DeCure for Mitochondrial DNA depletion syndrome 7 (hepatocerebral type)
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mitochondrial DNA depletion syndrome 7 (hepatocerebral type) — 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 moduleMitochondrial DNA depletion syndrome 7 (hepatocerebral type) 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 mitochondrial dna depletion syndrome 7 (hepatocerebral type) 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
pitrilysin metallopeptidase 1 (PITRM1) — PITRM1 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 diphenylmethyldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4RPU · 2.265 Å · ligand [4-(diphenylmethyl)piperazin-1-yl](3-methyl-4-nitrophenyl)methanone (3UE). Experimental structure, not a prediction.
What the evidence adds up to
Mutations in MPV17 cause the hepatocerebral form of mitochondrial DNA depletion syndrome. In a yeast model carrying the orthologous SYM1 gene, seven patient-derived missense mutations all disrupted oxidative phosphorylation and mtDNA stability. All mutant proteins still reached the mitochondria, and only one mutation clearly reduced protein stability. The common defect was failure to assemble into a high molecular weight complex of unknown composition, with mutant proteins found free or in partially assembled forms.
A 2013 study reported four Polish infants from two unrelated families with a novel homozygous p.Pro64Arg MPV17 mutation. Disease began in the first weeks of life with failure to thrive, hypotonia, and liver dysfunction, and relatively mild neurological involvement. All four died before one year of age. Laboratory findings included progressive liver failure, recurrent hypoglycaemia, lactic acidaemia, hyperferritinaemia, and increased transferrin saturation. Post-mortem liver samples from two patients showed a severe reduction in the mtDNA/nuclear DNA ratio, and western blotting showed low levels of complexes I, III, and IV. The authors noted that the p.Pro64Arg phenotype differed from that of the more common p.Arg50Gln mutation, suggesting a genotype-phenotype correlation.
A 2018 histopathology review of 13 children who died of hepatocerebral mitochondrial depletion syndrome, including cases with DGUOK, MPV17, and POLG mutations, found a moderately reproducible pattern of liver parenchymal damage in autopsy and biopsy specimens. The authors considered this pattern potentially helpful for differential diagnosis and for guiding diagnostic investigation in families of children who died from early-onset acute liver failure and encephalopathy.
No treatment or intervention was tested in any of these studies. What remains missing is any clinical trial, any attempt to raise mtDNA copy number or restore complex assembly, and any patient stratification beyond the genetic diagnosis itself. Funding for basic research on the high molecular weight complex and for any therapeutic development in this uniformly fatal infantile disease is absent.
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 Pediatric Gastroenterology and Nutrition · 2018 · 15 citations
Severe Deoxyguanosine Kinase Deficiency in Austria
AbstractMutations in the nuclear gene DGUOK, encoding deoxyguanosine kinase, cause an infantile hepatocerebral type of mitochondrial depletion syndrome (MDS). We report 6 MDS patients harboring bi-allelic DGUOK mutations, of which 3 are novel, including a large intragenic Austrian founder deletion. One patient was diagnosed with hepatocellular carcinoma aged 6 months, supporting a link between mitochondrial DNA depletion and tumorigenesis; liver transplantation proved beneficial with regard to both tumor treatment and psychomotor development.
Pathological alleles of MPV17 modeled in the yeast Saccharomyces cerevisiae orthologous gene SYM1 reveal their inability to take part in a high molecular weight complex
AbstractMitochondrial DNA depletion syndromes (MDDS) are a genetically and clinically heterogeneous group of human diseases caused by mutations in nuclear genes and characterized by a severe reduction in mitochondrial DNA (mtDNA) copy number leading to impaired energy production in affected tissues and organs. Mutations in the MPV17 gene, whose role is still elusive, were described as cause of the hepatocerebral form of MDDS and Navajo neuro-hepathopathy. The high degree of conservation observed between MPV17 and its yeast homolog SYM1 made the latter a good model for the study of the pathology. Here, we used Saccharomyces cerevisiae to elucidate the molecular consequences of seven MPV17 missense mutations identified in patients and localized in different protein domains. The phenotypic analysis of the appropriate sym1 mutant strains created demonstrated deleterious effect for all mutations regarding OXPHOS metabolism and mtDNA stability. We deepened the pathogenic effect of the mutations by investigating whether they prevented the correct protein localization into the mitochondria or affected the stability of the proteins. All the Sym1 mutant proteins correctly localized into the mitochondria and only one mutation predominantly affects protein stability. All the other mutations compromised the formation of the high molecular weight complex of unknown composition, previously identified both in yeast, cell cultures and mouse tissues, as demonstrated by the consistent fraction of the Sym1 mutant proteins found free or in not fully assembled complex, strengthening its role as protein forming part of a high molecular weight complex.
