DeCure for Holoprosencephaly 12 with or without pancreatic agenesis
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for holoprosencephaly 12 with or without pancreatic agenesis — 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 moduleHoloprosencephaly 12 with or without pancreatic agenesis 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 holoprosencephaly 12 with or without pancreatic agenesis 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
CCR4-NOT transcription complex subunit 1 (CNOT1) — CNOT1 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 8FY3 · 2.88 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Complete agenesis of the pancreas is a rare and usually lethal condition. A 1994 case report describes a child who died 48 hours after birth with severe metabolic acidosis, the pancreas being the only absent organ. By 1998, only 11 cases had been reported in the literature, with associated findings including maternal diabetes, intrauterine growth retardation, sacral agenesis, and absence of the gall bladder. One case was the product of a brother-sister relationship, suggesting a genetic origin.
A 1997 study identified a single-base-pair deletion in codon 63 of the IPF1 gene (also called PDX1) in a patient with pancreatic agenesis. The patient was homozygous for the mutation; both parents were heterozygous. The mutation caused a frameshift that produced a truncated 13.2-kDa protein lacking the DNA-binding domain and nuclear localisation signal, which was confirmed to remain in the cytoplasm of Cos-1 cells. That patient had intrauterine growth retardation, neonatal diabetes, and exocrine pancreatic insufficiency, but was alive and doing well at 5 years of age on insulin and pancreatic enzyme supplements.
In mice, simultaneous deletion of both Gata4 and Gata6 in the pancreas caused severe pancreatic agenesis due to disrupted progenitor cell proliferation, defective branching morphogenesis, and failure to induce differentiation of CPA1- and NEUROG3-expressing cells. Loss of either Gata4 or Gata6 alone produced only mild defects that resolved postnatally. The IPF1/PDX1 gene is essential for proliferation and branching of the pancreatic dorsal bud in mice, and its human homologue is responsible for the agenesis case described. Other genes such as isl-1, pax4, and pax6 have been identified in mice as critical for islet cell development, but their roles in human pancreatic agenesis are not yet known.
What is still missing is a systematic understanding of how many genes can cause this condition in humans, and whether the GATA4/GATA6 pathway is involved in human cases beyond the mouse model. No clinical trial or treatment beyond insulin and enzyme replacement has been tested. Patient stratification by genotype is not yet possible because so few cases have been genetically characterised.
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 Clinical Investigation · 2012 · 167 citations · open access
Pancreas-specific deletion of mouse Gata4 and Gata6 causes pancreatic agenesis
AbstractPancreatic agenesis is a human disorder caused by defects in pancreas development. To date, only a few genes have been linked to pancreatic agenesis in humans, with mutations in pancreatic and duodenal homeobox 1 (PDX1) and pancreas-specific transcription factor 1a (PTF1A) reported in only 5 families with described cases. Recently, mutations in GATA6 have been identified in a large percentage of human cases, and a GATA4 mutant allele has been implicated in a single case. In the mouse, Gata4 and Gata6 are expressed in several endoderm-derived tissues, including the pancreas. To analyze the functions of GATA4 and/or GATA6 during mouse pancreatic development, we generated pancreas-specific deletions of Gata4 and Gata6. Surprisingly, loss of either Gata4 or Gata6 in the pancreas resulted in only mild pancreatic defects, which resolved postnatally. However, simultaneous deletion of both Gata4 and Gata6 in the pancreas caused severe pancreatic agenesis due to disruption of pancreatic progenitor cell proliferation, defects in branching morphogenesis, and a subsequent failure to induce the differentiation of progenitor cells expressing carboxypeptidase A1 (CPA1) and neurogenin 3 (NEUROG3). These studies address the conserved and nonconserved mechanisms underlying GATA4 and GATA6 function during pancreas development and provide a new mouse model to characterize the underlying developmental defects associated with pancreatic agenesis.
