Ignite Creation Date:
2025-12-24 @ 4:46 PM
Ignite Modification Date:
2025-12-26 @ 3:36 AM
Study NCT ID:
NCT06111950
Status:
RECRUITING
Last Update Posted:
2024-10-09
First Post:
2023-03-31
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Study of the Pathophysiology of RNU4ATAC and RTTN Associated Syndromes
Sponsor:
Organization:
Raw JSON
{'hasResults': False, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24'}, 'conditionBrowseModule': {'meshes': [{'id': 'C537577', 'term': 'Microcephalic osteodysplastic primordial dwarfism, type 1'}, {'id': 'C535866', 'term': 'Roifman syndrome'}, {'id': 'C537038', 'term': 'Lowry Wood syndrome'}, {'id': 'D030342', 'term': 'Genetic Diseases, Inborn'}], 'ancestors': [{'id': 'D009358', 'term': 'Congenital, Hereditary, and Neonatal Diseases and Abnormalities'}]}, 'interventionBrowseModule': {'meshes': [{'id': 'D001800', 'term': 'Blood Specimen Collection'}], 'ancestors': [{'id': 'D013048', 'term': 'Specimen Handling'}, {'id': 'D019411', 'term': 'Clinical Laboratory Techniques'}, {'id': 'D019937', 'term': 'Diagnostic Techniques and Procedures'}, {'id': 'D003933', 'term': 'Diagnosis'}, {'id': 'D011677', 'term': 'Punctures'}, {'id': 'D013514', 'term': 'Surgical Procedures, Operative'}, {'id': 'D008919', 'term': 'Investigative Techniques'}]}}, 'protocolSection': {'designModule': {'phases': ['NA'], 'studyType': 'INTERVENTIONAL', 'designInfo': {'allocation': 'NON_RANDOMIZED', 'maskingInfo': {'masking': 'NONE'}, 'primaryPurpose': 'OTHER', 'interventionModel': 'SINGLE_GROUP'}, 'enrollmentInfo': {'type': 'ESTIMATED', 'count': 45}}, 'statusModule': {'overallStatus': 'RECRUITING', 'startDateStruct': {'date': '2024-08-27', 'type': 'ACTUAL'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2024-10', 'completionDateStruct': {'date': '2029-08-27', 'type': 'ESTIMATED'}, 'lastUpdateSubmitDate': '2024-10-08', 'studyFirstSubmitDate': '2023-03-31', 'studyFirstSubmitQcDate': '2023-10-26', 'lastUpdatePostDateStruct': {'date': '2024-10-09', 'type': 'ACTUAL'}, 'studyFirstPostDateStruct': {'date': '2023-11-01', 'type': 'ACTUAL'}, 'primaryCompletionDateStruct': {'date': '2029-08-27', 'type': 'ESTIMATED'}}, 'outcomesModule': {'primaryOutcomes': [{'measure': 'Identification of RNU4ATAC mutations consequences at the cellular level', 'timeFrame': '5 years', 'description': 'The dysfunctions present in the different cell types obtained from RNU4ATAC patients will be identified by comparison with the controls, and will be compared with those present in RTTN patients.\n\nConsequences in cells of patients of RNU4ATAC mutations on the length and the structure of the primary cilium, as measured by fluorescence microscopy, and on the formation of small nuclear ribonucleoprotein (snRNPs) particles, as measured by glycerol gradient sedimentation analysis'}], 'secondaryOutcomes': [{'measure': 'Minor splicing anomalies', 'timeFrame': '5 years', 'description': 'The number and list of U12 genes for which an alteration of splicing will be identified in patient cells relatively to control cells will be compared, taking into account the different phenotypes (TALS, RFMN, LWS and other pathologies possibly identified).\n\nConsequences in cells of patients of RNU4ATAC mutations on minor intron splicing, as measured by intron retention analysis with the IRFinder and KisSplice bioinformatics softwares following RNA-sequencing experiments'}, {'measure': 'Understanding of neuronal differentiation anomalies', 'timeFrame': '5 years', 'description': 'Abnormalities in the behaviour of cells differentiated into neuronal progenitors will be identified by comparison with the controls, and will be compared taking into account the different phenotypes (TALS, RFMN, LWS and other pathology(s)) possibly identified).