variants (p.Leu51Pro, p.Gly123Val, p.Leu314Arg, p.Arg318Gly, p.Arg388Gln, p.Arg495Cys, p.Arg557His, and p.Arg932Cys) Acromesomelic Dysplasia, Maroteaux type 1 and short stature located on diverse domains and broadly classified as variants of uncertain significance. The evaluated variants are either reported in patients with acromesomelic dysplasia in the homozygous state or short stature in the heterozygous state. Our investigation included the evaluation of their expression, subcellular trafficking and localization, N-glycosylation profiles, and cyclic guanosine monophosphate (cGMP) production activity. Results and Discussion: Our results indicate that variants p.Leu51Pro, p.Gly123Val, p.Leu314Arg, p.Arg388Gln have defective cellular trafficking, being sequestered within the endoplasmic reticulum (ER), and consequently impaired cGMP production ability. Conversely, variants p.Arg318Gly, p.Arg495Cys, and p.Arg557His seem to display a non-statistically significant behavior that is slightly comparable to WT-NPR2. On the other hand, p.Arg932Cys which is located within the guanylyl cyclase active site displayed normal cellular trafficking profile albeit with defective cGMP. Collectively, our data highlights the genotype-phenotype relationship that might be responsible for the milder symptoms observed in short stature compared to acromesomelic dysplasia. This study enhances our understanding of the functional consequences of several NPR2 variants, shedding light on their mechanisms and roles in related genetic disorders which might also help in their pathogenicity re-classification.
https://doi.org/10.3389/fcell.2023.1294748AbstractMutations in the transforming growth factor β-binding protein-like domain 5 (TB5) region of FBN1 can lead to autosomal acromelic dysplasia and Marfan syndrome, which are two diseases with apparently opposite phenotypes. We identified six patients with acromelic dysplasia carrying either the previously reported mutations c.5284G > A (p.Gly1762Ser) and c.5096A > G (p.Tyr1699Cys) or the novel mutation c.5260G > A (p.Gly1754Ser). A systematic review of patients with mutations in the FBN1-TB5 region showed that acromelic dysplasia is caused only by in-frame amino acid substitutions. In contrast, truncating mutations in the FBN1-TB5 have been reported only in Marfan syndrome. Acromelic dysplasia subtypes that share symptoms with Marfan syndrome are associated with FBN1-TB5 disulfide disruptions, which are also commonly found in Marfan syndrome. These results suggest that the type and location of mutations in the FBN1-TB5 region determine the clinical spectrum of fibrillinopathy.
https://doi.org/10.1002/bdr2.1814Disease 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.
