Instituto Valenciano de Microbiología

Masía El Romeral
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Stickler syndrome ... (Stickler syndrome) - Genes COL2A1, COL9A1, COL9A2, COL9A3, COL11A1 and COL11A2

Stickler syndrome is a congenital process affecting the fibrillar collagen connective tissue and generates predominantly ophthalmological, auditory and articular manifestations. These signs and symptoms vary widely among affected individuals.

A characteristic feature of Stickler syndrome is a somewhat flattened facial appearance due to bone underdevelopment in the center of the face, including the cheeks and nasal bridge. A particular group of physical characteristics called Pierre Robin sequence is also frequent common in people with Stickler syndrome. Pierre Robin sequence includes cleft palate, and micrognatia glossoptosis. This combination of features can cause feeding problems and difficulty breathing. In addition, many people with Stickler syndrome have severe myopia. Other eye problems may include glaucoma, cataracts and retinal detachment. In some cases, these abnormalities may cause eye problems vision or blindness. Other manifestations features include hearing loss due to abnormalities of the middle ear and skeletal abnormalities affecting the joints. The joint abnormalities can cause hypermobility (although joints become less flexible with age), arthritis , and in the vertebrae scoliosis or kyphosis and including platyspondyly.

They described various types of Stickler syndrome, which are distinguished by their genetic causes and patterns of signs and symptoms. In particular, eye abnormalities and severity of hearing loss differ by type. Type I has the highest risk of retinal detachment. Type II also includes ocular abnormalities. Type III does not include oftlamológicas anomalies, so it is often called non - ocular Stickler syndrome. Types II and III are more likely to show a significant hearing loss. Types IV, V, and VI are very rare and each have been diagnosed in only a few individuals.

A similar syndrome Stickler called Marshall syndrome, process characterized by facial distinctive appearance, eye abnormalities, hearing loss, and early onset arthritis. Also, Marshall syndrome may also include short stature. Some researchers have rated the Marshall syndrome as a variant of Stickler syndrome, while others believe they are different processes.

Stickler syndrome may be due to mutations in the COL2A1, COL9A1, COL9A2, COL9A3, COL11A1 and COL11A2 gene, each being responsible for the different types of the syndrome. Between 80 and 90% of all cases are due to mutations in the COL2A1 gene, followed by mutations in the gene COL11A1 representing between 10 to 20% of cases. All genes associated with Stickler syndrome encode components of collagens that provide structure and strength to connective tissues that support joints and organs of the body. Mutations in any of these genes alter the coding processing or assembly of collagen molecules. Defective collagen molecules or reduced amounts of collagen alter the development of connective tissues in many different parts of the body, leading to the various features of Stickler syndrome. Not all people with Stickler syndrome have mutations in one of the known genes. It is believed that mutations in other genes can also result in this process, but have not identified the genes.

Mutations in the COL2A1 gene, located on the long arm of chromosome 12 (12q13.11), are responsible for 80 to 90% of all cases of the syndrome. This gene encodes a component of collagen type II, called the pro-alpha1 (II) chain. This type of collagen is found primarily in the vitreous and cartilage. Collagen type II is essential for normal bone development and other connective tissues that form the support frame body. Collagen type II is also part of the vitreous, the inner ear, and the nucleus pulposus. They have identified about 200 mutations in the COL2A1 gene in people with Stickler syndrome, designated as type I. Many of these mutations result encoding an abnormally short pro-alpha1 (II) chain can not be incorporated a fiber type II collagen. Other mutations create a premature stop signal encoding the pro-alpha1 (II) chain. As a result of these genetic mutations of COL2A1, cells encode only half the normal amount of the collagen chain, reducing the amount of type II collagen in cartilage and other tissues. Deficiency type II collagen underlying signs and symptoms of Stickler syndrome type I.

Mutations in the COL11A1 gene, located on the short arm of chromosome 1 (1p21), are responsible for 10 to 20% of all cases of the syndrome. The COL11A1 gene encoding the pro-alpha1 chain (XI), component collagen type XI. Type XI collagen adds the structure and strength to connective tissues supporting the muscles, joints, organs and skin. Collagen type XI is also part of the vitreous, the inner ear, and the nucleus pulposus of the vertebrae. In addition, type XI collagen also helps maintain separation and diameter of the fibrils of type II collagen. The type II collagen is an important component of the eye and mature cartilage tissue. The size and arrangement of collagen fibrils type II is essential for the normal structure of these tissues. They have identified more than two dozen COL11A1 gene mutations in people with type II Stickler syndrome. Some of these mutations change specific amino acids or eliminate a small number of amino acids of the pro-alpha1 chain (XI). Other mutations omitted DNA segments encoding the protein, resulting in an abnormally short chain pro-alpha1 (XI). All these changes reduce the production or assembly of collagen molecules XI. Defective collagen disrupts the normal development of connective tissue in many different parts of the body, which leads to the variety of signs and symptoms of Stickler syndrome.

Types I, II, and III Stickler Syndrome are inherited in an autosomal dominant pattern, which means that a copy of the altered gene in each cell is sufficient to express the alteration. In some cases, an affected person inherits a genetic mutation from an affected parent. Other cases are due to new mutations that occur in people with no history of Stickler syndrome in your family. Marshall syndrome generally also have an autosomal dominant inheritance. Meanwhile, types IV, V and VI are inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform detection of mutations associated with Stickler syndrome by complete PCR amplification of the exons of the COL2A1, COL11A1, COL9A1, COL9A2, COL9A3 and COL11A2 respectively and subsequent sequencing genes. It is recommended to start the study of the COL2A1 gene exons, responsible for most cases of the syndrome, with the possible reduction of time and cost involved in most cases. If not, it is recommended to continue the study by exons of the gene COL11A1.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample) if postnatal diagnosis. For prenatal diagnosis, amniotic fluid or chorionic villi.