Grange syndrome is a rare condition that primarily affects the blood vessels. It is characterized by narrowing (stenosis) or blockage (occlusion) of arteries that supply blood to various organs and tissues, including the kidneys, brain, and heart. Stenosis or occlusion of the arteries that supply blood to the kidneys (renal arteries) can result in chronic high blood pressure (hypertension). Blockage of the arteries that carry blood to the brain (cerebral arteries) can cause a stroke.

Additional features of Grange syndrome can include short fingers and toes (brachydactyly), fusion of some of the fingers or toes (syndactyly), fragile bones that are prone to breakage, and learning disabilities. Most people with this disorder also have heart defects that are present from birth.

Grange syndrome results from mutations in the YY1AP1 gene. The protein produced from this gene is part of a group of proteins (a complex) that helps regulate several critical functions within cells. These include gene activity (expression), repair of damaged DNA, cell specialization (differentiation), and cell growth and division (proliferation). Researchers believe that this protein complex plays a particularly important role in smooth muscle cells, which line the walls of blood vessels.

Mutations in the YY1AP1 gene likely disrupt the function of the complex, which leads to reduced proliferation and differentiation of smooth muscle cells. However, it is unclear how these changes lead to narrowing and blockage of arteries. It is also unknown how YY1AP1 gene mutations are related to other features of Grange syndrome, such as bone abnormalities and learning disabilities.

Normal Function

The YY1AP1 gene provides instructions for making part of a group of associated proteins known as the INO80 chromatin remodeling complex. In the cell nucleus, this complex attaches (binds) to chromatin, which is the network of DNA and proteins that packages DNA into chromosomes. The structure of chromatin can be changed (remodeled) to alter how tightly DNA is packaged. Chromatin remodeling by the INO80 chromatin remodeling complex allows cells to control the activity (expression) of certain genes. This complex also helps regulate several other critical cell functions, including repair of damaged DNA, cell specialization (differentiation), and cell growth and division (proliferation). Activity of the INO80 chromatin remodeling complex appears to be particularly important in smooth muscle cells, which line the walls of blood vessels.

Health Conditions Related to Genetic Changes

Grange syndrome

At least five mutations in the YY1AP1 gene have been identified in people with Grange syndrome. This rare condition causes narrowing (stenosis) and blockage (occlusion) of blood vessels that supply blood to many organs and tissues, including the kidneys, brain, and heart. Grange syndrome can also be associated with short fingers and toes (brachydactyly), fusion of some of the fingers or toes (syndactyly), fragile bones that are prone to breakage, learning disabilities, and heart defects.

Mutations in the YY1AP1 gene are described as "loss-of-function" because they prevent the production of any functional YY1AP1 protein. A loss of this protein disrupts the function of the INO80 chromatin remodeling complex, which alters the activity of multiple genes in smooth muscle cells. Researchers suspect that these changes in gene expression lead to reduced cell proliferation and differentiation. However, it is unclear how these changes cause narrowing and blockage of arteries. It is also unknown how YY1AP1 gene mutations are related to other features of Grange syndrome, such as bone abnormalities and learning disabilities.

Other Names for This Gene

• GRNG
• HCCA1
• HCCA2
• hepatocellular carcinoma susceptibility protein
• hepatocellular carcinoma-associated protein 2
• YAP
• YY1AP

Genomic Location

This condition is thought to be inherited in an autosomal recessive pattern, which means both copies of the YY1AP1 gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Grange syndrome has been reported to affect at least six individuals from three families.