Summary: Mutations in the gene ZNRF3 can lead to abnormal mental sizes—either very large or very small—causing several neurological symptoms. This protein, known for its part in tumor, is vital in regulating brain cell production.
The study discovered that certain gene variants disrupt the harmony of brain cell growth, which has potential implications for cancer risk in people with excessively large brains.
Major Information
- Abnormalities in the ZNRF3 protein can lead to the head expanding too much or reducing its size.
- The bacteria’s malfunction is linked to neurological signs and a higher risk of developing cancer.
- ZNRF3 variants affect the Wnt signaling road, essential for brain cell rules.
Origin: University of Zurich
A protein called , ZNRF3,  , known to be involved in cancers, also messes with the head. To create a right-sized head, the human mind requires two copies of this protein. The brain will either have the incorrect copy or the incorrect copy, causing various neurological symptoms, known as the mirror effect.
We recently witnessed a patient with a very uncommon condition, including an excessively little brain, conversation delay, and ectodermal dysplasia, an intrinsic condition that affects hair, nails, teeth, and skin.
We sequenced portion of her Genome and found a flaw in one version of the gene , ZNRF3,  , a protein that was not still associated with instinctive problems. This error results in the production of a dangerous protein. Thus, we suspected that this was the reason.
We have since collected the DNA of eleven additional people who are alleged to have a dangerous mutation in the same gene from other countries. Most of them had a faulty version of , ZNRF3 , and showed varying developmental signs with an unnaturally large head.
In the test, we tested the defective versions of the protein and discovered a link between the patient’s mind size and the mutation location. We finally managed to identify the root of these individuals ‘ illness after a lengthy medical journey.
Research on exceptional conditions is made possible by international collaboration.
We relied on international collaboration through professional marketing directories, where we posted our member protein and found games from all over the world because the situation described here is incredibly rare.
11 more patients with cautious protein changes were able to be identified from our database. Eight of them had one inaccurate version of , ZNRF3, while four people had lost one version.
Seven of the eight patients with faulty copies had changing developmental issues and a large brain, while one had serious developmental delay and a small brain.
The four patients with only one practical version showed no cerebral symptoms, but malfunctions in various organs, such as the heart, endocrine gland or kidney. No patient was seen to have lost both copies, which suggests that life is a contradiction in the absence of this gene.
ZNRF3 , is often mutated in several cancers
The gene , ZNRF3 , produces two copies of a protein that prevents the brain from making too many or too few brain cells. It does the same for many other organs, so mutations in the DNA sequence can cause uncontrolled cell proliferation and are therefore linked to a variety of tumors, including colon or adrenal cancer.
One of our analyses revealed that there is a small region of the , ZNRF3 , gene, called RING, where many mutations found in cancers are located compared to the rest of the gene.
In fact, the majority of those who have abnormally large brains have mutations in the RING region. They may therefore have an increased risk of developing tumors throughout their lifetime.
Two regions in the , ZNRF3 , gene are critical for brain size
Our analyses revealed that almost all mutations that cause abnormal development are found in two distinct regions of the gene: one in the RING region and the other in a smaller region crucial for interaction with another gene, known as RSPO. It turns out that the majority of the RING region defects were caused by people who had abnormally large brains, whereas the majority of the RSPO-interacting defects were caused by people who had abnormally small brains.
However, one patient had an abnormally small brain and a fault in the RING region. We looked at his family history and discovered that his mother frequently used drugs while pregnant, which might explain why his brain is abnormally small rather than large. Apparently, environmental influences can override genetic defects in this condition.
Molecular defects are explained by lab experiments and modeling.
The gene , ZNRF3 , orchestrates the perfect balance of biochemical signals, particularly in the Wnt signaling pathway, needed to produce the right number of brain cells. This gene works in concert with the gene , RSPO, which also interacts with the Wnt signaling. In the lab, we created different defective versions of the , ZNRF3 , gene and measured the signal that represents changes in the Wnt signaling pathway.
We found that the faults in the RING region ( from the patients with abnormally large brains ) increased the Wnt signaling, while the mutations in the , RSPO-interacting region ( from the patients with abnormally small brains ) decreased the Wnt signaling.
These findings demonstrated that a balanced Wnt signaling, which when turned too much or too little, can lead to the brain expanding or shrinking.
Additionally, sophisticated modeling of the defective ZNRF3 , protein revealed impaired binding to the interacting protein RSPO for the defects in the RING region and impaired enzyme functions for the defects in the RING-interacting region.
Better patient care and monitoring of cancer risk
As FDA-approved modulators of the Wnt signaling pathway are available, these findings open the possibility of using Wnt modulators therapeutically. However, this intervention must be approached with caution because a Wnt inhibitor should only be used in patients with abnormally large brains and not those with abnormally small brains, even if the same gene is faulty.
The gene ZNRF3  joins a list of other tens of genes that are related to brain size and are involved in the Wnt signaling pathway. Nonetheless, it is so far the only one of these genes to lead to opposing brain sizes with a distinct region-specific pattern, known as a mirror effect.
Since the Wnt signaling pathway is linked to cancer when disrupted, monitoring and intervention could be planned and personalized for patients with a faulty , ZNRF3 , gene.
About this research in brain development and genetics
Author: Barbara Simpson
Source: University of Zurich
Contact: Barbara Simpson – University of Zurich
Image: The image is credited to Neuroscience News
Original Research: Open access.
Anita Rauch et al.'” Deleterious ZNRF3 germline variants cause neurodevelopmental disorders with mirror brain phenotypes via domain-specific effects on Wnt/-catenin signaling.” American Journal of Human Genetics
Abstract
Deleterious ZNRF3 germline variants with mirror brain phenotypes due to domain-specific effects on Wnt/-catenin signaling are responsible for neurodevelopmental disorders with mirror brain phenotypes.
Zinc and RING finger 3 ( ZNRF3 ) is a negative-feedback regulator of Wnt/β-catenin signaling, which plays an important role in human brain development.
Although somatically frequently mutated in cancer, germline variants in , ZNRF3 , have not been established as causative for neurodevelopmental disorders ( NDDs ). We identified 12 individuals with , ZNRF3 , variants and various phenotypes via GeneMatcher/Decipher and evaluated genotype-phenotype correlation.
We performed structural modeling and representative deleterious and control variants were assessed using , in , vitro , transcriptional reporter assays with and without Wnt-ligand Wnt3a and/or Wnt-potentiator R-spondin ( RSPO ). Eight individuals harbored , de novo , missense variants and presented with NDD.
We discovered missense variants that cluster in the RING ligase domain with macrocephalic NDD. According to structural modeling, the ubiquitin ligase function’s disruption was likely to compromise Wnt receptor turnover.
Accordingly, the functional assays showed enhanced Wnt/β-catenin signaling for these variants in a dominant negative manner. Contrary to what a microcephalic NDD patient had, a missense variant in the RSPO-binding domain was found to be responsible for the RSPO-binding domain’s disruption of binding affinity and for attenuated Wnt/-catenin signaling in the same tests.
Additionally, four individuals harbored , de novo , truncating or , de novo , or inherited large in-frame deletion variants with non-NDD phenotypes, including heart, adrenal, or nephrotic problems.
The effects on Wnt/-catenin signaling were comparable between the truncating variant and the empty vector, and between benign variants and the wild type, in contrast to NDD-associated missense variants.
In summary, we provide evidence for mirror brain size phenotypes caused by distinct pathomechanisms in Wnt/β-catenin signaling through protein domain-specific deleterious , ZNRF3 , germline missense variants.
