RDMM-Europe – Solve-RD

New Publication: Model matchmaking via the Solve-RD Rare Disease Models & Mechanisms Network (RDMM-Europe)

The European Rare Disease Models & Mechanisms Network (RDMM-Europe) has been established within Solve-RD. RDMM-Europe is a brokerage service to promote fruitful collaborations between clinicians and model organism experts with the aim of filling the gap between RD gene discovery and functional validation of potentially new disease genes and/or novel disease mechanisms.

In our article we describe the network and infrastructure that we have successfully implemented to support the use of model organisms in rare disease research, we share our processes and highlight several examples of modeling approaches that clearly illustrate the benefit and need of functional validation in model organisms to accelerate the assessment of new disease-gene associations. The article also showcases the main objectives of the funded projects, highlights examples of validation projects in different models and provides links to recent publications related to some of these projects.

The article has now been accepted for publication in Lab Animal: Kornelia Ellwanger, Julie A. Brill [...] Olaf Riess. Model matchmaking via the Solve-RD Rare Disease Models & Mechanisms Network (RDMM-Europe). Lab Anim (NY). 2024 Jun 24. https://doi.org/10.1038/s41684-024-01395-2. Epub ahead of print.

RDMM-Europe project published!

Solve-RD partner Laurence Faivre from CHU Dijon and colleagues from CHU Rouen, France identified 5 patients with a recurrent de novo variant p.(Arg126Gln) in FEM1B and a neurodevelopmental disorder associated with a variable set of malformations, including brain anomalies, clubfeet, skeletal abnormalities.

The RDMM-Europe Seeding Grant awarded to Ype Elgersma at Erasmus University Medical Center in Rotterdam helped to assess the pathogenicity of this rare genetic variant. The project involved expression of the mutant form in developing mouse embryos and in primary neuronal cultures and demonstrated the toxicity of FEM1BR126Q variant compared to FEM1B.

The collaborative work was now accepted for publication in Genetics in Medicine:

François Lecoquierre, […] Laurence Faivre, Ype Elgersma, Antonio Vitobello. A recurrent missense variant in the E3 ubiquitin ligase substrate recognition subunit FEM1B causes a rare syndromic neurodevelopmental disorder. Genetics in Medicine, Volume 26, Issue 6, 2024, 101119, ISSN 1098-3600, https://doi.org/10.1016/j.gim.2024.101119

RDMM-Europe project published!

Solve-RD partners and Henry Houlden at the UCL Queen Square Institute of Neurology identified novel missense variants in the gene ACBD6 in a large cohort of unrelated patients with complex dystonia parkinsonism ataxia phenotype. The patients presented moderate-to-severe delay in psychomotor development predominantly affecting the acquisition of walking skills, speech, intellectual functioning (global developmental delay, moderate to severe intellectual disability, severe speech disorder, diverse behavioural abnormalities), variable dysmorphisms and seizures. The RDMM-Europe committees suggested to connect the group with Gaurav K. Varshney at the Oklahoma Medical Research Foundation and Solve-RD provided Seeding Grant funding to support the validation of the gen disease association using zebrafish as a model.

The collaborative work was now accepted for publication in Brain.

Rauan Kaiyrzhanov, Aboulfazl Rad, Sheng-Jia Lin [...] Reza Maroofian. Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders. Brain (2023) https://doi.org/10.1093/brain/awad380

RDMM-Europe project published!

Stefan Barakat and Tjakko van Ham at Erasmus University Medical Center in Rotterdam have received a Seeding Grant via the Solve-RD Rare Disease Models & Mechanisms Network (RDMM-Europe) program in May 2022. The funding supported their work to confirm pathogenicity of AMFR dysfunction causing autosomal recessive spastic paraplegia (HSP) by using zebrafish models. AMFR was proposed for functional validation within the RDMM programme by Solve-RD partners Reza Maroofian and Henry Houlden at the UCL Queen Square Institute of Neurology. They have initially identified a homozygous frameshift mutation of AMFR within a shared RoH region in two affected siblings suffering from Hereditary Spastic Paraplegia (HSP). By international collaborations and data sharing similar biallelic loss of function mutations of the same gene were found in a total of 20 affected individuals from 8 consanguineous families.

The collaborative work was now accepted for publication in Acta Neuropathologica.

Ruizhi Deng, Eva Medico-Salsench, Anita Nikoncuk et al. AMFR dysfunction causes autosomal recessive spastic paraplegia in human that is amenable to statin treatment in a preclinical model. Acta Neuropathol (2023). https://doi.org/10.1007/s00401-023-02579-9

RDMM-Europe project published!

Solve-RD partners Antonio Vitobello from the University Hospital Dijon-Bourgogne and Elke Bogaert & Bart Dermaut from Ghent University in Belgium were connected by our European Rare Disease Models & Mechanisms Network (RDMM-Europe) initiative. They received Seeding Grant funding to generate Drosophila models that support the validation of new SRSF1 variants identified in a cohort of patients with syndromic developmental disorder associated with intellectual disability. Their findings have now been accepted for publication in The American Journal of Human Genetics.

Elke Bogaert, Aurore Garde, Thierry Gautier et al. SRSF1 haploinsufficiency is responsible for a syndromic developmental disorder associated with intellectual disability. The American Journal of Human Genetics (2023). https://doi.org/10.1016/j.ajhg.2023.03.016