Jax Labs eBook - 22


Mouse models in rare disease gene
discovery and validation
Genetic mutations have been shown to
cause more than 80% of rare diseases.
Armed with this genomic information,
scientists have directed their efforts
to develop in vitro and in vivo models to
understand the molecular mechanisms
underlying the diseases. Due to the
established technologies for genome
manipulation and its high genomic and
functional conservation with humans,
the mouse model has been by far the
most used organism in orphan drug
development (Vaquer et al., 2013).
Mouse models represent very
convenient tools to understand how
specific mutations identified in patients
can influence the function of specific
organs and tissues. This is extremely
important in cases where more than one
system is affected by a single mutation,
such as mutations with pleiotropic effects
or affecting metabolism (Ittisoponpisan
et al., 2017). Furthermore, in many
22 | GENengnews.com

cases, the introduction of a mutation in
the mouse genome corresponding to a
human disease-associated variant results
in a mouse strain exhibiting at least some
of the clinical phenotypes (Lutz, 2018).
Mouse models are also widely used
to simplify and focus genomic research
aimed at identifying novel rare disease

link the appearance of certain symptoms
to specific genes. For example, copy
number variations associated with
seizures at a particular time of day in
humans were identified because they
disrupted the circadian cycle in mice
(Webber et al., 2009; Boulding and
Webber, 2012). McGary and colleagues

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genes by analyzing large genomic
rearrangements leading to copy number
variations. In this case, the primary
purpose of the mouse model is to restrict
the genomic region associated with a
specific disease to one or a few genes
by analyzing the data associated with
previously described mouse phenotypes
and correlate them to the human
pathological manifestation. Using this
approach, researchers have been able to

describe an intriguing extension of this
approach, suggesting that the analysis
and correlation of orthologous phenotypes
(phenologs) can be used to identify new
disease-causing phenotypes (McGary et
al., 2010).
Mouse models are also used to
investigate the relationship between
different diseases and explore the role
of genetic modifiers in the disease
progression. In a revealing example,


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