DeCure for PPARG-related familial partial lipodystrophy
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for PPARG-related familial partial lipodystrophy — 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 modulePPARG-related familial partial lipodystrophy 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 pparg-related familial partial lipodystrophy 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
peroxisome proliferator activated receptor gamma (PPARG) — PPARG 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 9cisdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3DZY · 3.1 Å · ligand (9cis)-retinoic acid (9CR). Experimental structure, not a prediction.
What the evidence adds up to
A three-generation Canadian kindred with partial lipodystrophy and a normal LMNA gene sequence carried a heterozygous T→A mutation in PPARG exon 5, predicting F388L in helix 8 of the ligand-binding pocket. The mutation was absent from unaffected family members and unrelated controls. The mutant receptor showed significantly decreased basal transcriptional activity and impaired stimulation by a synthetic ligand. The germline transmission of a transactivation-deficient PPARG mutant established that autosomal dominant partial lipodystrophy is genetically heterogeneous.
A separate kindred with partial lipodystrophy carried a C190S mutation in zinc-finger 2 of the DNA-binding domain. The mutation was absent from one unaffected family member and 124 controls. C190S PPARγ had significantly lower ability to activate a reporter gene than wild-type, both in the absence and presence of rosiglitazone, and showed reduced DNA-binding capacity. No dominant-negative effect was observed. In another family, a D424N substitution in the ligand-binding domain was found in two affected patients but not in an unaffected relative or 124 controls. D424N PPARγ had significantly lower transcriptional activity than wild-type and did not exert a negative effect on the wild-type protein. Partial activation of D424N PPARγ was achieved with rosiglitazone, suggesting possible treatment potential of that agent.
A Turkish family with a novel H449L PPARG mutation was compared with six subjects carrying the classic LMNA R482W mutation. Fat loss was generally less prominent in the PPARG group, limited to the extremities, with preserved truncal fat. All four H449L carriers had insulin resistance, hypertriglyceridaemia and non-alcoholic fatty liver disease, but severity was variable; three had overt diabetes or impaired glucose tolerance. Pioglitazone therapy in those three individuals resulted in modest improvement in metabolic control and, in the two female subjects, regular menstrual cycles. A 2019 review noted that studies delineating differential responsiveness of PPARγ mutants to endogenous and synthetic ligands illustrate the potential for pharmacogenetics to inform therapeutic decisions in PPARG-related lipodystrophy.
What is still missing is a sufficiently large cohort to stratify patients by specific PPARG mutation, because different mutants respond differently to thiazolidinediones and some may not respond at all. No randomised controlled trial of any PPARγ agonist in FPLD3 has been completed. Funding for natural history studies and genotype-phenotype correlation in this very rare condition remains scarce.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Diabetes · 2002 · 263 citations · open access
<i>PPARG</i> F388L, a Transactivation-Deficient Mutant, in Familial Partial Lipodystrophy
AbstractAutosomal dominant familial partial lipodystrophy (FPLD) due to mutant LMNA encoding nuclear lamin A/C is characterized by adipose tissue repartitioning together with multiple metabolic disturbances, including insulin resistance and dyslipidemia. There is emerging evidence that some rare mutations in peroxisome proliferator-activated receptor-gamma (PPAR-gamma), encoded by PPARG, might be associated with human lipodystrophy. We report a three-generation Canadian kindred ascertained based upon partial lipodystrophy, with a normal LMNA gene sequence. Candidate gene sequencing showed that all four affected subjects were heterozygous for a novel T-->A mutation at PPARG nucleotide 1164 in exon 5 that predicted substitution of phenylalanine at codon 388 by leucine (F388L). The mutation was absent from normal family members and normal unrelated subjects, and altered a highly conserved residue within helix 8 of the predicted ligand-binding pocket of PPAR-gamma. The mutant receptor had significantly decreased basal transcriptional activity and impaired stimulation by a synthetic ligand. The germline transmission of a transactivation-deficient mutation in PPARG suggests that autosomal dominant partial lipodystrophy is genetically heterogeneous. Our findings are consistent with the idea that mutant PPARG can underlie the partial lipodystrophy phenotype.
AbstractCONTEXT: Mutations in PPARG are associated with insulin resistance and familial partial lipodystrophy, a disease characterized by altered distribution of sc fat and symptoms of the metabolic syndrome. The encoded protein, peroxisome proliferator-activated receptor (PPAR)-gamma, plays a pivotal role in regulating lipid and glucose metabolism, the differentiation of adipocytes, and other cellular regulatory processes. OBJECTIVES: The objective of the study was to detect a novel PPARG mutation in a kindred with partial lipodystrophy and analyze the functional characteristics of the mutant protein. PATIENTS AND METHODS: In three subjects with partial lipodystrophy, one unaffected family member, and 124 unaffected subjects, PPARG was screened for mutations by direct sequencing. Body composition, laboratory abnormalities, and hepatic steatosis were assessed in each affected subject. Transcriptional activity was determined, and EMSA was performed to investigate DNA binding capacity of the mutant protein. RESULTS: We identified a PPARG mutation, C190S, causing partial lipodystrophy with metabolic alterations in three affected family members. The mutation was absent in the unaffected family member and unaffected controls. The mutation is located within zinc-finger 2 of the DNA binding domain. C190S PPARgamma has a significantly lower ability to activate a reporter gene than wild-type PPARgamma in absence and presence of rosiglitazone. A dominant-negative effect was not observed. Compared with wild-type PPARgamma, C190S PPARgamma shows a reduced capacity to bind DNA. CONCLUSION: Mutation of a zinc-binding amino acid of PPARgamma leads to an altered protein-DNA binding pattern, resulting in a partial loss of function, which in turn is associated with partial lipodystrophy.
