Clinical trial NCT06111950: Study of the Pathophysiology of RNU4ATAC and RTTN Associated Syndromes
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
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
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2023-11-01
Enrollment: 45
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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.


Eligibility criteria: Inclusion Criteria:

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
* Presence of bi-allelic mutations of RNU4ATAC or RTTN in the fetus
* Written parental consent
* Affiliation to a Social Security scheme

Exclusion Criteria:

Subject participating in another research including an exclusion period still in progress.

Primary outcomes:
measure: Identification of RNU4ATAC mutations consequences at the cellular level
timeFrame: 5 years
Secondary outcomes:
measure: Minor splicing anomalies
timeFrame: 5 years
measure: Understanding of neuronal differentiation anomalies
timeFrame: 5 years
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Centre de référence des anomalies du développement et syndromes malformatifs du Sud-Ouest Occitanie Réunion, CHU de Bordeaux-GH Pellegrin
city: Bron
country: France
facility: Centre de référence anomalies du développement de Lyon, Hôpital Femme Mère Enfant
city: Dijon
country: France
facility: Centre de référence des anomalies du développement et syndromes malformatifs de l'Est, CHU de DIJON
city: Lille
country: France
facility: Centre de référence des anomalies du développement et syndromes malformatifs de l'inter région Nord-Ouest, Hôpital J de Flandre
city: Paris
country: France
facility: Unité Fonctionelle d'embryo-fœtopathologie, Hôpital Necker-Enfants Malades
city: Rennes
country: France
facility: Centre de référence des anomalies du développement et syndromes malformatifs de l'Ouest, Hôpital Sud
Study officials:
References: