FLNA gene

filamin A

The FLNA gene provides instructions for producing the protein filamin A, which helps build cells' extensive internal network of protein filaments called the cytoskeleton. The cytoskeleton gives structure to cells and allows them the flexibility to change shape. Filamin A primarily attaches (binds) to another protein called actin and helps it form the branching network of filaments that make up the cytoskeleton. Filamin A can also bind to many other proteins in the cell to carry out various functions, including the attachment of cells to one another (cell adhesion), cell movement (migration), determination of cell shape, and cell survival. These numerous functions involving filamin A have been found to play roles in regulating skeletal and brain development, the formation of heart tissue and blood vessels, and blood clotting.

Filamin A is also involved in the organization of the extracellular matrix, which is the lattice of proteins and other molecules outside the cell. Filamin A binds to proteins called integrins, which span the cell membrane and anchor cells to the extracellular matrix. Through this binding, cells are correctly positioned and signals can be exchanged between the cell and the extracellular matrix.

More than 15 mutations in regions of the FLNA gene called exons 4, 22, 29, 33, and 44 through 46 have been identified in people with frontometaphyseal dysplasia. This condition involves abnormalities in skeletal development and other health problems, including kidney, heart, and lung defects. The FLNA gene mutations that cause frontometaphyseal dysplasia are described as "gain-of-function" because they appear to enhance the activity of the filamin A protein or give the protein a new, atypical function. Different mutations in the FLNA gene appear to produce specific changes in the protein, resulting in particular signs and symptoms that are classified as individual FLNA-related disorders. Researchers believe that the mutations involved in frontometaphyseal dysplasia may change the way the filamin A protein helps regulate processes involved in skeletal development, but it is not known how changes in the protein relate to the specific signs and symptoms of the condition.

At least three mutations in the FLNA gene have been identified in people with intestinal pseudo-obstruction, a condition characterized by impairment of the muscle contractions that move food through the digestive tract (peristalsis).

The FLNA gene mutations that cause intestinal pseudo-obstruction include deletions or duplications of genetic material. The mutations are thought to reduce levels of the filamin A protein or impair its function; this type of mutation is called "loss of function". Research suggests that decreased filamin A function may affect the shape of cells in the smooth muscles of the gastrointestinal tract during development before birth, causing abnormalities in the layering of these muscles. Smooth muscles line the internal organs; they contract and relax without being consciously controlled. In the digestive tract, abnormal layering of these muscles may interfere with peristalsis.

Deletions or duplications of genetic material can affect all or part of the FLNA gene, and may also include nearby genes on the X chromosome. Changes in these additional genes may account for some of the other signs and symptoms, such as neurological abnormalities and unusual facial features, that occur in some affected individuals.

At least 10 mutations in a region of the FLNA gene called exon 22 have been identified in people with Melnick-Needles syndrome. This condition involves abnormalities in skeletal development and other health problems. The FLNA gene mutations associated with Melnick-Needles syndrome are described as "gain-of-function" because they appear to enhance the activity of the filamin A protein or give the protein a new, atypical function. Researchers believe that the mutations involved in Melnick-Needles syndrome may change the way the filamin A protein helps regulate processes involved in skeletal development, but it is not known how changes in the protein relate to the specific signs and symptoms of the condition.

At least four mutations in regions of the FLNA gene called exons 3, 4, and 5 have been identified in people with otopalatodigital syndrome type 1. This condition primarily involves abnormalities in skeletal development. The FLNA gene mutations that cause otopalatodigital syndrome type 1 all result in changes to the filamin A protein in the region that binds to actin. The mutations responsible for otopalatodigital syndrome type 1 are described as "gain-of-function" because they appear to enhance the activity of the filamin A protein or give the protein a new, atypical function. Researchers believe that the mutations involved in otopalatodigital syndrome type 1 may change the way the filamin A protein helps regulate processes involved in skeletal development, but it is not known how changes in the protein relate to the specific signs and symptoms of the condition.

At least 16 mutations in regions of the FLNA gene called exons 3, 4, and 5 have been identified in people with otopalatodigital syndrome type 2. This condition involves abnormalities in skeletal development that are typically more severe than in otopalatodigital syndrome type 1 (described above). The mutations in exons 3, 4, and 5 result in changes to the filamin A protein in the region that binds to actin. The mutations responsible for otopalatodigital syndrome type 2 are described as "gain-of-function" because they appear to enhance the activity of the filamin A protein or give the protein a new, atypical function. Researchers believe that the mutations involved in otopalatodigital syndrome type 2 may change the way the filamin A protein helps regulate processes involved in skeletal development, but it is not known how changes in the protein relate to the specific signs and symptoms of the condition or why mutations in the same region can lead to a spectrum of signs and symptoms.

More than 130 FLNA gene mutations have been identified in individuals with periventricular heterotopia, a condition in which nerve cells (neurons) do not move (migrate) properly during the early development of the fetal brain leading to seizures and other neurological problems. Most of these mutations result in a protein that is too short and cannot perform its function, which makes the cytoskeleton disorganized and impairs cell movement. Neurons that do not migrate properly during development form clumps around the fluid-filled cavities (ventricles) near the center of the brain, resulting in the signs and symptoms of periventricular heterotopia.

In some cases, mutations result in the substitution of one protein building block (amino acid) for another amino acid in the protein sequence. These mutations may result in the production of a partially functional protein, causing a milder form of the disorder.

At least four mutations in the FLNA gene have been found to cause X-linked cardiac valvular dysplasia, a condition characterized by abnormally thick heart valves. Most of these mutations change single protein building blocks in the filamin A protein. These mutations likely alter the shape of the protein, impairing its ability to bind to actin and other proteins. As a result, the cell cytoskeleton is weakened and valve cells as well as the extracellular matrix are disorganized. The cells are not positioned properly within the valve, so the valve becomes malformed. In addition, the cells' decreased ability to change shape impairs the valves' ability to open and close when the heart pumps blood. It appears that excess proteins are produced in the abnormal extracellular matrix, causing the valves to become thickened and further impairing their ability to open and close normally.

It is unclear why the heart valves are the only tissue affected by these FLNA gene mutations. The mutations that cause X-linked cardiac valvular dysplasia occur in a different part of the gene than those that cause other disorders (described above). It has been suggested that the region of the filamin A protein affected by these mutations is necessary for binding to other proteins that play a significant role in heart development.

Genetics Home Reference provides information about FG syndrome.

Cytogenetic Location: Xq28, which is the long (q) arm of the X chromosome at position 28

Molecular Location: base pairs 154,348,529 to 154,374,638 on the X chromosome (Homo sapiens Annotation Release 108, GRCh38.p7) (NCBI)

Cytogenetic Location: Xq28, which is the long (q) arm of the X chromosome at position 28
  • ABP-280
  • ABPX
  • actin-binding protein 280
  • DKFZp434P031
  • filamin 1
  • filamin A, alpha
  • filamin A, alpha (actin binding protein 280)
  • FLN
  • FLN1
  • FLNA_HUMAN