COL11A1

At least seven variants in the COL11A1 gene have been identified in people with fibrochondrogenesis type 1, a disorder of bone growth characterized by severe skeletal abnormalities, hearing loss, and vision loss. Infants with fibrochondrogenesis type 1 have a very narrow chest that prevents the lungs from developing normally. Most children with this condition are stillborn or die shortly after birth from respiratory failure, although some have lived into childhood.

Some cases of fibrochondrogenesis type 1 result from a combination of COL11A1 gene variants. Specifically, one copy of the gene has a variant that prevents the production of any functional pro-alpha1(XI) chain, and the other copy has a variant that results in an abnormal version of the pro-alpha1(XI) chain. When the abnormal chain is incorporated into collagen molecules, it creates defective type XI collagen. The abnormal collagen weakens connective tissues, impairing the formation of bones throughout the skeleton and causing changes in the eye and inner ear that lead to vision and hearing problems.

In at least two reported cases, fibrochondrogenesis type 1 has been caused by combinations of COL11A1 gene variants that completely eliminate the production of the pro-alpha1(XI) chain. Researchers speculate that a loss of this chain changes the structure of type XI collagen molecules and disrupts its ability to form cross-links. However, the effects of these variants are still under study.

Variants in the COL11A1 gene account for 10 to 20 percent of all cases of Stickler syndrome. Signs and symptoms of this condition include a distinctive facial appearance, eye abnormalities, hearing loss, and joint problems. These signs and symptoms tend to be less severe than those of fibrochondrogenesis (described above). However, they vary widely among affected individuals.

More than two dozen COL11A1 gene variants have been found in people with Stickler syndrome. Some of these variants change single protein building blocks (amino acids) or delete a small number of amino acids from the pro-alpha1(XI) chain. Other variants cause segments of DNA to be skipped when the protein is made, resulting in an abnormally short pro-alpha1(XI) chain. All of these changes impair the production or assembly of type XI collagen molecules. Defective collagen disrupts the normal development of connective tissues in many different parts of the body, which leads to the varied signs and symptoms of Stickler syndrome.

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Variants in the COL11A1 gene can also cause Marshall syndrome, a condition that is very similar to Stickler syndrome. Some researchers have classified Marshall syndrome as a variant of Stickler syndrome, while others consider it to be a separate disorder. Most of the variants associated with Marshall syndrome cause a segment of DNA in the COL11A1 gene to be skipped when the protein is made, resulting in an abnormally short pro-alpha1(XI) chain. This shortened protein impairs the formation of mature type XI collagen, which leads to the abnormal development of connective tissues and the signs and symptoms of Marshall syndrome.