ANO5

The ANO5 gene provides instructions for making a protein called anoctamin 5. While the specific function of this protein is not well understood, it belongs to a family of proteins that are believed to function as calcium-activated chloride channels.

Chloride channels, which transport negatively charged chlorine atoms (chloride ions) in and out of cells, play a key role in a cell's ability to generate and transmit electrical signals. Studies suggest that the anoctamin proteins function as chloride channels that are turned on (activated) in the presence of positively charged calcium atoms (calcium ions), although the mechanism for this activation is not clear.

Chloride channels have many functions throughout the body. The anoctamin 5 protein is most abundant in muscles used for movement (skeletal muscles). For the body to move normally, skeletal muscles must tense (contract) and relax in a coordinated way. Muscle contraction and relaxation are controlled by the flow of certain ions into and out of muscle cells. Chloride channels spanning the muscle cell membrane control the flow of chloride ions into these cells.

The anoctamin 5 protein is also found in the muscle cells of the heart and in bone cells.

limb-girdle muscular dystrophy - caused by mutations in the ANO5 gene

At least five mutations in the ANO5 gene have been identified in people with limb-girdle muscular dystrophy type 2L. Limb-girdle muscular dystrophy is a group of related disorders characterized by muscle weakness and wasting, particularly in the shoulders, hips, thighs, and upper arms.

The ANO5 gene mutations identified in people with limb-girdle muscular dystrophy type 2L change a single protein building block (amino acid) in the anoctamin 5 protein sequence, disrupt how genetic information is pieced together to make a blueprint for producing the protein, or result in a premature stop signal that leads to an abnormally short protein. One of the mutations, designated c.191dupA or p.Asn64LysfsX15, is believed to be a relatively common cause of limb-girdle muscular dystrophy in people with northern European ancestry. This mutation results in a premature stop signal that would produce an abnormally short protein. Instead, a cellular error-catching mechanism called nonsense-mediated decay prevents the protein from being produced at all.

ANO5 gene mutations that eliminate or impair the role of the anoctamin 5 protein as a calcium channel likely lead to impaired muscle function, resulting in the signs and symptoms of limb-girdle muscular dystrophy.

other disorders - caused by mutations in the ANO5 gene

At least two ANO5 gene mutations have been identified in people with a similar muscle condition called Miyoshi distal myopathy. Some researchers believe that Miyoshi distal myopathy is not a separate disorder but rather a variation of limb-girdle muscular dystrophy. While in limb-girdle muscular dystrophy muscle weakness is typically most severe in the muscles close to the center of the body (proximal muscles), the effects of Miyoshi distal myopathy are most apparent in the muscles of the calves. Calf muscle weakness may make it difficult to stand on tiptoe. The muscle weakness progresses slowly; it may eventually affect the thighs and cause difficulty walking.

The ANO5 gene mutations identified in people with Miyoshi distal myopathy change a single amino acid in the anoctamin 5 protein or result in a premature stop signal that leads to an abnormally short protein. These mutations likely interfere with the role of the anoctamin 5 protein and lead to impaired muscle function, resulting in the signs and symptoms of Miyoshi distal myopathy.

At least one of the mutations that occurs in people with Miyoshi distal myopathy has also been identified in people with limb-girdle muscular dystrophy. It is not known why the same ANO5 gene mutation can result in different patterns of signs and symptoms.

At least two ANO5 gene mutations have been identified in people with a bone disorder called gnathodiaphyseal dysplasia. These mutations change single amino acids in the anoctamin 5 protein. The relationship of these protein changes to the fragile bones and jaw problems that occur in gnathodiaphyseal dysplasia is unknown. Researchers suggest that the mutations may affect the way cells process calcium, an important mineral in bones.