Novel c.<scp>191C</scp>>G (p.<scp>Pro64Arg</scp>) <i><scp>MPV17</scp></i> mutation identified in two pairs of unrelated Polish siblings with mitochondrial hepatoencephalopathy
AbstractThis study reports clinical, biochemical and histopathological findings associated with a novel homozygous MPV17 mutation in four patients with mitochondrial depletion syndrome. The severe course of the disease, which started in the first weeks of life, was dominated by a failure to thrive, hypotonia and liver dysfunction, with relatively mild neurological involvement. All affected infants died by 1 year of age. Laboratory findings included progressive liver failure (hypertransaminasaemia, icterus, and coagulopathy), recurrent hypoglycaemia, lactic acidaemia, hyperferritinaemia, and increased transferrin saturation. Histological and ultrastructural analyses uncovered significant lipid accumulation in hepatocytes and myocytes. A severe decrease in the mitochondrial/nuclear DNA (mtDNA/nDNA) ratio was found post-mortem in the livers (and in one muscle specimen) of both examined patients. Oxidative phosphorylation system (OXPHOS) Western blotting revealed low levels of complexes I, III and IV subunits. The highlights of our findings are as follows: (i) The novel p.Pro64Arg mutation is the second recurrent MPV17 mutation reported. The phenotype associated with the p.Pro64Arg mutation differs from the phenotype of the relatively common p.Arg50Gln mutation, suggesting the existence of a genotype-phenotype correlation. (ii) Tissues collected from patients during autopsy may be useful for both mtDNA/nDNA ratio assessment and OXPHOS Western blotting.
Polish Journal of Pathology · 2018 · 6 citations · open access
Histopathological liver findings in patients with hepatocerebral mitochondrial depletion syndrome with defined molecular basis
AbstractMitochondrial DNA depletion consisting of the systemic reduction of mtDNA copy number in cells may have a heterogenous genetic basis, resulting from a pathogenic change in the nuclear genes involved in mtDNA synthesis. The mode of inheritance is autosomal recessive. Severe hepatocerebral disease represents one of many different clinical forms of so-called mitochondrial depletion syndrome (MDS). We present the liver histopathology of 13 children who eventually died in the course of hepatocerebral MDS confirmed molecularly, harbouring mutations of <i>DGUOK</i>, <i>MPV17</i>, and <i>POLG </i>genes. Material comprising eight autopsy and five liver biopsy specimens showed a moderately reproducible pattern of parenchymal damage, which we consider potentially helpful in the differential diagnosis and planning of the diagnostic investigation in families of children who died due to early-onset acute liver failure and encephalopathy.
Deoxyribonucleotides and Disorders of Mitochondrial DNA Integrity
AbstractMitochondrial DNA (mtDNA) depends on numerous nuclear encoded factors and a constant supply of deoxyribonucleoside triphosphates (dNTP), for its maintenance and replication. The function of proteins involved in nucleotide metabolism is perturbed in a heterogeneous group of disorders associated with depletion, multiple deletions, and mutations of the mitochondrial genome. Disturbed homeostasis of the mitochondrial dNTP pools are likely the underlying cause. Understanding of the biochemical and molecular basis of these disorders will promote the development of new therapeutic approaches. This article reviews the current knowledge of deoxyribonucleotide metabolism in relation to disorders affecting mtDNA integrity.
Clinical and molecular characterization of three patients with Hepatocerebral form of mitochondrial DNA depletion syndrome: a case series
AbstractAbstract Background Mitochondrial DNA depletion syndromes (MDS) are clinically and phenotypically heterogeneous disorders resulting from nuclear gene mutations. The affected individuals represent a notable reduction in mitochondrial DNA (mtDNA) content, which leads to malfunction of the components of the respiratory chain. MDS is classified according to the type of affected tissue; the most common type is hepatocerebral form, which is attributed to mutations in nuclear genes such as DGUOK and MPV17. These two genes encode mitochondrial proteins and play major roles in mtDNA synthesis. Case presentation In this investigation patients in three families affected by hepatocerebral form of MDS who were initially diagnosed with tyrosinemia underwent full clinical evaluation. Furthermore, the causative mutations were identified using next generation sequencing and were subsequently validated using sanger sequencing. The effect of the mutations on the gene expression was also studied using real-time PCR. A pathogenic heterozygous frameshift deletion mutation in DGUOK gene was identified in parents of two affected patients (c.706–707 + 2 del: p.k236 fs) presenting with jaundice, impaired fetal growth, low-birth weight, and failure to thrive who died at the age of 3 and 6 months in family I. Moreover, a novel splice site mutation in MPV17 gene (c.461 + 1G > C) was identified in a patient with jaundice, muscle weakness, and failure to thrive who died due to hepatic failure at the age of 4 months. A 5-month-old infant presenting with jaundice, dark urine, poor sucking, and feeding problems was also identified to have another novel mutation in MPV17 gene leading to stop gain mutation (c.277C > T: p.(Gln93*)). Conclusions These patients had overlapping clinical features with tyrosinemia. MDS should be considered a differential diagnosis in patients presenting with signs and symptoms of tyrosinemia.
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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