DeCure for PLIN1-related familial partial lipodystrophy
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for PLIN1-related familial partial lipodystrophy — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease modulePLIN1-related familial partial lipodystrophy maps to a 1-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 plin1-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.
What the evidence adds up to
Perilipin (PLIN1) is a constitutive adipocyte lipid droplet coat protein. In 2011, two different C-terminal PLIN1 frame shift mutations (Leu-404fs and Val-398fs) were identified in patients with a novel subtype of partial lipodystrophy, hypertriglyceridemia, severe insulin resistance, and type 2 diabetes. When overexpressed in preadipocytes, both mutants fail to inhibit basal lipolysis. Bimolecular fluorescence complementation assays showed that the mutants fail to bind ABHD5, permitting its constitutive coactivation of ATGL, resulting in increased basal lipolysis. siRNA-mediated knockdown of either ABHD5 or ATGL expression in stably transfected cells expressing mutant PLIN1 reduced basal lipolysis. The 2011 authors suggested that pharmacological inhibition of ATGL could have therapeutic potential.
A 2018 study sequenced PLIN1 in 2208 individuals and identified 6 (1 in 368) with a PLIN1 null variant; none had clinical or biochemical evidence of overt lipodystrophy. In the type 2 diabetes knowledge portal, 14 of 17,000 individuals (1 in 1214) with PLIN1 null variants showed no association with biomarkers of lipodystrophy. PLIN1 null variants occurred too frequently in gnomAD (126 of 138,632; 1 in 1100) to be a cause of rare overt monogenic partial lipodystrophy. The 2018 authors concluded that heterozygous variants predicted to result in PLIN1 haploinsufficiency are not a cause of familial partial lipodystrophy and should not be reported as disease-causing. A 2019 review noted that these reports of PLIN1 heterozygous null variant carriers with apparent absence of a lipodystrophy phenotype challenge the understanding of perilipin 1's role in the pathogenesis of FPLD4.
A 2019 study of 11 new patients from 5 independent families with heterozygous frameshift variants of PLIN1 described three variants: p.Val398Glyfs*167, and two new variants p.Gly362Glyfs*63 and p.Pro403Argfs*164. On adipose tissue samples, the PLIN1 variant led to an abnormal longer form of perilipin 1 with fat fibrosis. The main signs of FPLD4 included partial but sometimes generalised lipoatrophy of post-pubertal occurrence, muscular hypertrophy, acromegaloid facies, hirsutism, and metabolic complications (hypertriglyceridemia, insulin-resistance, diabetes, liver steatosis). Lipoatrophy might be missing or difficult to identify in men and youth. Leptin level was low or inappropriate to BMI, which was below 30 but not always very low. A 2023 prospective observational study in a Greek referral centre enrolled 39 patients who fulfilled clinical criteria of FPLD; genetic analysis included sequence and deletion/duplication analyses of LMNA and PPARG, but not PLIN1. In most patients no significant changes were detected at the exon level, and any mutations that led to changes at the protein level were not associated with the lipodystrophic phenotype. Treatment with metreleptin in specific FPLD patients significantly improved glycemic and lipidemic control, sustained at 12-month follow-up.
