Study of the Pathophysiology of RNU4ATAC and RTTN Associated Syndromes

NCT06111950 | Recruiting

• 1 other identifier: 69HCL20_0599
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 6

Brief Summary

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. The 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. To 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.

Conditions

Taybi Linder Syndrome; Microcephalic Osteodysplastic Primordial Dwarfism Types I and III; Roifman Syndrome; Lowry Wood Syndrome

Keywords

Genetic diseases; Splicing; Minor introns; U4atac; Primary cillium

Outcome Measures

Primary Outcomes (1)

• Identification of RNU4ATAC mutations consequences at the cellular level

  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. Consequences 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

  5 years

Secondary Outcomes (2)

• Minor splicing anomalies

  5 years

• Understanding of neuronal differentiation anomalies

  5 years

Study Arms (5)

RNU4ATAC patient

OTHER

Patient with bi-allelic mutation of the RNU4ATAC gene

Other: Blood samples; Other: Skin biopsies

RNU4ATAC fetus

OTHER

Fetus with bi-allelic mutation of the RNU4ATAC gene

Other: Fetal samples

RNU4ATAC parent

OTHER

Parent of patient or fetus with bi-allelic mutation of the RNU4ATAC gene and who present themselve mono-allelic mutation of the RNU4ATAC gene

Other: Blood samples

RTTN patient

OTHER

Patient with bi-allelic mutation of the RTTN gene

Other: Blood samples; Other: Skin biopsies

RTTN fetus

OTHER

Fetus with bi-allelic mutation of the RTTN gene

Other: Fetal samples

Interventions

Blood samples OTHER

Blood samples of 5 ml to 15 ml depending on their weight

RNU4ATAC parent; RNU4ATAC patient; RTTN patient

Skin biopsies OTHER

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.

RNU4ATAC patient; RTTN patient

Fetal samples OTHER

Skin, muscle, brain and bone biopsies will be collected from fetuses in the autopsy room after the medical termination of pregnancy or miscarriage

RNU4ATAC fetus; RTTN fetus

Eligibility Criteria

• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• TALS, RFMN, LWS or other pathology patients
• Woman or man
• All ages
• Presence of bi-allelic mutations of RNU4ATAC or RTTN
• Written consent of parents or legal guardian(s)
• Affiliation to a Social Security scheme
• Healthy participants (Parent of the patient)
• Woman or man
• Major
• Presence of mono-allelic mutations of RNU4ATAC
• Written consent of the participant
• Affiliation to a Social Security scheme
• Parents having recourse to a medical termination of pregnancy or having had a spontaneous miscarriage (for fetus samples)
• Woman or man
• Major

Sponsors & Collaborators

• Hospices Civils de Lyon: lead

Study Sites (6)

Centre de référence des anomalies du développement et syndromes malformatifs du Sud-Ouest Occitanie Réunion, CHU de Bordeaux-GH Pellegrin

Bordeaux, 33000, France

NOT YET RECRUITING

Centre de référence anomalies du développement de Lyon, Hôpital Femme Mère Enfant

Bron, 69500, France

RECRUITING

Centre de référence des anomalies du développement et syndromes malformatifs de l'Est, CHU de DIJON

Dijon, 9000, France

NOT YET RECRUITING

Centre de référence des anomalies du développement et syndromes malformatifs de l'inter région Nord-Ouest, Hôpital J de Flandre

Lille, 59000, France

NOT YET RECRUITING

Unité Fonctionelle d'embryo-fœtopathologie, Hôpital Necker-Enfants Malades

Paris, 75743, France

NOT YET RECRUITING

Centre de référence des anomalies du développement et syndromes malformatifs de l'Ouest, Hôpital Sud

Rennes, 35000, France

NOT YET RECRUITING

MeSH Terms

Conditions

Microcephalic osteodysplastic primordial dwarfism, type 1; Roifman syndrome; Lowry Wood syndrome; Genetic Diseases, Inborn

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Central Study Contacts

Sylvie MAZOYER, Dr

CONTACT

04 81 10 65 33; sylvie.mazoyer@inserm.fr

Patrick EDERY, Pr

CONTACT

04 72 12 96 98; charles-patrick.edery@chu-lyon.fr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 31, 2023
• First Posted: November 1, 2023
• Study Start: August 27, 2024
• Primary Completion (Estimated): August 27, 2029
• Study Completion (Estimated): August 27, 2029
• Last Updated: October 9, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

FR (6)