AbstractComplete agenesis of pancreas is a rare and lethal condition. Four cases have previously been reported in combination with other malformations, such as severe intrauterine growth retardation, hyperglycaemia and meconium ileus. We report a case of pancreatic agenesis as a single anomaly. The child died when 48 h old with severe metabolic acidosis. The literature is surveyed and the pathogenesis is discussed.
Journal of Pediatric Gastroenterology and Nutrition · 1998 · 0 citations
Genes in the Development of the Pancreas
AbstractPancreatic Agenesis Attributable to a Single Nucleotide Deletion in the Human IPF1 Gene Coding Sequence. Stoffers DA, Zinkin NT, Stanojevic, Clarke WL, Habener JF. Nature Genetics 1997;15:106-10. Summary: A patient with pancreatic agenesis had a singlebase-pair deletion in codon 63 of the insulin promoter factor gene (ipf1), which encodes for a transcription factor that is critical in the development of the pancreas in mice. Both parents were heterozygous for this frameshift mutation. Conceptual translation of the mutant gene product predicts a truncated 13.2-kDa protein with 59 novel codons. Expression of the mutantipf1 in Cos-1 cells confirmed the expression of a truncated 13.2-kDa protein of the predicted size. Because the mouse and human ipf1 genes exhibit 100% amino acid identity in their homeodomain regions, this protein appears likely to be critical for normal pancreatic development in humans as well as in mice. Review: Complete pancreatic agenesis is a rare disorder, usually resulting in death in infancy, secondary to diabetes mellitus. Associated findings have included maternal diabetes, intrauterine growth retardation, sacral agenesis, severe acidosis, and absence of the gall bladder. Only 11 cases have been reported (Nat Genet 1997;15:106-10; Helv Paediatr Acta 1970;5:522-6; Prenat Diagn 1991;11:329-31;Acta Paediatr 1994;83:791-3). One case was the product of a brother-sister relationship, suggesting that this defect may be of genetic origin (Acta Paediatr Acad Sci Hung 1976;17:175-176). A related condition, partial pancreatic agenesis or agenesis of the dorsal pancreas, is more common but has also been associated with diabetes melitis and with congenital heart disease, polysplenia, and recurrent pancreatitis(Pancreas 1990;5:493-7; Gastroenterology 1993;104:1182-6;J Med Genet 1994;31:331-3; Dig Dis Sci 1994;391708-13;Gastrointest Endosc 1995;42:485-8). Familial occurrence of partial pancreatic agenesis has been reported (Gastroenterology 1993;104:1182-6; Gastrointest Endosc 1995;42:485-8). The cause of these rare conditions has been a matter of speculation. In the human fetus, the pancreas develops as dorsal and ventral outpouchings of the foregut at 5 weeks of gestation. Rotation and fusion of these anlage produce the developed pancreas. The mystery of the origins of the different types of tissues and organs and their positioning in the developing embryo is yielding its secrets to the new tools of molecular biology. Differential expression of select sets of genes from among the 100,000 genes present in our genome confers the unique phenotype of each cell type and also the patterning of the embryo. The precise location of individual organs in the developing embryo of all animals including vertebrates is under the control of a unique set of genes, the HOX genes, first discovered in insects and named the homeotic complex(HOM-C). The HOX genes are highly conserved and appear to have evolved by duplication and divergence from a common ancestral cluster. In mammals, there are 38 HOX genes grouped into 13 paralogous sets arranged in 4 clusters. These genes assign the positional identity to cells along the anteroposterior axis of the developing embryo. Mutations in the HOX genes cause transformation of embryonic tissues from one segment to that of another segment, resulting in inappropriate positioning of organs, thus producing flies with extra sets of wings or with various head anomalies (e.g., legs instead of antennae). Thus a missing organ, as occurs in pancreatic agenesis, might be secondary to mutations in one or more paralogs in one or more HOX clusters. Stoffers et al. describe the genetic mutation associated with pancreatic agenesis in an infant. This infant had intrauterine growth retardation, neonatal diabetes, and exocrine pancreatic insufficiency. The absence of the