AN EXAMPLE OF A RARE DISEASE: the Rubinstein Taybi Syndrome (RTS)
RTS is the one of the 7,000 rare diseases recorded to date. It is defined as “a rare malformation syndrome characterized by congenital anomalies (microcephaly, specific facial characteristics, broad thumbs and halluces and postnatal growth retardation), short stature, intellectual disability and behavioural characteristics”.
N.B. : to learn more about rare diseases and this syndrome in particular, please follow the link Orphanet.
THE REFERENCE CENTRE WITHIN CHU OF BORDEAUX (FR) – RESEARCH ON RTS
Service de Génétique Médicale
CHU de Bordeaux
33076 Bordeaux Cedex – France
Phone: +33 (0)5 57 82 03 63
July 2018: Aurélia (our running mate but also Doctor) got an interview with the team who is leading the research on RTS (Rubinstein Taybi Syndrome). This team is supported by the French Foundation for Rare Diseases.
Please find below the translation of this interview explaining what this team is doing.
INTERVIEW OF THE RTS REFERENCE CENTRE TEAM OF BORDEAUX – CONCERNING THE RESEARCH PROJECT FINANCED BY THE FFRD
1st part : how do genetics help to better understand the disease ?
- What do we know about the transmission modus of the disease?
This syndrome is in most of the case acquired or de novo, that is to say that the genetic abnormality is produced during the development of the embryo after a DNA lesion of one of the gamete which has created that embryo. Parents do bear it. There is, therefore, no risk of syndrome recurrence in case of another pregnancy. However, very exceptionally (<1%), several gametes can be concerned by the lesion and there will be then a probability of germ mosaicism. This is this minor risk which legitimates a demand of prenatal diagnosis for a later pregnancy, when the genetic abnormality has been detected on the 1st child. Some very rare case of mosaicism on one the parent have been found, that is to say that the abnormality of the child has been detected in a given ratio of the cells making up the different organs of one of the parent.There is a risk of transmission as the anomaly can concern a certain ratio of the gametes. Finally, some family cases of RTS have been detected, associated to mutations of CREBBP or EP300, with a minor impact on the function of these genes which can vary from one individual to another. The risk of transmission is then 1 out of 2.
- Do we know the genes involved in this disease et what role do they have?
- How can you explain that RTS can affect several organs?
- How can you explain than the RTS affects children’s psychomotor development, and especially the cognitive functions?
Currently, 2 genes are known as responsible of the RTS. These are the CREBBP and the EP300 genes, which are coming from the duplication of the same initial gene during the evolution. There are called “paralogue”. They have the same function in the cell but do not systematically act at the same time in the same cells nor on the same targets, which could explain the differences between the patients carrying a CREBBP mutation and a EP300 mutation and the fact that the loss of function of one is not compensated by the other. This loss or just sometimes the reduction of CREBBP proteins function (also called CBP) or p300 is linked to the anomaly of one single of these 2 genes CREBBP and EP300 existing in the autosomes couples, 16 for CREBBP, and 22 pour EP300.
The function of these genes, as currently known, is an orchestrating one, facilitating the expression of numerous other genes, which explains that many organs development processes and many specialized cellular functions can be infected. The 2 proteins are playing their role in the core of the cell where, on one hand, they bind themselves to other proteins such as CREB which controls the metabolism (in particular the one of the lipids), but also on another hand they modify the proteins enveloping the double DNA helix, called histones. Consequently, allowing the opening of the histones envelop through a chemical modification, the acetylation, they are easing up the binding to the DNA of regulation proteins or transcription factors. This is a regulating mechanism, called epigenetic, which does not affect the DNA itself, fundamental mechanism in the embryo development then during life. We are far away from knowing all the aspects of normal functioning and from neuro-development mechanism malfunction, involving CREBBP and p300. Nevertheless, it has been now demonstrated than these 2 proteins play a major role in the building of the long-term memory in the brain, fundamental for the learning and the development of cognitive functions.
- Do other genes exist which are still to be discovered?