A 2024 systematic review noted that the function of perilipin 1 in human metabolism was recently highlighted by PLIN1 variants associated with severe familial partial lipodystrophy and early onset acute coronary syndrome, while certain variants have been reported to have a protective effect on cardiovascular disease. The role of this protein remains controversial in mice and variant interpretation in humans is still conflicting. What is still missing is a clear understanding of which PLIN1 variants are truly pathogenic versus benign, given that null variants appear not to cause disease while specific frameshift mutations do. Large-scale studies clarifying the genetic and allelic heterogeneity of the disease, along with parameters predicting treatment response, are lacking. No clinical trial of ATGL inhibition in PLIN1-related lipodystrophy has been reported.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Biological Chemistry · 2011 · 100 citations · open access
Human Frame Shift Mutations Affecting the Carboxyl Terminus of Perilipin Increase Lipolysis by Failing to Sequester the Adipose Triglyceride Lipase (ATGL) Coactivator AB-hydrolase-containing 5 (ABHD5)
AbstractPerilipin (PLIN1) is a constitutive adipocyte lipid droplet coat protein. N-terminal amphipathic helices and central hydrophobic stretches are thought to anchor it on the lipid droplet, where it appears to function as a scaffold protein regulating lipase activity. We recently identified two different C-terminal PLIN1 frame shift mutations (Leu-404fs and Val-398fs) in patients with a novel subtype of partial lipodystrophy, hypertriglyceridemia, severe insulin resistance, and type 2 diabetes (Gandotra, S., Le Dour, C., Bottomley, W., Cervera, P., Giral, P., Reznik, Y., Charpentier, G., Auclair, M., Delépine, M., Barroso, I., Semple, R. K., Lathrop, M., Lascols, O., Capeau, J., O'Rahilly, S., Magré, J., Savage, D. B., and Vigouroux, C. (2011) N. Engl. J. Med. 364, 740-748.) When overexpressed in preadipocytes, both mutants fail to inhibit basal lipolysis. Here we used bimolecular fluorescence complementation assays to show that the mutants fail to bind ABHD5, permitting its constitutive coactivation of ATGL, resulting in increased basal lipolysis. siRNA-mediated knockdown of either ABHD5 or ATGL expression in the stably transfected cells expressing mutant PLIN1 reduced basal lipolysis. These insights from naturally occurring human variants suggest that the C terminus sequesters ABHD5 and thus inhibits basal ATGL activity. The data also suggest that pharmacological inhibition of ATGL could have therapeutic potential in patients with this rare but metabolically serious disorder.
Cardiovascular Research · 2024 · 37 citations · open access
Perilipin 1: a systematic review on its functions on lipid metabolism and atherosclerosis in mice and humans
AbstractThe function of perilipin 1 in human metabolism was recently highlighted by the description of PLIN1 variants associated with various pathologies. These include severe familial partial lipodystrophy and early onset acute coronary syndrome. Additionally, certain variants have been reported to have a protective effect on cardiovascular diseases. The role of this protein remains controversial in mice and variant interpretation in humans is still conflicting. This literature review has two primary objectives (i) to clarify the function of the PLIN1 gene in lipid metabolism and atherosclerosis by examining functional studies performed in cells (adipocytes) and mice and (ii) to understand the impact of PLIN1 variants identified in humans based on the variant's location within the protein and the type of variant (missense or frameshift). To achieve these objectives, we conducted an extensive analysis of the relevant literature on perilipin 1, its function in cellular models and mice, and the consequences of its mutations in humans. We also utilized bioinformatics tools and consulted the Human Genetics Cardiovascular Disease Knowledge Portal to enhance the pathogenicity assessment of PLIN1 missense variants.
The Journal of Clinical Endocrinology & Metabolism · 2018 · 28 citations · open access
PLIN1 Haploinsufficiency Is Not Associated With Lipodystrophy
AbstractContext: Monogenic partial lipodystrophy is a genetically heterogeneous disease where only variants with specific genetic mechanisms are causative. Three heterozygous protein extending frameshift variants in PLIN1 have been reported to cause a phenotype of partial lipodystrophy and insulin resistance. Objective: We investigated if null variants in PLIN1 cause lipodystrophy. Methods: As part of a targeted sequencing panel test, we sequenced PLIN1 in 2208 individuals. We also investigated the frequency of PLIN1 variants in the gnomAD database, and the type 2 diabetes knowledge portal. Results: We identified 6/2208 (1 in 368) individuals with a PLIN1 null variant. None of these individuals had clinical or biochemical evidence of overt lipodystrophy. Additionally, 14/17,000 (1 in 1214) individuals with PLIN1 null variants in the type 2 diabetes knowledge portal showed no association with biomarkers of lipodystrophy. PLIN1 null variants occur too frequently in gnomAD (126/138,632; 1 in 1100) to be a cause of rare overt monogenic partial lipodystrophy. Conclusions: Our study suggests that heterozygous variants that are predicted to result in PLIN1 haploinsufficiency are not a cause of familial partial lipodystrophy and should not be reported as disease-causing variants by diagnostic genetic testing laboratories. This finding is in keeping with other known monogenic causes of lipodystrophy, such as PPARG and LMNA, where only variants with specific genetic mechanisms cause lipodystrophy.
