DeCure for Dyskeratosis congenita, autosomal recessive 1
DeCure's autonomous Dermatology AI scientist is researching a drug-repurposing hypothesis for dyskeratosis congenita, autosomal recessive 1 — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleDyskeratosis congenita, autosomal recessive 1 maps to a 3-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 dyskeratosis congenita, autosomal recessive 1 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
regulator of telomere elongation helicase 1 (RTEL1) — RTEL1 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 8P8H · 2.3 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Dyskeratosis congenita is a rare hereditary disease that occurs predominantly in males. The classic clinical triad is reticulate hyperpigmentation, nail dystrophy and leukoplakia. The disease increases the risk of malignancy and other potentially lethal complications such as bone marrow failure, lung and liver diseases. Mutations in 19 genes are associated with the condition, and a fifth of pathogenic mutations are found in DKC1, the gene coding for dyskerin. Inheritance patterns include X-linked recessive, autosomal dominant and autosomal recessive, but in 30–40% of patients the inheritance pattern remains unknown.
In one Japanese kindred, two male patients with X-linked dyskeratosis congenita were found to share a novel missense mutation L398P in the DKC1 gene, a T-to-C transition at nucleotide 1285 in exon 12. Despite carrying the same mutation, one patient had significantly milder haematological symptoms than the other, indicating that other factors determine disease severity. No treatment or drug intervention was tested in that report.
The 2019 review notes that dyskeratosis congenita is difficult to diagnose because of its genetic and clinical heterogeneity. The 2020 review is a literature review that addresses clinical and genetic aspects but does not report any therapeutic trial. No abstract describes a drug being tested in patients with dyskeratosis congenita, autosomal recessive 1 or any other subtype. What is still missing is any clinical trial data, any funded drug-repurposing study, and any patient stratification strategy that might account for the variable severity seen even within families carrying the same mutation.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
JDDG Journal der Deutschen Dermatologischen Gesellschaft · 2020 · 63 citations
Dyskeratosis congenita: a literature review
AbstractDyskeratosis congenita is a rare hereditary disease that occurs predominantly in males and manifests clinically as the classic triad of reticulate hyperpigmentation, nail dystrophy and leukoplakia. It increases the risk of malignancy and other potentially lethal complications such as bone marrow failure, lung and liver diseases. Mutations in 19 genes are associated with dyskeratosis congenita, and a fifth of the pathogenic mutations are found in DKC1, the gene coding for dyskerin. This review aims to address the clinical and genetic aspects of the disease.
European Respiratory Journal · 2013 · 56 citations · open access
Pulmonary fibrosis in dyskeratosis congenita with<i>TINF2</i>gene mutation
AbstractTo the Editor:
Dyskeratosis congenita is a rare inherited disorder of ectodermal dysplasia characterised by the classical mucocutaneous triad of abnormal skin pigmentation, nail dystrophy and leukoplakia [1–3], at least one of which is present in around 80–90% of dyskeratosis congenita cases. Bone marrow failure is another common feature, and a variety of other abnormalities ( e.g. dental, gastrointestinal, neurological, ophthalmic, pulmonary and skeletal) have been also described [1–3]. The main causes of mortality in dyskeratosis congenita are bone marrow failure, pulmonary disease and malignancy [1]. Three modes of inheritance have been recognised: X-linked recessive, autosomal dominant and autosomal recessive [1, 3]. Eight dyskeratosis congenita genes ( DKC1 (dyskeratosis congenita 1), TERC (telomerase RNA component), TERT (telomerase reverse transcriptase), NOP10 (nucleolar protein 10), NHP2 , TINF2 (TERF1-interacting nuclear factor 2), TCAB1 and RTEL1 (regulation of telomere elongation helicase 1)) have already been identified, and their mutations account for ∼60% of all dyskeratosis congenita cases [1]. Among the dyskeratosis congenita genes, mutations in TERC , TERT and DKC1 have recently been reported to be associated with familial pulmonary fibrosis and idiopathic pulmonary fibrosis, and pulmonary fibrosis is recognised as one of the features of dyskeratosis congenita. However, the relationship between mutations in the other dyskeratosis congenita genes and pulmonary fibrosis has not yet been clarified. To the best of our knowledge, this is the first case report describing a dyskeratosis congenita patient with pulmonary fibrosis who had a TINF2 mutation.
