New COL3A1 Mutation Linked to Vascular EDS in Japanese Woman

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by Marta Figueiredo PhD |

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COL3A1 mutation | Ehlers-Danlos News | illustration of DNA

A new mutation in the COL3A1 gene has been linked to vascular Ehlers-Danlos syndrome (vEDS) in a woman in Japan, scientists report.

This genetic variant — which was not found among more than 8,000 healthy Japanese people nor in worldwide databases of disease-associated variants — adds to the increasing number of COL3A1 mutations linked to vEDS.

The study also supports the combination of databases of variants in healthy populations and of disease-causing mutations to confirm the uniqueness of newly identified genetic variations in Japanese people, the researchers noted.

Ehlers–Danlos syndrome type IV with a novel COL3A1 exon 14 skipping variation confirmed by Tohoku Medical Megabank Organization genomic database,” the case report, was published in The Journal of Dermatology.

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Ehlers-Danlos syndrome (EDS) comprises a group of related genetic diseases characterized by weakness in the connective tissue that provides structure and support through the body.

Vascular EDS is characterized by thin, translucent skin, easy bruising, characteristic facial features — sometimes called a “Madonna face” — fragile blood vessels, and a high risk of organ damage due to tissue rupture.

It is mostly caused by mutations in the COL3A1 gene, which provides instructions to produce collagen type 3, a protein found in the connective tissue of the skin, lungs, and vascular system.

Now, researchers have identified a new COL3A1 mutation associated with vEDS in a 36-year-old Japanese woman.

She was referred to the dermatology clinic of Tohoku University Hospital due to low muscle tone, easy bruising, and excessive bleeding when she had surgery to remove noncancerous growths in her uterus.

The woman had a “Madonna face” with large eyes, nasal thinning, small earlobes, and thin, translucent skin with dilated or broken blood vessels near its surface. She had a history of carotid-cavernous sinus fistula — an abnormal connection between the carotid artery in the neck and the network of veins at the back of the eye — that was resolved at age 26.

None of her relatives “had clinical features suggesting a fragile skin condition,” the researchers wrote.

Analysis of a skin biopsy showed varied diameters of collagen fibrils in the dermis — the thickest, deeper layer of the skin that is made up of connective tissue — consistent with EDS. Also, patient-derived skin cells grown in the lab had reduced levels of collagen type 3, relative to cells from a healthy person.

Genetic analysis of the COL3A1 gene region revealed a mutation (c.951+2T>G) in a splice site that leads to exon 14 skipping and likely results in a shorter, nonworking collagen type 3 protein. Splicing is a natural process that removes dispensable sections of genetic information (introns) and joins those containing information needed to build a protein (exons) in an intermediate molecule derived from DNA that guides protein production.

The newly identified genetic variation was not listed in any of eight independent, worldwide databases of disease-associated mutations. It was also not present in the genome (the complete set of DNA) of 8,380 healthy Japanese people included in the Tohoku Medical Megabank Organization (ToMMo) database.

These findings suggest that the mutation is not a common genetic variation in the Japanese population (at least in the country’s Tohoku region), and that it is a de novo disease-causing mutation that reduces collagen type 3 levels.

De novo mutations are those that, instead of being inherited, appear for the first time in one family member.

Notably, 13 COL3A1 mutations that registered as disease-related variants in worldwide genetic databases were also identified in the ToMMo database and in a multiracial, healthy-variant database, and some at much higher frequencies than that estimated for vEDS.

This observation suggests that these variants “are unlikely to cause vascular EDS” on their own and that “careful validations are required to examine if gene variants are pathogenic [disease-causing], because genetic variants are known to vary among racial groups,” the team wrote.

Overall, vEDS in this woman was caused by a new mutation in the COL3A1 gene, and “these statistical genetics approaches with the combination of the ToMMo database of 8380 Japanese individuals and pathogenic genetic databases are a useful method to confirm the uniqueness of novel variation in Japanese,” the team wrote.