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.
International Journal of Molecular Sciences · 2023 · 10 citations · open access
Familial Partial Lipodystrophy: Clinical Features, Genetics and Treatment in a Greek Referral Center
AbstractFamilial partial lipodystrophy (FPLD) is a rare syndrome in which a patient's phenotype is not merely dependent on the specific genetic mutation, but it is also defined by a combination of other demographic, environmental and genetic factors. In this prospective observational study in a Greek referral center, we enrolled 39 patients who fulfilled the clinical criteria of FPLD. A genetic analysis was conducted, which included sequence and deletion/duplication analyses of the LMNA and PPRARG genes, along with anthropometric and metabolic parameters. The treatment responses of patients who were eligible for treatment with metreleptin were evaluated at 3 and 12 months. In most of the patients, no significant changes were detected at the exon level, and any mutations that led to changes at the protein level were not associated with the lipodystrophic phenotype. On the contrary, various changes were detected at the intron level, especially in introns 7 and 10, whose clinical significance is considered unknown. In addition, treatment with metreleptin in specific FPLD patients significantly improved glycemic and lipidemic control, an effect which was sustained at the 12-month follow-up. More large-scale studies are necessary to clarify the genetic and allelic heterogeneity of the disease, along with other parameters which could predict treatment response.
Journal of the Endocrine Society · 2019 · 0 citations · open access
SUN-037 Diagnosis Challenge in Type 4 Familial Partial Lipodystrophic Syndrome
AbstractIntroduction: Type 4 familial partial lipodystrophic syndrome (FPLD4) is an autosomal dominant disease due to frameshift variants of PLIN1 gene. This gene encodes perilipin 1, a protein playing a key role in the structure of the adipocyte lipid droplet and in the regulation of lipolysis. Only 6 independent families with FPLD4 have been described. The aim of this work was to identify the major signs of the disease in the largest cohort of FPLD4 patients reported to date. Patients and Methods: Clinical and biological phenotype of 11 new patients with a family history of lipodystrophic syndrome and bearing a frameshift variant of PLIN1 gene, were investigated after written informed consent. Histological examination, and perilipin 1 protein expression analyses by western blot on whole cell extracts were performed on biopsies of adipose tissue in 2 patients. Results: We identified 3 heterozygous frameshift variants of PLIN1, segregating with the disease in 11 patients from 5 independent families. Our team had already described the p.Val398Glyfs*167 variant, and 2 new variants p.Gly362Glyfs*63 and p.Pro403Argfs*164 were identified. In all patients next generation sequencing (NGS) excluded any other molecular defect known to be responsible for lipodystrophy. On the studied adipose tissue samples, the PLIN1 variant leads to an abnormal longer form of perilipin 1 with fat fibrosis. The main signs of FPLD4 associate a partial, but also sometimes generalized lipoatrophy of post-pubertal occurrence and a phenotype of variable severity including muscular hypertrophy, acromegaloid facies, hirsutism, and metabolic complications (hypertriglyceridemia, insulin-resistance, diabetes, liver steatosis). Lipoatrophy might be missing or difficult to identify in men and youth. Leptin level was low or inappropriate to BMI, which was below 30 but not always very low. Conclusion: The clinical phenotype of FPLD4 is quite homogeneous, but the clinical diagnosis requires a careful clinical examination and/or an expert advice. An early genetic diagnosis is recommended to confirm the disease and prevent metabolic complications.
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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