Specific modifier genes determine the phenotype of the mutation

Noncompact cardiomyopathy is a type of heart disease caused by defects that occur during fetal development and can have different effects on the patient's health, including sudden cardiac death
.
The role of
intercellular signaling in cardiovascular development and disease groups.
The National Center for Cardiovascular Investigation (CNIC) previously reported that the disease may be caused
by two different mutations in the Mindbomb1 gene (Mib1).

The same team has now shown that the presence of one of these Mib1 mutations does not always lead to non-compact cardiomyopathy
.
Instead, the results depend on the genetic environment provided by other genetic mutations that "modify" the effects of
the Mib1 mutation.

In the Circulation paper, scientists describe how the mutation environment that accompanies a so-called "causal" mutation in noncompact cardiomyopathy affects the severity and appearance of different abnormalities, so the precise results depend on the patient's specific combination of
mutations.

In 2013, the team identified two mutations in Mib1 in two different families as the cause of
left ventricular noncompact (LVNC).
The health effects of LVNC can be very diverse, leading to sudden cardiac death in severe cases and caused by defects that appear before birth
.
Building on earlier research, the team, led by Dr.
José Luis de la Pompa, aimed to analyze the specific mechanism
by which Mib1 is so important for the correct development of the heart.
In this analysis, the team used the CRISPR-Cas9 molecular scissors technique to insert mutations that cause LVNC into the
mouse genome.

Analysis of these mouse models showed that LVNC developed in these animals only when they carried two allele copies of one of the Mib1 mutations
.
As Dr.
De la Pompa explains, "This is different from the patient's condition, whose disease manifests itself as the presence of a single copy of
the MIB1 mutant.
In addition to this, the mice developed heart valve defects, either alone or in combination with
LVNCs.
”

First author Marcos Siguero Álvarez explained that these differences suggest that LVNC patients with MIB1 mutations may additionally have "mutations in other genes that lead to the severity and diversity
of the observed defects.
" ”

To uncover the truth, the research team sought help from LVNC patients and their families, as well as partners from different centers, in particular Dr.
Juan Ramón Gimeno.

With the support of these stakeholders, the scientists were able to sequence
the DNA of LVNC patients and their healthy family members who carry the MIB1 mutation.

Complete sequencing of the protein-coding genomes (exomes) of members of these two families revealed that LVNC and MINDBOMB1 mutations were accompanied by additional gene mutations
that may help heart development.
José Luis de la Pompa clarifies that "these results suggest that these congenital heart diseases may be caused by a combination of a small group of genes (oligogenetic) or a single gene (single-gene inheritance)"
.

The team validated the data
on a mouse model.
"When we simultaneously introduced a series of mutations found in one of the two LVNC families, the mice developed heart chamber defects that lead to LVNC-like disease and affect heart function
.
In contrast, a mutant group from another family resulted in valve defects, suggesting that additional variants act as modifiers for the mutant effect of Mindbomb1," explains Marcos Siguero álvarez
.

A key feature of these experiments is that only one allele copy is inserted into
the mice for each mutant.
In other words, as seen in patients, mutant variants produce phenotypes
through dominant effects.

José Luis de la Pompa commented: "These findings advance specific knowledge about LVNC and more generally reinforce the idea that congenital heart disease is not always a single gene, but rather involves the intervention
of several mutations through oligogenetic inheritance.
"

Dr De la Pompa added that sequencing of new genes will help advance diagnosis, while studies of interactions between multiple mutant variants will help design new treatments
.

Another important finding was that analysis of cardiomyocytes differentiated from patient stem cells in vitro showed that non-compact cardiomyopathy was associated
with defects in cardiomyocyte maturation and increased cardiomyocyte proliferation.

Recently, a further study co-led by the CNIC team confirmed this finding
.
This study identified the MINDBOMB1 mutation in patients with familial or sporadic aortic valve defects (mitral valve), confirming the significance
of MIB1 mutations in human valve disease.

Human Hereditary Cardiomyopathy Shares a Genetic Substrate With Bicuspid Aortic Valve