KAL1

The KAL1 gene provides instructions for making a protein called anosmin-1. This protein is involved in development before birth. Anosmin-1 is located on the surface of cells and may act as part of the extracellular matrix, an intricate lattice of proteins and other molecules that forms in the spaces between cells. Anosmin-1 is found in many parts of the developing embryo, including the respiratory tract, kidneys, digestive system, and certain regions of the brain.

Researchers are working to determine the functions of anosmin-1. They have discovered that, in the developing brain, this protein is involved in the movement (migration) of nerve cells and the outgrowth of axons, which are specialized extensions of nerve cells that transmit nerve impulses. The protein's structure suggests that it may also play a role in regulating contact between nerve cells (cell adhesion).

Anosmin-1 appears to help control the growth and migration of a group of nerve cells that are specialized to process smells (olfactory neurons). These nerve cells come together into a bundle called the olfactory bulb, which is critical for the perception of odors. Studies suggest that anosmin-1 is also involved in the migration of neurons that produce a hormone called gonadotropin-releasing hormone (GnRH). GnRH controls the production of several other hormones that direct sexual development before birth and during puberty. These hormones are important for the normal function of the gonads (ovaries in women and testes in men).

Kallmann syndrome - caused by mutations in the KAL1 gene

At least 60 mutations in the KAL1 gene have been identified in people with Kallmann syndrome type 1. In some cases, mutations delete part or all of the KAL1 gene. Other mutations change single protein building blocks (amino acids) in anosmin-1 or alter the size of the protein. Although KAL1 mutations disrupt the protein's normal function during embryonic development, it is unclear how these genetic changes lead to the characteristic features of Kallmann syndrome.

Researchers suspect that the altered anosmin-1 protein is unable to direct the migration of olfactory nerve cells and GnRH-producing nerve cells to their usual locations in the developing brain. If olfactory nerve cells do not extend to the olfactory bulb, a person's sense of smell will be impaired. Misplacement of GnRH-producing neurons prevents the production of certain sex hormones, which interferes with normal sexual development and causes puberty to be delayed or absent.

It is unknown how KAL1 mutations lead to other signs and symptoms of Kallmann syndrome, including a failure of one kidney to develop (unilateral renal agenesis), hearing loss, and mirror movements of the hands (bimanual synkinesia). Because the features of this condition vary among individuals, researchers believe that additional genetic and environmental factors are likely to be involved.