A 43-year-old female visited our hospital with cough and progressive dyspnoea. She had never smoked, and had a …
Journal of Pediatric Gastroenterology and Nutrition · 2009 · 28 citations
Severe Variant of X‐linked Dyskeratosis Congenita (Hoyeraal‐Hreidarsson Syndrome) Causes Significant Enterocolitis in Early Infancy
AbstractHoyeraal-Hreidarsson syndrome (HHS, OMIM 300240) is a severe clinical variant of X-linked dyskeratosis congenita (DC) (1,2). In the majority of patients, the disease is caused by mutations in the X-linked dyskeratosis congenita gene DKC1(3). Mutations within the same regions in the DKC1 gene can cause either the clinical phenotype of HHS or DC. DKC1 encodes for the nucleoprotein dyskerin, which is a cofactor of human telomerase responsible for maintaining telomere length after DNA replication (4). In contrast to dyskeratosis congenita HHS manifests within the first years of life (5). The disease is characterized by progressive bone marrow failure with pancytopenia and concomitant immunodeficiency with several phenotypes (most commonly B- and natural killer [NK]–cell deficiency) (6). Neurological features are ataxia, microcephaly, and developmental delay (7). Patients usually have a history of intrauterine growth retardation. The typical skin and hair lesions with alopecia and nail dystrophy giving dyskeratosis congenita its name appear later during the course of the disease. Chronic bloody diarrhoea may be present in the early course of the disease. Attempts of bone marrow transplantation with different results have been made and death usually occurs at the end of the first decade (8). PATIENT REPORTS Patient 1 The boy was a child of unrelated parents born at term with weight, length, and head circumference being 2 SD below the mean. He presented with watery diarrhoea and pancytopenia from the eighth month of life. On admission at the age of 14 months abdominal distension, microcephaly, ataxia, and developmental delay were evident. Colonoscopy showed nonspecific pancolitis and ileitis with pieces of dissected mucosal tissue floating in the lumen. Histopatholgical evaluation demonstrated signs of chronic nonspecific inflammation with reduction of colon crypts and fibrosis of the lamina propria in parallel with apoptotic cell death (Fig. 1A). The patient acquired Pneumocystis jiroveci pneumonia and absence of B and NK cells and low levels of immunoglobulins in the blood were detected (Table 1). Molecular genetic analysis of the DKC1 gene revealed a previously published mutation in exon 10 (c.1058C>T; Ala353Val). Bloody diarrhoea with 15 to 20 stools per day was unresponsive to prednisolone, azathioprine, mesalazine, and cyclosporine. Severe abdominal pain requiring continuous analgesia was partially released by high doses of prednisolone, but finally an ileostomy was performed leading to relevant relief of pain. Recurrent bleeding episodes occurred from a nonhealing enterostoma with increased vascularization (Fig. 1C and D). A distal and an esophageal stenosis were successfully treated with endoscopic dilatation and systemic steroids. At the age of 6 years the patient died of septicemia.FIG. 1: (A) Low magnification of colonic biopsy specimen of patient 1 shows atrophy and architectural distortion with pronounced rarefication of crypts and mild fibrosis of the lamina propria without evidence of lymphatic tissue. High magnification of the cryptal epithelium shows apoptotic cell death as well as some mitotic figures; in some crypts Paneth cells are present. In the lamina propria chronic inflammatory cells are mildly increased (eosinophils, macrophages, and few plasma cells). (B) Colonoscopy of patient 2 revealing non-specific pancolitis and ileitis with pieces of dissected mucosal tissue floating in the lumen. (C) Photograph of nonhealing enterostoma (patient 1). (D) Contrast enhanced transverse magnetic resonance imaging sections of the abdomen showing massive neovascularization around the stoma (arrow) leading to difficult wound healing and recurrent bleeding (patient no. 1).TABLE 1: Distribution of lymphocytes and qualitative testing of T cell function of peripheral bloodPatient 2 The boy was born at 34 weeks of gestational age after fetal distress. Birth weight, length, and head circumference were between 1 and 2 SD of the mean and regression of gain of weight, length, and head circumference was visible since the second year of life (all 2 SD below the mean). In addition, developmental delay with ataxia was present. At the age of 36 months bloody diarrhea occurred and subsequently pancytopenia was detected. Immunological workup showed reduction of B and NK cells and the boy acquired P jiroveci infection. Colonoscopy revealed similar findings as in the first patient (Fig. 1B). Histology showed signs of increased basal apoptosis and sparse mononuclear infiltrates in the lamina propria. Genetic analysis revealed a previously unpublished mutation in exon 11 of the DKC1 gene (c.1133G>A; Arg378Gln). A trial of azathioprine was unsuccessful and cyclosporine A had to be discontinued because of hypertension. Finally, ileostomy was performed as in patient 1. Further palliative care permitted a painless time at home with his family. At the age of 5 years 4 months the patient died of septicemia. DISCUSSION We report 2 patients with Hoyeraal-Hreidarsson syndrome who presented with intractable diarrhea because of severe enterocolitis. Gastrointestinal complications dominated the further course of the disease with painful recurrent episodes of bowel obstruction, which were partially relieved by high-dose corticosteroids, but finally required surgical resections, dilatations, and ileostomy in both patients. To gain knowledge about the occurrence of gastrointestinal finding in HHS, we performed a PubMed search and found 23 reported cases of HHS. Table 1 gives the clinical manifestations extracted from these reports including our patients (no. 24 and no. 25). Involvement of the gastrointestinal system in HHS includes oral ulcerations, esophageal dysmotility with stenosis, and severe diarrhea resulting from enterocolitis. Diarrhea was reported in 52% (13 of 25) of all described patients in the literature (Table 2). The mean age of onset of diarrhea was 12 months (±10, range 1–36). In 7 patients (28%) diarrhea was the initial complaint of the disease, suggesting that inflammation of the gut is a consistent and early finding in HHS. Specimens of colonic mucosa were obtained in 5 patients including ours. All of the specimens showed mononuclear infiltrate and reduction of crypts. Ulcerations of the oral cavity were observed in 16 of the 25 patients and represent the most common gastrointestinal findings in HHS (64%). Esophageal dysmotility was also a common complaint reported in 9 of the 25 patients (36%). Despite awareness of gastrointestinal involvement in HHS patients, it has not been appreciated as a main feature and reason for hospitalization. In our experience, the enteropathy does not respond to mesalazine or immunosuppressive drugs. However, painful obstructive episodes because of swelling of the intestinal mucosa can be improved by high-dose corticosteroids unless fibrotic stenosis has been occurred. Ileostomy gave some relief, but further resections because of obstructions were required during the course of the disease. Macroscopic findings of shedding of the mucosal layer and the histopathological findings of only mild mononuclear infiltrates seem to be typical for the enterocolitis in HHS.TABLE 2: Clinical and biochemical features of all patients published and the present 2 patientsThere are few patients with HHS and DC in whom stem cell transplantation was performed showing no relevant improvement of the course (9). In our patients, we decided against stem cell transplantation for several reasons: an immunoablative therapy would have been necessary because T cell function was normal in both patients, thus exacerbation of the gastrointestinal situation was likely to occur; lymphocytes and fibroblasts of patients with HHS have an increased sensitivity to alkylating agents commonly used for conduction therapy leading to major telomere shortening (10); patients with HHS in whom transplantation was performed showed no benefit; and transplantation may only lead to an improvement of the hematological and immunological situations and does not correct for the defect of the gastrointestinal mucosa. Attempts at liver–small bowel transplantation have been performed in cases of multiple intestinal atresia with immunodeficiency (11). Although this approach may relieve some of the gastrointestinal problems, there is no influence on pancytopenia and immunodeficiency, suggesting a lack of feasibility in patients with HHS. Conclusions The clinical course of patients with HHS can be dominated by involvement of the oral, esophageal, and gastrointestinal mucosa and may precede the hematological and immunological problems. Hoyeraal-Hreidarsson syndrome has to be considered in infants and young children with intractable diarrhea and intestinal failure.
Pediatric Hematology and Oncology · 2002 · 20 citations
A NOVEL MISSENSE MUTATION IN THE DKC1 GENE IN A JAPANESE FAMILY WITH X-LINKED DYSKERATOSIS CONGENITA
AbstractThe authors report 2 male patients with dyskeratosis congenita (DC) in a Japanese kindred. Sequencing of the complementary DNA of the dyskerin gene (DKC1) revealed a T-to-C transition at nucleotide 1285 in exon 12 that resulted in a novel missense mutation L398P. Despite harboring the same mutation in the DKC1 gene, one patient had significantly milder hematological symptoms than the other, indicating that there may be other factors that determine the severity of DC.
AbstractDyskeratosis congenita (DC) is a rare disease and a genetic heterogeneity of bone marrow failure, characterized by muco-cutaneous triad of mucosal leukoplakia, abnormal skin pigmentation, nails dystrophy and often involving multiple organs or systems. The inheritance patterns of DC include X-linked recessive, autosomal dominant and recessive patterns. However, the inheritance patterns in 30%-40% of DC patients remained unknown. Dyskeratosis congenita is difficult to diagnose because of its genetic and clinical heterogeneity. This article will review and discuss the state-of-the-art progresses in genetics, clinical manifestation, diagnosis, differential diagnosis, treatment and prognosis of DC.
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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