Uncovering the biology of a painful and disfiguring pediatric disease – Medical Xpress

June 12, 2017 Accumulation of extracellular material in mice uterus. Credit: EPFL

Hyaline Fibromatosis Syndrome (HFS) is a rare but severegenetic disease that affectsbabies, children, and adults. A glassy substance called hyalineaccumulates in the skin and various organs of patients, causing painful deformities and may lead to early death.The disease is caused by genemutations that destroythe function of a protein whosephysiological function is little understood.EPFL scientists have now studied and characterized its function for the first time, showing that it binds and controls the body levels of an important type of collagen. The work is published in Nature Communications.

HFS is caused by a mutation of a gene called CMG2,also abbreviated asANTXR2 because it renders cells sensitive to anthrax infections. Thegene produces a protein that is embedded in the membrane of cells, and is known to bind anthrax toxins internalizing them into the cell where they exert their action. This is however not the physiological function of this protein.

The HFS mutation of the gene causes the proteinto lose its function. A hallmark of the disease is theaccumulation of collagen in large nodules under the skin. Collagen isthe most abundant protein in mammals, found in skin, cartilage, blood vessels, and even teeth. There are many different types of collagen, which surround cells and support the body's various tissues andorgans by forming elastic or rigid structuralnetworks.

The lab of Gisou Van der Goot at EPFLhas now shown for the first timethat the CMG2 protein interacts with a type of collagen called collagen VI. Normally,CMG2 binds collagen VI and, when there is too much,internalizes it into the cell's lysosomes for degradation. The study suggests that, in HFS, the mutation of the CMG2gene disrupts the function of the protein, leading to accumulation of collagen VI in various parts of the body.

Collagen VI is a typeof collagen that recent studies havefound in multiple sites in the body, such as the heart, neurons, immune cells, tendons, lungs, and the skin. Depending on the type oftissue, it plays different protective and mechanicalroles, but it has also been shown to be involved in a number of diseases, including the growth of cancer tumors.

The EPFL researchers studied HFS nodules inmouse models as well as a human patient.The femaleHFSmicecharacteristically suffer from accumulation of collagen in the uterus, which makes them sterile.The humanpatient had nodules at various body sites including the scalp and behind the ear. Studying tissuesamples, the researchers found that the nodules in both mice and human were rich in collagen VI.

Wanting to understand the relationship between CMG2 and collagen VI, the team developed double-knockout mice in which the genes for both proteins CMG2 and collagen VIhad been deleted. Previous studies have shown that CMG2-knockout mice are infertile due to uterine nodules that render them infertile. But remarkably, the scientists found that when the gene for collagen VI was deleted too, the mice regained their fertility, confirming that CMG2 and collagen VI are somehow connected in HFS.

Further studies showedthat CMG2physically bindscollagen VIthrough a specialized domain. The CMG2 protein then acts as a receptor, sending a signal into the cell, causing collagen VI to be internalized and degraded inside the cell's lysosomes.

The study reveals a major physiological function for CMG2 and demonstrates its interaction with collagen VI. This interaction explains how major HSF symptoms arise whenmutation of the CMG2 gene disrupts the ability of the CMG2 proteintocontrol the levels of collagenVI,which thenover-accumulates andproduces the painful and disfiguring symptoms of the disease.

Explore further: Collagen's role in skin cancer

More information: Jrme Burgi et al. CMG2/ANTXR2 regulates extracellular collagen VI which accumulates in hyaline fibromatosis syndrome, Nature Communications (2017). DOI: 10.1038/ncomms15861

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Taking 250mg of healthy adult male facial skin surface lipid pheromone by mouth ameliorates this condition, perhaps. (n=1)

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Uncovering the biology of a painful and disfiguring pediatric disease - Medical Xpress