\n\nConsequences of RNU4ATAC mutations on the ability of induced pluripotent stem cells to differentiate towards the neuronal lineage, as measured by immunocytochemistry'}]}, 'oversightModule': {'oversightHasDmc': False, 'isFdaRegulatedDrug': False, 'isFdaRegulatedDevice': False}, 'conditionsModule': {'keywords': ['Genetic diseases', 'Splicing', 'Minor introns', 'U4atac', 'Primary cillium'], 'conditions': ['Taybi Linder Syndrome', 'Microcephalic Osteodysplastic Primordial Dwarfism Types I and III', 'Roifman Syndrome', 'Lowry Wood Syndrome']}, 'descriptionModule': {'briefSummary': 'In the human genome, about 750 genes contain one intron excised by the minor spliceosome. These genes are named U12 genes, and these introns, minor or U12 introns. The minor spliceosome comprises its own set of snRNAs, among which U4atac. Its non-coding gene, RNU4ATAC, has been found mutated in Taybi-Linder (TALS), Roifman (RFMN) and Lowry-Wood syndromes (LWS). These rare developmental disorders associate ante- and post-natal growth retardation, microcephaly, skeletal dysplasia, intellectual disability, retinal dystrophy and immunodeficiency. Their physiopathological mechanisms remain unsolved: the number of U12 genes involved, their identity and function, or the cellular mechanisms impacted by the splicing defect, are still unknown.\n\nThe hypothesis of the study is that U12 genes coding for primary cilia components are particularly sensitive to minor splicing defects caused by RNU4ATAC mutations. Indeed, a child showing signs of TALS but negative for RNU4ATAC was found to carry a homozygous variant in the RTTN gene, coding for the rotatin protein located at the centrosome and the base of the primary cilia and playing a role in maintaining these structures. In addition, bi-allelic RNU4ATAC mutations were identified in five patients presenting with traits suggestive of the Joubert syndrome (JBTS), a well-characterized ciliopathy. These patients also present with traits typical of TALS/RFMN/LWS.\n\nTo better understand the causes of these pathologies, a cohort of patients with syndromes associated with bi-allele mutations of the RNU4ATAC or RTTN gene will be gathered, in order to conduct studies on the cells of these patients. Blood samples will be taken, as well as skin biopsies, if possible. These samples will be used to create induced pluripotent stem cell lines. Blood samples will also be collected from the parents of RNU4ATAC patients, to eliminate in transcriptomic analyses expression variations due to differences in genetic background. Biopsies of skin, muscle and brain tissue will be collected on foetuses carrying two-allele RNU4ATAC or RTTN mutations whose parents have had a miscarriage or have chosen to have a medical abortion. The biological samples collected will be used to study the transcription level of U12 genes, the splicing of their pre-messenger RNA, their main cellular functions, and the structural characteristics of tissues and cells.'}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['CHILD', 'ADULT', 'OLDER_ADULT'], 'healthyVolunteers': True, 'eligibilityCriteria': 'Inclusion Criteria:\n\nTALS, RFMN, LWS or other pathology patients\n\n* Woman or man\n* All ages\n* Presence of bi-allelic mutations of RNU4ATAC or RTTN\n* Written consent of parents or legal guardian(s)\n* Affiliation to a Social Security scheme\n\nHealthy participants (Parent of the patient)\n\n* Woman or man\n* Major\n* Presence of mono-allelic mutations of RNU4ATAC\n* Written consent of the participant\n* Affiliation to a Social Security scheme\n\nParents having recourse to a medical termination of pregnancy or having had a spontaneous miscarriage (for fetus samples)\n\n* Woman or man\n* Major\n* Presence of bi-allelic mutations of RNU4ATAC or RTTN in the fetus\n* Written parental consent\n* Affiliation to a Social Security scheme\n\nExclusion Criteria:\n\nSubject participating in another research including an exclusion period still in progress.'}, 'identificationModule': {'nctId': 'NCT06111950', 'acronym': 'ATAC', 'briefTitle': 'Study of the Pathophysiology of RNU4ATAC and RTTN Associated Syndromes', 'organization': {'class': 'OTHER', 'fullName': 'Hospices Civils de Lyon'}, 'officialTitle': 'Study of the Consequences of Mutations of the RNU4ATAC and RTTN Genes by Transcriptomic, Biochemical and Cellular Approaches in Order to Determine the Pathophysiology of Their Associated Syndromes: Microcephalic Osteodysplastic Primordial Dwarfism Type I/III, Roifman Syndrome and Lowry-Wood Syndrome', 'orgStudyIdInfo': {'id': '69HCL20_0599'}}, 'armsInterventionsModule': {'armGroups': [{'type': 'OTHER', 'label': 'RNU4ATAC patient', 'description': 'Patient with bi-allelic mutation of the RNU4ATAC gene', 'interventionNames': ['Other: Blood samples', 'Other: Skin biopsies']}, {'type': 'OTHER', 'label': 'RNU4ATAC fetus', 'description': 'Fetus with bi-allelic mutation of the RNU4ATAC gene', 'interventionNames': ['Other: Fetal samples']}, {'type': 'OTHER', 'label': 