The International Mouse Phenotyping Consortium: comprehensive knockout phenotyping underpinning the study of human disease

Groza, Tudor; Gómez, Federico López; Mashhadi, Hamed Haseli; Muñoz‐Fuentes, Violeta; Güneş, Osman; Wilson, Robert; Cacheiro, Pilar; Frost, Anthony; Keskivali-Bond, Piia; Vardal, Bora; McCoy, Aaron; Cheng, Tsz Kwan; Santos, Luís; Wells, Sara; Smedley, Damian; Mallon, Ann‐Marie; Parkinson, Helen

doi:10.1093/nar/gkac972

Cited by 137 publications

(108 citation statements)

References 44 publications

(23 reference statements)

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“…( A ) Venn diagram illustrating that of 3073 proteins with significant correlation to at least 1 Ca 2+ wave parameter of interest, 647 had orthologues with glycemic SNPs. ( B ) Of the 647 candidates, 9 were previously suggested to be secreted (61-64), 20 had existing KO mice with at least one metabolic phenotype (65), and 36 had existing compounds targeting them (57-60). ( C ) Example comparisons of strain variance for proteins (left column, (4)) and Ca 2+ traits (right column).…”

Section: Resultsmentioning

confidence: 99%

Novel regulators of islet function identified from genetic variation in mouse islet Ca²⁺oscillations

Emfinger

Clark

Schueler

et al. 2022

Preprint

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Insufficient insulin secretion to meet metabolic demand results in diabetes. The intracellular flux of Ca2+ into β-cells triggers insulin release. Since genetics strongly influences variation in islet secretory responses, we surveyed islet Ca2+ dynamics in eight genetically diverse mouse strains. We found high strain variation in response to four conditions: 1) 8 mM glucose; 2) 8 mM glucose plus amino acids; 3) 8 mM glucose, amino acids, plus 10nM GIP; and 4) 2 mM glucose. These stimuli interrogate β-cell function, α-cell to β-cell signaling, and incretin responses. We then correlated components of the Ca2+ waveforms to islet protein abundances in the same strains used for the Ca2+ measurements. To focus on proteins relevant to human islet function, we identified human orthologues of correlated mouse proteins that are proximal to glycemic-associated SNPs in human GWAS. Several orthologues have previously been shown to regulate insulin secretion (e.g. ABCC8, PCSK1, and GCK), supporting our mouse-to-human integration as a discovery platform. By integrating these data, we nominated novel regulators of islet Ca2+ oscillations and insulin secretion with potential relevance for human islet function. We also provide data for identifying appropriate mouse strains in which to study these regulators.

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Section: Resultsmentioning

confidence: 99%

Novel regulators of islet function identified from genetic variation in mouse islet Ca²⁺oscillations

Emfinger

Clark

Schueler

et al. 2022

Preprint

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“…For example, the deep integration between OBA and HPO will facilitate the use of gene-phenotype associations derived from GWAS studies in variant prioritisation software such as Exomiser 75 , which is used for clinical diagnostics. This has the potential to significantly extend the existing sources of gene-phenotype data from annotations of Mendelian disease resources such as OMIM and Orphanet as well as model organism resources such as MGI 5 , IMPC 7 and ZFIN 76 .…”

Section: Discussion and Future Workmentioning

confidence: 99%

The Ontology of Biological Attributes (OBA) - Computational Traits for the Life Sciences

Stefancsik

Balhoff

Balk

et al. 2023

Preprint

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Existing phenotype ontologies were originally developed to represent phenotypes that manifest as a character state in relation to a wild-type or other reference. However, these do not include the phenotypic trait or attribute categories required for the annotation of genome-wide association studies (GWAS), Quantitative Trait Loci (QTL) mappings or any population-focused measurable trait data. Moreover, variations in gene expression in response to environmental disturbances even without any genetic alterations can also be associated with particular biological attributes. The integration of trait and biological attribute information with an ever increasing body of chemical, environmental and biological data greatly facilitates computational analyses and it is also highly relevant to biomedical and clinical applications. The Ontology of Biological Attributes (OBA) is a formalised, species-independent collection of interoperable phenotypic trait categories that is intended to fulfil a data integration role. OBA is a standardised representational framework for observable attributes that are characteristics of biological entities, organisms, or parts of organisms. OBA has a modular design which provides several benefits for users and data integrators, including an automated and meaningful classification of trait terms computed on the basis of logical inferences drawn from domain-specific ontologies for cells, anatomical and other relevant entities. The logical axioms in OBA also provide a previously missing bridge that can computationally link Mendelian phenotypes with GWAS and quantitative traits. The term components in OBA provide semantic links and enable knowledge and data integration across specialised research community boundaries, thereby breaking silos.

