Modeling Rare Human Disorders in Mice: The Finnish Disease Heritage

Zárybnický, Tomáš; Heikkinen, Anne; Kangas, Salla M.; Karikoski, Marika; Martínez-Nieto, Guillermo Antonio; Salo, Antti M.; Uusimaa, Johanna; Vuolteenaho, Reetta; Hinttala, Reetta; Sipilä, Petra; Kuure, Satu

doi:10.3390/cells10113158

Cited by 4 publications

(4 citation statements)

References 186 publications

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“…Together with the research community and systematic phenotyping conducted by the International Mouse Phenotyping Consortium (IMPC; ), knockout (KO) mice for the majority of genes causing FDH have already been generated. However, as many of the disease-causing variants of FDH are missense and the knock-in mouse models expressing the Finnish major mutations are currently not available, only a few of the existing KO mouse lines recapitulate the full spectrum of FDH disease symptoms ( Table 2 ) ( Zárybnický et al, 2021 ). Thus, strategies for better in vivo and in vitro disease models that faithfully genocopy disease-specific variants and phenocopy the FDH disease symptoms are needed and constantly developed.…”

Section: The Fdhmentioning

confidence: 99%

The Finnish genetic heritage in 2022 – from diagnosis to translational research

Uusimaa

Kettunen

Varilo

et al. 2022

Disease Models &Amp; Mechanisms

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Isolated populations have been valuable for the discovery of rare monogenic diseases and their causative genetic variants. Finnish disease heritage (FDH) is an example of a group of hereditary monogenic disorders caused by single major, usually autosomal-recessive, variants enriched in the population due to several past genetic drift events. Interestingly, distinct subpopulations have remained in Finland and have maintained their unique genetic repertoire. Thus, FDH diseases have persisted, facilitating vigorous research on the underlying molecular mechanisms and development of treatment options. This Review summarizes the current status of FDH, including the most recently discovered FDH disorders, and introduces a set of other recently identified diseases that share common features with the traditional FDH diseases. The Review also discusses a new era for population-based studies, which combine various forms of big data to identify novel genotype–phenotype associations behind more complex conditions, as exemplified here by the FinnGen project. In addition to the pathogenic variants with an unequivocal causative role in the disease phenotype, several risk alleles that correlate with certain phenotypic features have been identified among the Finns, further emphasizing the broad value of studying genetically isolated populations.

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Section: The Fdhmentioning

confidence: 99%

The Finnish genetic heritage in 2022 – from diagnosis to translational research

Uusimaa

Kettunen

Varilo

et al. 2022

Disease Models &Amp; Mechanisms

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“…Mouse models provide an invaluable resource to investigate the functionality of genes as well as contribute to the discovery of new genes involved in human disease ( Baldridge et al, 2021 ). Genetically modified mice have markedly facilitated the understanding and characterisation of Mendelian disorders, providing insights into the disease mechanisms and the development of therapeutic options ( Zarybnicky et al, 2021 ; Murillo-Cuesta et al, 2020 ). Reproducibility is vital in mouse disease modelling.…”

Section: Introductionmentioning

confidence: 99%

Knockout mice are an important tool for human monogenic heart disease studies

Cacheiro

Spielmann

Mashhadi

et al. 2023

Disease Models &Amp; Mechanisms

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Mouse models are relevant to study the functionality of genes involved in human diseases, however, translation of phenotypes can be challenging. Herein, we investigated genes related to monogenic forms of cardiovascular disease based on the Genomics England PanelApp and aligned them to the International Mouse Phenotyping Consortium data. We found 153 genes associated to cardiomyopathy, cardiac arrhythmias or congenital heart disease in humans, 151 with a one2one mouse orthologs. For 37.7% (57/151) viability and heart data captured by electrocardiography, transthoracic echocardiography, morphology and pathology from embryos and young adult mice was available. In knockout mice, 75.4% (43/57) of these genes showed non-viable phenotypes, whereas records of prenatal, neonatal or infant death in humans were found for 35.1% (20/57). Multisystem phenotypes are common, with 58.8% (20/34) of heterozygous (homozygous lethal) and 78.6% (11/14) of homozygous (viable) mice showing cardiovascular, metabolic/homeostasis, musculoskeletal, hematopoietic, nervous system and/or growth abnormalities mimicking the clinical manifestations observed in patients. This IMPC data is critical beyond cardiac diagnostics given its multisystemic nature that allows detecting abnormalities across physiological systems, providing a valuable resource to understand pleiotropic effects.

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“…Mouse models have been developed for rare human skeletal disorders (12), muscular dystrophies and congenital myopathies (13), rare metabolic, neuromuscular and opthalmological diseases (8), as well as rare neurodevelopmental (14), and neurodegenerative disorders (3,15). Mouse models are valuable for the study of the genetic mutations, molecular biology, and phenotypic expression of these rare human diseases (16,17).…”

Section: Introduction Introductionmentioning

confidence: 99%

Genetically modified mice for research on human diseases: A triumph for Biotechnology or a work in progress?

Brown

2022

The EuroBiotech Journal

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Genetically modified mice are engineered as models for human diseases. These mouse models include inbred strains, mutants, gene knockouts, gene knockins, and ‘humanized’ mice. Each mouse model is engineered to mimic a specific disease based on a theory of the genetic basis of that disease. For example, to test the amyloid theory of Alzheimer’s disease, mice with amyloid precursor protein genes are engineered, and to test the tau theory, mice with tau genes are engineered. This paper discusses the importance of mouse models in basic research, drug discovery, and translational research, and examines the question of how to define the “best” mouse model of a disease. The critiques of animal models and the caveats in translating the results from animal models to the treatment of human disease are discussed. Since many diseases are heritable, multigenic, age-related and experience-dependent, resulting from multiple gene-gene and gene-environment interactions, it will be essential to develop mouse models that reflect these genetic, epigenetic and environmental factors from a developmental perspective. Such models would provide further insight into disease emergence, progression and the ability to model two-hit and multi-hit theories of disease. The summary examines the biotechnology for creating genetically modified mice which reflect these factors and how they might be used to discover new treatments for complex human diseases such as cancers, neurodevelopmental and neurodegenerative diseases.

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Modeling Rare Human Disorders in Mice: The Finnish Disease Heritage

Cited by 4 publications

References 186 publications

The Finnish genetic heritage in 2022 – from diagnosis to translational research

The Finnish genetic heritage in 2022 – from diagnosis to translational research

Knockout mice are an important tool for human monogenic heart disease studies

Genetically modified mice for research on human diseases: A triumph for Biotechnology or a work in progress?

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