NCT06111950: ATAC

Study of the Pathophysiology of RNU4ATAC and RTTN Associated Syndromes

Recruiting now NA Last updated 9 October 2024

What this trial tests

NA trial testing Blood samples in Taybi Linder Syndrome in 45 participants. Currently enrolling.

Timeline

27 August 2024

Primary endpoint
27 August 2029

27 August 2029

Quick facts

Lead sponsor	Hospices Civils de Lyon
Phase	NA
Status	Recruiting now
Study type	INTERVENTIONAL
Allocation	non randomized
Design	single group
Masking	none
Primary purpose	other
Enrollment	45
Start date	27 August 2024
Primary completion	27 August 2029
Estimated completion	27 August 2029
Sites	6 locations across France

Drugs / interventions tested

• Blood samples — full drug profile →
• Skin biopsies — full drug profile →
• Fetal samples

Conditions studied

• Taybi Linder Syndrome — all drugs for Taybi Linder Syndrome →
• Microcephalic Osteodysplastic Primordial Dwarfism Types I and III — all drugs for Microcephalic Osteodysplastic Primordial Dwarfism Types I and III →
• Roifman Syndrome — all drugs for Roifman Syndrome →
• Lowry Wood Syndrome — all drugs for Lowry Wood Syndrome →

Sponsor

Hospices Civils de Lyon — full company profile →

Who can join

Eligibility, any sex, with Taybi Linder Syndrome or Microcephalic Osteodysplastic Primordial Dwarfism Types I and III. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

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.

Publications & conference data

No peer-reviewed publications indexed yet for this trial.