'RNU4ATAC parent', 'description': 'Parent of patient or fetus with bi-allelic mutation of the RNU4ATAC gene and who present themselve mono-allelic mutation of the RNU4ATAC gene', 'interventionNames': ['Other: Blood samples']}, {'type': 'OTHER', 'label': 'RTTN patient', 'description': 'Patient with bi-allelic mutation of the RTTN gene', 'interventionNames': ['Other: Blood samples', 'Other: Skin biopsies']}, {'type': 'OTHER', 'label': 'RTTN fetus', 'description': 'Fetus with bi-allelic mutation of the RTTN gene', 'interventionNames': ['Other: Fetal samples']}], 'interventions': [{'name': 'Blood samples', 'type': 'OTHER', 'description': 'Blood samples of 5 ml to 15 ml depending on their weight', 'armGroupLabels': ['RNU4ATAC parent', 'RNU4ATAC patient', 'RTTN patient']}, {'name': 'Skin biopsies', 'type': 'OTHER', 'description': 'Biopsies of fragment of skin 2 to 3 mm long by 1 mm wide and 1 mm deep will preferably be taken on the inside of the arm, in the upper third, between the bend of the elbow and the hollow of the armpit under strict sterility conditions.', 'armGroupLabels': ['RNU4ATAC patient', 'RTTN patient']}, {'name': 'Fetal samples', 'type': 'OTHER', 'description': 'Skin, muscle, brain and bone biopsies will be collected from fetuses in the autopsy room after the medical termination of pregnancy or miscarriage', 'armGroupLabels': ['RNU4ATAC fetus', 'RTTN fetus']}]}, 'contactsLocationsModule': {'locations': [{'zip': '33000', 'city': 'Bordeaux', 'status': 'NOT_YET_RECRUITING', 'country': 'France', 'contacts': [{'name': 'Didier LACOMBE, MD, PhD', 'role': 'CONTACT', 'email': 'didier.lacombe@chu-bordeaux.fr', 'phone': '05 56 79 56 48', 'phoneExt': '+33'}], 'facility': 'Centre de référence des anomalies du développement et syndromes malformatifs du Sud-Ouest Occitanie Réunion, CHU de Bordeaux-GH Pellegrin', 'geoPoint': {'lat': 44.84124, 'lon': -0.58046}}, {'zip': '69500', 'city': 'Bron', 'status': 'RECRUITING', 'country': 'France', 'contacts': [{'name': 'Patrick EDERY, MD, PhD', 'role': 'CONTACT', 'email': 'charles-patrick.edery@chu-lyon.fr', 'phone': '04 72 12 96 98'}], 'facility': 'Centre de référence anomalies du développement de Lyon, Hôpital Femme Mère Enfant', 'geoPoint': {'lat': 45.73865, 'lon': 4.91303}}, {'zip': '9000', 'city': 'Dijon', 'status': 'NOT_YET_RECRUITING', 'country': 'France', 'contacts': [{'name': 'Laurence OLIVIER-FAIVRE, MD, PhD', 'role': 'CONTACT', 'email': 'laurence.faivre@chu-dijon.fr', 'phone': '03 80 29 53 13', 'phoneExt': '+33'}], 'facility': "Centre de référence des anomalies du développement et syndromes malformatifs de l'Est, CHU de DIJON", 'geoPoint': {'lat': 47.31344, 'lon': 5.01391}}, {'zip': '59000', 'city': 'Lille', 'status': 'NOT_YET_RECRUITING', 'country': 'France', 'contacts': [{'name': 'Sylvie MANOUVRIER-HANU, MD, PhD', 'role': 'CONTACT', 'email': 'sylvie.manouvrier@chru-lille.fr', 'phone': '03 20 44 49 11', 'phoneExt': '+33'}], 'facility': "Centre de référence des anomalies du développement et syndromes malformatifs de l'inter région Nord-Ouest, Hôpital J de Flandre", 'geoPoint': {'lat': 50.63391, 'lon': 3.05512}}, {'zip': '75743', 'city': 'Paris', 'status': 'NOT_YET_RECRUITING', 'country': 'France', 'contacts': [{'name': 'Tania ATTIE-BITTACH, MD, PhD', 'role': 'CONTACT', 'email': 'tania.attie@inserm.fr', 'phone': '01 44 49 51 44', 'phoneExt': '+33'}], 'facility': "Unité Fonctionelle d'embryo-fœtopathologie, Hôpital Necker-Enfants Malades", 'geoPoint': {'lat': 48.85341, 'lon': 2.3488}}, {'zip': '35000', 'city': 'Rennes', 'status': 'NOT_YET_RECRUITING', 'country': 'France', 'contacts': [{'name': 'Sylvie ODENT, MD, PhD', 'role': 'CONTACT', 'email': 'sylvie.odent@chru-rennes.fr', 'phone': '02 99 26 67 44', 'phoneExt': '+33'}], 'facility': "Centre de référence des anomalies du développement et syndromes malformatifs de l'Ouest, Hôpital Sud", 'geoPoint': {'lat': 48.11109, 'lon': -1.67431}}], 'centralContacts': [{'name': 'Sylvie MAZOYER, Dr', 'role': 'CONTACT', 'email': 'sylvie.mazoyer@inserm.fr', 'phone': '04 81 10 65 33', 'phoneExt': '+33'}, {'name': 'Patrick EDERY, Pr', 'role': 'CONTACT', 'email': 'charles-patrick.edery@chu-lyon.fr', 'phone': '04 72 12 96 98', 'phoneExt': '+33'}]}, 'ipdSharingStatementModule': {'ipdSharing': 'NO'}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'Hospices Civils de Lyon', 'class': 'OTHER'}, 'responsibleParty': {'type': 'SPONSOR'}}}}