Arthrogryposis distal type 2B; Sheldon syndrome-Hall (Distal arthrogryposis type 2B -DA2B-; Sheldon-Hall syndrome) - Genes MYH3, TNNI2, TNNT3 and TPM2
Distal Arthrogryposis is a clinically and genetically heterogeneous disorder characterized by a closed fist, overlapping fingers, camptodactilia, ulnar deviation and foot deformities from birth. This disorder includes malformations of the limbs, in the absence of a neurological disease or muscle primary. Other signs may include triangular face inclined downwardly palpebral fissures, nasolabial folds, a small mouth with an arched hard palate, webbed neck and short stature.
Distal Arthrogryposis Type 1 (DA1) is not associated with other anomalies, while other forms of distal arthrogryposis (DA) have additional phenotypic characteristics. Congenital contracture distal arthrogryposis type 2B (DA2B), (syndrome Sheldon-Hall, SHS) are similar to those observed in (DA1), but affected individuals tend to have more prominent nasolabial folds, have oblique palpebral fissures down, and a small mouth. Distal arthrogryposis type 2B (DA2B) is the most common of distal arthrogryposis.
Distal arthrogryposis type 2B, or Sheldon-Hall syndrome, may be due to mutations in MYH3, TNNI2, TNNT3 or TPM2 genes. These genes encode proteins that are involved in muscle contraction.
The MYH3 gene, located on the short arm of chromosome 17 (17p13.1), encodes a protein called myosin chain 3 embryonic skeletal muscle. This protein belongs to a group of proteins that are involved in cell movement and transport of materials within the cells and between cells. This protein is usually only active before birth and is important in early muscle development. Thick filaments consist of myosin with thin filaments of another protein called actin, are the primary components of muscle fibers and are important for muscle contraction. They have identified at least 18 MYH3 gene mutations in people with type 2B or distal arthrogryposis Sheldon-Hall syndrome. It is considered that these genetic changes interfere with the ability of the protein to bind to actin and other muscle proteins, and may also affect the formation of thick filaments. Mutations likely prevent muscle contractions are properly controlled and interfering with muscle development before birth, resulting in muscle contractures and other skeletal abnormalities associated with the process.
The TNNI2 gene, located on the short arm of chromosome 11 (11p15.5), encoding the protein troponin I, found in skeletal muscles. Troponin I is one of the three proteins which comprise the troponin complex in muscle cells, consisting of the subunits of troponin T, troponin C and troponin I. The troponin complex, along with calcium, helps regulate contraction and muscle tension. The troponin complex, tropomyosin with, is responsible for calcium - dependent regulation of the contraction of striated muscle. C subunit binds Ca2 + and subunit I binds to actin and inhibits the actin-myosin interaction. The T subunit binds to the troponin complex and tropomyosin complex, also with Ca2 + requirement. Ca 2+ binding to troponin trimeric complex initiates the process of muscle contraction. Increasing Ca 2+ concentrations produce a conformational change in the troponin complex that is transmitted dimers tropomyosin located along actin filaments. It has been found that this component is also present in the vascular smooth muscle and may play a role in regulating smooth muscle function. Besides muscle tissues, this protein is found in the corneal epithelium, cartilage, where it is an angiogenesis inhibitor, inhibits tumor growth and metastasis, and in the mammary gland, where it functions as a co-activator receptor alpha estrogen receptor related. This protein also suppresses tumor growth in human ovarian carcinoma.
They have been described at least four mutations in the gene TNNI2 in people with type 2B or distal arthrogryposis Sheldon-Hall syndrome. It is likely that these genetic changes can prevent the troponin complex lock the thick and thin filament binding to control muscle contractions, leading to contractures and other associated anomalies and skeletal muscle.
The TNNT3 gene, located on the short arm of chromosome 11 (11p15.5) encodes troponin T protein, found in skeletal muscles. Troponin T is one of the three proteins which comprise the troponin complex in muscle cells. The troponin complex, along with calcium, helps regulate muscle contraction. Have identified at least two mutations in genes TNNT3 people with type 2BO distal arthrogryposis syndrome Sheldon-Hall. These genetic changes can prevent the troponin complex block the binding to control muscle contractions thick and thin filament, leading to muscle contractions and other associated skeletal anomalies.
The TPM2 gene, located on the short arm of chromosome 9 (9p13), encoding the protein tropomyosin beta (?), which is part of the family of tropomyosins. These proteins regulate muscle contraction by controlling the joining of two muscle, actin and myosin proteins. In non - muscle cells tropomyosin protein play a role in the control of cell shape. These interactions are essential for the stabilization and maintenance of the sarcomeres within the muscle cells. They have identified at least 10 genetic mutations in people with TPM2 distal arthrogryposis syndrome type 2BO Sheldon-Hall. These genetic changes may alter the structure of the ?-tropomyosin and normal function of the protein in control muscle contractions, resulting in muscle contractures and other associated skeletal anomalies.
2BO distal arthrogryposis syndrome type Sheldon-Hall is inherited in an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient for the disease to be expressed. In approximately 50% of cases, an affected person inherits the mutation from one affected parent. Other cases are due to new mutations in the gene and occur in people with no history of disease in your family.
Tests in IVAMI: in IVAMI perform the detection of mutations associated with distal arthrogryposis type 2B or Sheldon-Hall syndrome by complete PCR amplification of exons delos MYH3, TNNI2, TNNT3 and TPM2 genes, respectively, and subsequent sequencing .
Recom m ended samples: 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).