Pleiotropy data resource as a primer for investigating co-morbidities/multi-morbidities and their role in disease

Muñoz-Fuentes, Violeta; Haselimashhadi, Hamed; Westerberg, Henrik; Parkinson, Helen; Mason, Jeremy

doi:10.1007/s00335-021-09917-w

Cited by 3 publications

(3 citation statements)

References 35 publications

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“…The knowledge externalised by the resource supports the identification of new mouse models of rare and common human diseases, new gene functions and the development of novel methodological approaches that form the basis of new gene-disease associations. Moreover, it underpins successful experiments effectively uncovering pleiotropy (4)(5)(6), of particular importance when elucidating the genetic causes of syndromic disorders, as well as wideranging sexual dimorphism (7).…”

Section: Introductionmentioning

confidence: 99%

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

Groza

Gómez

Mashhadi

et al. 2022

Nucleic Acids Research

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The International Mouse Phenotyping Consortium (IMPC; https://www.mousephenotype.org/) web portal makes available curated, integrated and analysed knockout mouse phenotyping data generated by the IMPC project consisting of 85M data points and over 95,000 statistically significant phenotype hits mapped to human diseases. The IMPC portal delivers a substantial reference dataset that supports the enrichment of various domain-specific projects and databases, as well as the wider research and clinical community, where the IMPC genotype–phenotype knowledge contributes to the molecular diagnosis of patients affected by rare disorders. Data from 9,000 mouse lines and 750 000 images provides vital resources enabling the interpretation of the ignorome, and advancing our knowledge on mammalian gene function and the mechanisms underlying phenotypes associated with human diseases. The resource is widely integrated and the lines have been used in over 4,600 publications indicating the value of the data and the materials.

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Section: Introductionmentioning

confidence: 99%

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

Groza

Gómez

Mashhadi

et al. 2022

Nucleic Acids Research

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179

132

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“…For each knockout (KO) line, abnormal phenotypes are being ascertained across a range of physiological systems through comparison with wild-type lines ( Kurbatova et al, 2015 ; Haselimashhadi et al, 2020 ). These gene–phenotype associations have been investigated to increase our knowledge on human disease using multiple, complementary approaches: (1) to learn about sexual dimorphism and pleiotropic traits ( Karp et al, 2017 ; Munoz-Fuentes et al, 2022 ), (2) to reveal previously unidentified candidate genes for multiple physiological systems and disease types ( Higgins et al, 2022 ; Bowl et al, 2017 ; Chee et al, 2023 ; Cacheiro et al, 2022 , 2020 ) and (3) to investigate how well the current phenotypic screens capture specific human traits ( Cacheiro et al, 2023 ; Lindovsky et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Computational identification of disease models through cross-species phenotype comparison

Cacheiro,

Pava,

Parkinson

et al. 2024

Disease Models &Amp; Mechanisms

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The use of standardised phenotyping screens to identify abnormal phenotypes in mouse knockouts, together with the use of ontologies to describe such phenotypic features, allows the implementation of an automated and unbiased pipeline to identify new models of disease by performing phenotype comparisons across species. Using data from the International Mouse Phenotyping Consortium (IMPC), approximately half of mouse mutants are able to mimic, at least partially, the human ortholog disease phenotypes as computed by the PhenoDigm algorithm. We found the number of phenotypic abnormalities in the mouse and the corresponding Mendelian disorder, the pleiotropy and severity of the disease, and the viability and zygosity status of the mouse knockout to be associated with the ability of mouse models to recapitulate the human disorder. An analysis of the IMPC impact on disease gene discovery through a publication-tracking system revealed that the resource has been implicated in at least 109 validated rare disease–gene associations over the last decade.

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“…The molecular mechanisms of microphthalmia, anophthalmia, and coloboma (MAC) spectrum disease are not fully defined. This study searched 8267 single gene knockout mouse lines produced and phenotyped by the International Mouse Phenotyping Consortium [1][2][3][4], to identify the novel genes and pathways required for mammalian eye development and MAC spectrum disease.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide screening reveals the genetic basis of mammalian embryonic eye development

Chee

Lanoue²,

Clary³

et al. 2023

BMC Biol

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Background Microphthalmia, anophthalmia, and coloboma (MAC) spectrum disease encompasses a group of eye malformations which play a role in childhood visual impairment. Although the predominant cause of eye malformations is known to be heritable in nature, with 80% of cases displaying loss-of-function mutations in the ocular developmental genes OTX2 or SOX2, the genetic abnormalities underlying the remaining cases of MAC are incompletely understood. This study intended to identify the novel genes and pathways required for early eye development. Additionally, pathways involved in eye formation during embryogenesis are also incompletely understood. This study aims to identify the novel genes and pathways required for early eye development through systematic forward screening of the mammalian genome. Results Query of the International Mouse Phenotyping Consortium (IMPC) database (data release 17.0, August 01, 2022) identified 74 unique knockout lines (genes) with genetically associated eye defects in mouse embryos. The vast majority of eye abnormalities were small or absent eyes, findings most relevant to MAC spectrum disease in humans. A literature search showed that 27 of the 74 lines had previously published knockout mouse models, of which only 15 had ocular defects identified in the original publications. These 12 previously published gene knockouts with no reported ocular abnormalities and the 47 unpublished knockouts with ocular abnormalities identified by the IMPC represent 59 genes not previously associated with early eye development in mice. Of these 59, we identified 19 genes with a reported human eye phenotype. Overall, mining of the IMPC data yielded 40 previously unimplicated genes linked to mammalian eye development. Bioinformatic analysis showed that several of the IMPC genes colocalized to several protein anabolic and pluripotency pathways in early eye development. Of note, our analysis suggests that the serine-glycine pathway producing glycine, a mitochondrial one-carbon donator to folate one-carbon metabolism (FOCM), is essential for eye formation. Conclusions Using genome-wide phenotype screening of single-gene knockout mouse lines, STRING analysis, and bioinformatic methods, this study identified genes heretofore unassociated with MAC phenotypes providing models to research novel molecular and cellular mechanisms involved in eye development. These findings have the potential to hasten the diagnosis and treatment of this congenital blinding disease.

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Pleiotropy data resource as a primer for investigating co-morbidities/multi-morbidities and their role in disease

Cited by 3 publications

References 35 publications

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

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

Computational identification of disease models through cross-species phenotype comparison

Genome-wide screening reveals the genetic basis of mammalian embryonic eye development

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