Journal of Medical Genetics · 2007 · 39 citations · open access
New <i>PPARG</i> mutation leads to lipodystrophy and loss of protein function that is partially restored by a synthetic ligand
AbstractPURPOSE: Familial partial lipodystrophy caused by mutations in the PPARG gene is characterised by altered distribution of subcutaneous fat, muscular hypertrophy and symptoms of metabolic syndrome. PPARG encodes peroxisome proliferator-activated receptor (PPAR)gamma, a nuclear hormone receptor playing a crucial role in lipid and glucose metabolism and in several other cellular regulatory processes. METHODS: PPARG was screened for mutations by direct sequencing in two patients with lipodystrophy, one unaffected family member and 124 controls. Body composition was examined in affected patients, and they were investigated for abnormalities in laboratory results. Functional analysis of the mutant protein was assessed by determining transcriptional activity and possible interference with the wild-type protein. RESULTS: In two patients with familial partial lipodystrophy, we identified a nucleotide substitution in the PPARG gene. This mutation results in the substitution of aspartate by asparagine at residue 424 (D424N) in the ligand-binding domain of PPARgamma. The unaffected family member and all 124 controls did not carry this mutation. D424N PPARgamma had a significantly lower ability than wild-type PPARgamma to activate a PPARgamma-stimulated reporter gene, but did not exert a negative effect on the wild-type protein. Partial activation of D424N PPARgamma was achieved in the presence of the agonist rosiglitazone. CONCLUSION: We report a new PPARG mutation, D424N, which is located in the ligand-binding domain of the protein and leads to familial partial lipodystrophy. D424N PPARgamma exhibited a loss of function, which was partially restored by adding the PPARgamma agonist rosiglitazone, suggesting possible treatment potential of this agent.
Current Opinion in Lipidology · 2019 · 27 citations
Recent developments in lipodystrophy
AbstractPURPOSE OF REVIEW: Lipodystrophy syndromes have an estimated prevalence of 1.3-4.7 cases per million and as with other rare diseases conducting research can be challenging. The present review highlights recently published work that has provided insights into the field of non-HIV--associated lipodystrophy syndromes. RECENT FINDINGS: Lipodystrophies are a heterogenous group of disorders, as such research is often focused on specific subtypes of the condition. The identification of children carrying LMNA mutations has provided insights into the natural history of FPLD2, specifically that the adipose tissue phenotype predates the onset of puberty. Recent reports of PLIN1 heterozygous null variant carriers and the apparent absence of a lipodystrophy phenotype challenges our understanding of the molecular biology of perilipin 1 and its role in the pathogenesis of FPLD4. With a focus on therapeutics, studies delineating the differential responsiveness of PPARγ mutants to endogenous and synthetic ligands has illustrated the potential for pharmacogenetics to inform therapeutic decisions in lipodystrophy related to PPARG mutations, whereas robust human studies have provided insight into the food independent metabolic effects of leptin in lipodystrophy. Finally, rare syndromes of lipodystrophy continue to serve as an exemplar for the contribution of genetically determined adipose tissue expandability to metabolic disease in the general population. SUMMARY: Lipodystrophy research continues to illuminate our understanding of this rare disease and the possibility that lipodystrophy syndromes and the metabolic syndrome may have shared pathophysiology.
Diabetic Medicine · 2016 · 22 citations · open access
Familial partial lipodystrophy linked to a novel peroxisome proliferator activator receptor ‐γ (<i><scp>PPARG</scp></i>) mutation, H449L: a comparison of people with this mutation and those with classic codon 482 Lamin A/C (<i><scp>LMNA</scp></i>) mutations
AbstractAIMS: To describe the phenotype associated with a novel heterozygous missense PPARG mutation discovered in a Turkish family and to compare the fat distribution and metabolic characteristics of subjects with the peroxisome proliferator activator receptor -γ (PPARG) mutation with those of a cluster of patients with familial partial lipodystrophy with classic codon 482 Lamin A/C (LMNA) mutations. METHODS: The study involved four subjects with familial partial lipodystrophy who had a novel PPARG mutation (H449L) and six subjects with classic codon 482 LMNA mutations (R482W). RESULTS: Compared with subjects with LMNA R482W mutation, fat loss was generally less prominent in subjects with the PPARG H449L mutation. Partial fat loss was limited to the extremities, whilst truncal fat mass was preserved. The PPARG H449L mutation was associated with insulin resistance, hypertriglyceridaemia and non-alcoholic fatty liver disease in all affected subjects, but the severity was variable. Three out of four mutation carriers had overt diabetes or impaired glucose tolerance. Pioglitazone therapy in these three individuals resulted in a modest improvement in their metabolic control, and regular menstrual cycles in the two female subjects. CONCLUSIONS: We suggest that relatively modest fat loss in patients with PPARG mutations may render the recognition of the syndrome more difficult in routine clinical practice. The PPARG H449L mutation is associated with insulin resistance and metabolic complications, but their severity is variable among the affected subjects.
AbstractThe focus of this review is the lipodystrophy syndrome caused by mutation in the PPARγ nuclear receptor - partial familial lipodystrophy FPLD3. To provide a broader context for how these mutations act to generate the clinical features of partial lipodystrophy we will review the basic biology of PPARγ and also survey the set PPARγ genetic variants that do not cause lipodystrophy, but are nonetheless associated with clinically related syndromes, specifically type 2 diabetes.
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.
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