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“…The contribution of individual amino acids such as isoleucine to propionic acid production is unknown and will be addressed. We suggest the study of Acad8 and Acadsb KO mouse models, which are available through the International Mouse Phenotyping Consortium (Groza et al 2022).…”

Section: Discussionmentioning

confidence: 99%

Acyl-CoA dehydrogenase substrate promiscuity limits the potential for development of substrate reduction therapy in disorders of valine and isoleucine metabolism

Dodatko

Dwyer

Chen

et al. 2022

Preprint

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Toxicity of accumulating substrates is a significant problem in several disorders of valine and isoleucine degradation notably short-chain enoyl-CoA hydratase (ECHS1 or crotonase) deficiency, 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, propionic acidemia (PA) and methylmalonic aciduria (MMA). Isobutyryl-CoA dehydrogenase (ACAD8) and short/branched-chain acyl-CoA dehydrogenase (SBCAD,ACADSB) function in the valine and isoleucine degradation pathways, respectively. Deficiencies of these acyl-CoA dehydrogenase (ACAD) enzymes are considered biochemical abnormalities with limited or no clinical consequences. We investigated whether substrate reduction therapy through inhibition of ACAD8 and SBCAD can limit the accumulation of toxic metabolic intermediates in disorders of valine and isoleucine metabolism. Using analysis of acylcarnitine isomers, we show that 2-methylenecyclopropaneacetic acid (MCPA) inhibited SBCAD, isovaleryl-CoA dehydrogenase, short-chain acyl-CoA dehydrogenase and medium-chain acyl-CoA dehydrogenase, but not ACAD8. MCPA treatment of wild-type and PA HEK-293 cells caused a pronounced decrease in C3-carnitine. Furthermore, deletion ofACADSBin HEK-293 cells led to an equally strong decrease in C3-carnitine when compared to wild-type cells. Deletion ofECHS1in HEK-293 cells caused a defect in lipoylation of the E2 component of the pyruvate dehydrogenase complex, which was not rescued byACAD8deletion. MCPA was able to rescue lipoylation inECHS1KO cells, but only in cells with priorACAD8deletion. SBCAD was not the sole ACAD responsible for this compensation, which indicates substantial promiscuity of ACADs in HEK-293 cells for the isobutyryl-CoA substrate. Substrate promiscuity appeared less prominent for 2-methylbutyryl-CoA at least in HEK-293 cells. We suggest that pharmacological inhibition of SBCAD to treat PA should be investigated further.

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The International Mouse Phenotyping Consortium: comprehensive knockout phenotyping underpinning the study of human disease

Cited by 137 publications

References 44 publications

Novel regulators of islet function identified from genetic variation in mouse islet Ca²⁺oscillations

Novel regulators of islet function identified from genetic variation in mouse islet Ca²⁺oscillations

The Ontology of Biological Attributes (OBA) - Computational Traits for the Life Sciences

Acyl-CoA dehydrogenase substrate promiscuity limits the potential for development of substrate reduction therapy in disorders of valine and isoleucine metabolism

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The International Mouse Phenotyping Consortium: comprehensive knockout phenotyping underpinning the study of human disease

Cited by 137 publications

References 44 publications

Novel regulators of islet function identified from genetic variation in mouse islet Ca2+oscillations

Novel regulators of islet function identified from genetic variation in mouse islet Ca2+oscillations

The Ontology of Biological Attributes (OBA) - Computational Traits for the Life Sciences

Acyl-CoA dehydrogenase substrate promiscuity limits the potential for development of substrate reduction therapy in disorders of valine and isoleucine metabolism

Contact Info

Product

Resources

About

Novel regulators of islet function identified from genetic variation in mouse islet Ca²⁺oscillations

Novel regulators of islet function identified from genetic variation in mouse islet Ca²⁺oscillations