Distal arthrogryposis type 1 is a disorder characterized by joint deformities (contractures) that restrict movement in the hands and feet. The term "arthrogryposis" comes from the Greek words for joint (arthro-) and crooked or hooked (gryposis). The characteristic features of this condition include permanently bent fingers and toes (camptodactyly), overlapping fingers, and a hand deformity in which all of the fingers are angled outward toward the fifth finger (ulnar deviation). Clubfoot, which is an inward- and upward-turning foot, is also commonly seen with distal arthrogryposis type 1. The specific hand and foot abnormalities vary among affected individuals. However, this condition typically does not cause any signs and symptoms affecting other parts of the body.

Distal arthrogryposis type 1 can be caused by mutations in at least two genes: TPM2 and MYBPC1. These genes are active (expressed) in muscle cells, where they interact with other muscle proteins to help regulate the tensing of muscle fibers (muscle contraction). It is unclear how mutations in the TPM2 and MYBPC1 genes lead to the joint abnormalities characteristic of distal arthrogryposis type 1. However, researchers speculate that contractures may be related to problems with muscle contraction that limit the movement of joints before birth.

In some cases, the genetic cause of distal arthrogryposis type 1 is unknown. Researchers are looking for additional genetic changes that may be responsible for this condition.

Normal Function

The MYBPC1 gene provides instructions for making one version of a protein called myosin binding protein C. Several versions of myosin binding protein C are produced from different genes; these proteins are found in muscles used for movement (skeletal muscles) and in heart (cardiac) muscle. The version produced from the MYBPC1 gene, which is known as the slow skeletal isoform, is found primarily in skeletal muscles.

The slow isoform of myosin binding protein C is active during the development of skeletal muscles. Researchers believe that this protein helps regulate the tensing of muscle fibers (muscle contraction). Myosin binding protein C interacts with other muscle proteins, including myosin, actin, and titin. These proteins play essential roles in muscle cell structures called sarcomeres, which generate the mechanical force needed for muscles to contract. Studies suggest that myosin binding protein C contributes to the stability and maintenance of sarcomeres.

Health Conditions Related to Genetic Changes

Distal arthrogryposis type 1

At least one mutation in the MYBPC1 gene has been found to cause distal arthrogryposis type 1, a disorder characterized by joint deformities (contractures) in the hands and feet. The mutation changes a single protein building block (amino acid) in the slow isoform of myosin binding protein C. Specifically, the mutation replaces the amino acid tryptophan with the amino acid arginine at protein position 236 (written as Trp236Arg or W236R). It is unclear how the defective protein leads to contractures in people with distal arthrogryposis type 1, or why the joint problems are typically limited to the hands and feet. However, researchers speculate that contractures may be related to problems with muscle contraction that limit the movement of joints before birth.

Other Names for This Gene

• C-protein, skeletal muscle slow isoform
• MYBPCC
• MYBPCS
• MYPC1_HUMAN
• skeletal muscle C-protein
• slow MyBP-C

Genomic Location

Normal Function

The TPM2 gene provides instructions for making a protein called beta (β)-tropomyosin, which is part of the tropomyosin protein family. Tropomyosin proteins regulate the tensing of muscle fibers (muscle contraction) by controlling the binding of two muscle proteins, myosin and actin. In non-muscle cells, tropomyosin proteins play a role in controlling cell shape.

β-tropomyosin is found primarily in skeletal muscles, which are the muscles used for movement. This protein helps regulate muscle contraction by interacting with other muscle proteins, particularly myosin and actin. These interactions are essential for stabilizing and maintaining structures called sarcomeres within muscle cells. Sarcomeres are the basic units of muscle contraction; they are made of proteins that generate the mechanical force needed for muscles to contract.

Health Conditions Related to Genetic Changes

Cap myopathy

At least three TPM2 gene mutations have been identified in people with cap myopathy, a disorder that leads to muscle weakness (myopathy) and poor muscle tone (hypotonia). These mutations delete or duplicate genetic material in the TPM2 gene or replace single protein building blocks (amino acids) in the β-tropomyosin protein sequence. The specific effects of these TPM2 gene mutations are unclear, but researchers suggest they may interfere with normal actin-myosin binding, impairing muscle contraction and resulting in the muscle weakness that occurs in cap myopathy.

Distal arthrogryposis type 1

At least three mutations in the TPM2 gene have been found to cause distal arthrogryposis type 1, a disorder characterized by joint deformities (contractures) in the hands and feet. It is unclear how these mutations lead to contractures in people with distal arthrogryposis type 1, or why the joint problems are typically limited to the hands and feet. However, researchers speculate that contractures may be related to problems with muscle contraction that limit the movement of joints before birth.

Congenital fiber-type disproportion

MedlinePlus Genetics provides information about Congenital fiber-type disproportion

Nemaline myopathy

MedlinePlus Genetics provides information about Nemaline myopathy

Sheldon-Hall syndrome

At least six TPM2 gene mutations have been identified in people with Sheldon-Hall syndrome, a muscle and skeletal disorder similar to distal arthrogryposis type 1 (described above) that impairs joint movement in the hands and feet. Mutations in the TPM2 gene may alter the structure of β-tropomyosin and disrupt the protein's normal function in controlling muscle contractions, resulting in the contractures and other muscle and skeletal abnormalities associated with this condition.

Other Names for This Gene

• beta-tropomyosin
• NEM4
• TMSB
• TPM2_HUMAN
• tropomyosin 2 (beta)
• tropomyosin beta chain
• tropomyosin, skeletal muscle beta
• tropomyosin-2

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of an altered gene in each cell is sufficient to cause the disorder. In many cases, a person with distal arthrogryposis type 1 has a parent and other close family members with the condition.

Distal arthrogryposis type 1 affects an estimated 1 in 10,000 people worldwide.