pancreas was confirmed by ultrasound. The parents were not related. The infant was treated with insulin and pancreatic enzyme supplements and was doing well at 5 years of age. The patient was homozygous for a point mutation in the gene encoding a homeobox class transcription factor. Both parents were heterozygous for this single nucleotide deletion. Deletion of cytosine in codon 63 caused a frameshift that resulted in a nonfunctional 13.2-kDa protein containing a novel sequence of 59 amino acids but not the DNA binding domain or the nuclear localization signal. In vitro expression and immunocytochemical analysis of the mutant gene in Cos cells showed cytoplasmic localization of the truncated protein confirming the absence of a nuclear localization signal. The ipf gene, a homologue of the Xenopus laevis homebox gene, XIHbox-8 (not a member of the HOX gene cluster), codes for a transcription factor and is expressed in the entire early pancreatic rudiment and in part of the surrounding posterior foregut in the 15-20 somite stage rodent embryo. In adults, ipf1 is expressed only in the B cells and hence was named Idx1 (islet duodenal homeobox gene-1). The IPF1 protein binds to the insulin and somatostatin gene promoters and activates these genes in rodents. The gene, now renamed pdx-1 (pancreatic and duodenal homeobox gene-1), is a homologue of the vertebrate homeobox genes, including Hox 11 and pit-1, whose disruption in mice, results in asplenia and reduced or absent pituitary, respectively. Offield et al. demonstrated by targeted pdx-1 gene disruption analysis in mice that this gene is essential for proliferation and branching of the pancreatic dorsal bud but is not essential for the formation of the buds themselves(Development 1996;122:1409-16). A point mutation in the human homologue of this gene is responsible for pancreatic agenesis, as reported by Stoffers et al. Thus ipf1/stf-1/pdx-1/idx-1 may not be the master gene that initiates the formation of the embryonic pancreatic buds, but it is essential for the differentiation and proliferation of the dorsal bud that forms the dorsal pancreas. Ahlgren et al. reported that in homozygous pdx-1 mice the epithelium of the pancreatic bud is defective, whereas the mutant pancreatic mesenchyme is normal and is capable of serving as a functional inducing agent for wild-type pancreas (Nature 1997;385:257-60). Stoffers now documents that ipf1 is essential for pancreatic development in humans as well. Recently, Ahlgren et al. identified another (LIM class) homeobox gene,isl-1, as essential for the formation of islet cells in mice(Nature 1997;385:257-60). This gene, required for the development of acinar and islet cells, is expressed in the dorsal pancreatic epithelium and the surrounding mesenchyme in the 15-16 somite stage mouse embryo. Acinar, but not islet, cells develop from mutant epithelium when cultured with wild-type mesenchyme, suggesting that isl-1 may be the master gene for islet cell development. Isl-1 functions downstream from pdx-1, which promotes proliferation, differentiation, and branching of pancreatic cells. Whether all pancreatic cells transformed with a functionalisl-1 gene develop into islet cells and what the role of the human homologue is are not yet known. Recent studies by Sosa-Pineda et al. and St. Onge et al. identified the specific genes required for the development of islet cells into glucagon or insulin-producing cells in mice (Nature 1997;386:399-402;Nature 1997;387:406-9). Pax 4 and pax 6, two other homeobox genes identified by targeted disruption and reporter expression analysis, play a critical role in development of insulin- and glucagon-producing cells, respectively. We do not yet know the genes that specify the embryonic duodenal cells to form pancreatic buds, but it is clear that the information will be soon forthcoming. Thus, the results of the work by Stoffers et al. show that a gene involved in pancreatic development in humans forms an integral part of the equivalent genetic network involved in the development of the pancreas in mice. *Steven L. Werlin †A. Krishna Kumaran *Department of Pediatrics; Medical College of Wisconsin; Milwaukee, Wisconsin, U.S.A. †Department of Biology; Marquette University; Milwaukee, Wisconsin, U.S.A.
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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