The Canadian Rare Diseases Models and Mechanisms (RDMM) Network: Connecting Understudied Genes to Model Organisms

Abstract

Advances in genomics have transformed our ability to identify the genetic causes of rare diseases (RDs), yet we have a limited understanding of the mechanistic roles of most genes in health and disease. When a novel RD gene is first discovered, there is minimal insight into its biological function, the pathogenic mechanisms of disease-causing variants, and how therapy might be approached. To address this gap, the Canadian Rare Diseases Models and Mechanisms (RDMM) Network was established to connect clinicians discovering new disease genes with Canadian scientists able to study equivalent genes and pathways in model organisms (MOs). The Network is built around a registry of more than 500 Canadian MO scientists, representing expertise for over 7,500 human genes. RDMM uses a committee process to identify and evaluate clinician-MO scientist collaborations and approve 25,000 Canadian dollars in catalyst funding. To date, we have made 85 clinician-MO scientist connections and funded 105 projects. These collaborations help confirm variant pathogenicity and unravel the molecular mechanisms of RD, and also test novel therapies and lead to long-term collaborations. To expand the impact and reach of this model, we made the RDMM Registry open-source, portable, and customizable, and we freely share our committee structures and processes. We are currently working with emerging networks in Europe, Australia, and Japan to link international RDMM networks and registries and enable matches across borders. We will continue to create meaningful collaborations, generate knowledge, and advance RD research locally and globally for the benefit of patients and families living with RD.

Keywords: functional insight; gene discovery; model organisms; rare genetic diseases.

Figure 1

The Canadian Rare Diseases Models and Mechanisms Network Pathway: from Discovery to Functional Insight and Long-Term Collaborations The Canadian RDMM Network was developed to expedite collaboration between scientists and clinicians in model-based functional studies of rare disease (RD) genes. The RDMM Network has created a rapid and direct pathway from RD gene discovery to functional characterization studies in model organisms. The network supports the investigation of biological functions of RD genes and their roles in disease, testing of pathophysiological hypotheses, identification of therapeutic targets, and the development of long-term collaborations. This figure is a representation of the homepage of the RDMM website, where clicking on the circles provides access to relevant forms and information about the committees and adjudication processes. MO—model organism.

Figure 2

The Canadian Rare Diseases Models and Mechanisms Registry The RDMM Registry is a model organism (MO) matchmaking platform and the central resource for the Canadian Rare Diseases Models and Mechanisms (RDMM) Network. The RDMM Registry is a secure web-based platform with a user-friendly interface into which MO scientists enter their information and describe their research and relevant expertise with brief textual description, a list of relevant publications and, most importantly, a list of genes they are able to study. Registrants enter genes as Tier 1 (genes they are currently working on in a MO) or Tier 2 (genes they could quickly set up in a MO). The scientists then select appropriate gene ontology (GO) terms suggested by the RDMM Registry (based on the Tier 1 and 2 genes they list in their profile); the genes associated with the selected GO terms are added to their profile as Tier 3 genes.

Figure 3

Connections funded for genes submitted to the Canadian Rare Diseases Models and Mechanisms Network From 2014 to 2019, the clinical advisory committee (CAC) considered 135 rare disease (RD) genes, of which 95 were approved by the CAC for model organism (MO)-scientist matching. In addition, 116 known yet understudied genes were sent directly to the Bioinformatics Core (BIC) for MO-scientist matching. Of the 211 RD genes reviewed by the BIC, 140 genes had one (or more) MO-scientist match in the registry, so we removed the 71 genes with no MO-scientist match. After review of all potential clinician-MO scientist connections for these 140 genes, the scientific advisory committee (SAC) invited one (or more) MO proposal(s) for 101 genes, removing an additional 39 genes with no MO-scientist match. After review of the submitted MO proposals, for 77 genes, at least one MO proposal was funded, removing an additional 24 genes with no MO-scientist match. For eight of these 77 genes, two separate MO awards were made, for a total of 85 catalyst projects funded. In addition, the Network funded 10/17 follow-up studies of previously funded genes, as well as 10/29 projects from targeted calls with Canadian RD foundations. RD—rare disease; MO—model organism; CAC—clinical advisory committee; BIC—bioinformatics core; SAC—scientific advisory committee.

Figure 4

New Knowledge Generated by the Canadian Rare Diseases Models and Mechanisms (RDMM) Network Graphical summaries illustrating examples of the new knowledge attained through the Canadian RDMM Network. (A) Validate novel gene discoveries. Morpholino or CRISPR/Cas9-mediated disruption of the CEP55 ortholog in zebrafish embryos recapitulated the phenotypic features of MARCH syndrome (MIM: 236500). This provided functional evidence of the pathogenicity of homozygous truncating mutations in CEP55, a novel gene discovery in a single family with MARCH syndrome. (B) Functional data. Biallelic variants in LRRC56 were identified in three unrelated families with laterality defects and chronic pulmonary infections (MIM: 618254) where cultured epithelial cells showed severely dyskinetic cilia. Investigations in Trypanosoma brucei revealed LRRC56’s interactions with intracellular transport protein IFT88 in dynein transport during cilia assembly. (C) Biological insight. This represents the first animal model for pyridoxine-dependent epilepsy (MIM: 266100), a rare epilepsy syndrome first described more than 60 years ago. CRISPR/Cas9-mediated disruption of the ALDH7A1 ortholog in zebrafish recapitulated the human phenotype, including an almost immediate response to pyridoxine and pyridoxal 5′-phosphate. This work suggested a role for gamma aminobutyric acid (GABA) homeostasis in disease pathogenesis. (D) Identify therapeutic targets. Knockdown of nansa and npl in zebrafish embryos provided functional evidence for the role of NANS and NPL in sialic acid metabolism.^, Addition of sialic acid to embryo water partially rescued the skeletal phenotype associated with NANS, and the addition of N-acetyl mannosamine (ManNAc) rescued the myopathy phenotype associated with NPL. These data suggest potential treatment methods for human NANS and NPL deficiencies.