An abnormality of one of the 2 known genes is found in 70% of the patients clinically suspected of RTS, including atypical forms; in the majority of the cases a CREBBP anomaly is identified and in approximatively 8% this is concerning EP300. We can then wonder if other genes would be involved in RTS. Until today, not a single case has been found at patients having a typical syndrome, but the stress is put also on the coverage of different clinical tables which could involve the same genes. For instance, phenotype coverage between RTS and Cornelia de Lange syndrome has been discovered.
- How to establish a RTS diagnosis?
First there is a phase of clinical examination and additional analyses, then a confirming genetic study in order to identify the responsible anomaly in the CREBBP and EP300 genes. Several types of lesions have been identified on the patients, from the substitution of a DNA base to the loss of one part of the chromosome (what is to say several thousands or millions of bases). This currently requires multiplying the diagnosis techniques in order to be able to identify the mutation of each patient. There are very few so called recurrent mutations or found similar on several patients, which obliges to analyze at least all the coding sequences for these 2 proteins. But the non-coding regions of these genes are not explored within the diagnosis. Because of time and cost constraints, it is today not possible to perform the complete sequencing of CREBBP and EP300 genes, of big size. We have to wait after a larger access to higher broadband technologies in order to test patients without known abnormalities.
- If molecular genetics techniques allow to confirm the diagnosis in most of the case, can they now help in establishing a prognosis (predict the severity level of the disease)?
It is rather difficult to establish a prognosis based on molecular genetics because it requires to study very deeply a huge amount of cases and demonstrate links and correlations between the mutation type and the phenotype.
- Do perspectives of treatment exist today?
Yes, thanks to acetylation modification hypothesis described above, which could restore, at least partially, long term memory mechanisms.
- How does genetic mechanisms knowledge involved in RTS can allow a better RTS children care?
First, patient´s genetic abnormality knowledge enables diagnosis confirmation and more adapted care. Second, a better understanding of the normal role of the 2 proteins CREBBP–EP300 and an understanding about how their abnormalities lead to RTS are targeted for the discovery of more efficient therapies.
2nd part : presentation of RTS research main objectives by the team of Bordeaux and its work
- Which were the big milestones of RTS genetic research?
RTS has been described in 1963. Our team has been able to localize the concerned gene on 16p13.3 chromosome in 1992. CREBBP gene has been identified in 1995 and EP300 gene in 2005.
- How has been created Bordeaux RTS reference centre? What are its missions?
“Development abnormalities and malformation syndromes” reference centre from the Bordeaux CHU, coordinated by Pr. Didier Lacombe, has been labelled since the first bid solicitation in 2004. This label has been confirmed in 2017 with an extended perimeter (to Sud-Ouest Occitanie Réunion). The team is specialized on RTS since 1992, this reference centre is in charge of this syndrome since the beginning and has written RTS PNDS (Protocole National de Diagnostic et de Soins – National Protocole of Diagnosis and Treatment). Its missions are the ones of a rare diseases reference centre (CRMR). CRMRs are appeal structures, organized around a multiprofessional and multifunctional team, highly specialized, and recognized for their competence in rare disease affected people and their commitment in research and training-teaching.
- Could you please introduce the team ? (specialization, career path of each member, what does lead you to get interested to RTS…)
You will find a team introduction brochure here.
- Which studies have you already conducted?
We have conducted several clinical studies on the RTS, including behavioral psychology related specificities and dental abnormalities met by RTS children. We have also, since localization and identification of concerned gene, conducted several studies on molecular abnormalities, with recently the publication of the biggest worldwide patients serie with EP300 gene mutation. We have additionally performed the 1st clinical medicinal test in the world on RTS patients in Bordeaux in a monocentric process, in an attempt to improve memory and cognitive difficulties of RTS children. RTS is a model rare disease, especially for long term memory disorders. A study of our group about motricity specificities has just been published.
- Do you have other projects in progress or to be launched?
We have several projects in progress. A university thesis in sciences will be considered in November 2019 with a young colleague, concerning fundamental aspects of cellular targets with construction of iPS (induced pluripotent stem cells) type cells derived from patients’ cells and differentiated by neurons. We have got the mouse model back to Bordeaux and some analyses are in progress on that model, in order to try new therapeutic approaches. An American team got in touch with us for this. Finally a psychology thesis has also started on psycho-behavioral aspects.
If you are interested in knowing more about rare diseases, please find below a link to Orphanet.