2.1. COL4A1-Related Brain Small-Vessel Disease

Mutations in the COL4A1 gene have been found to cause COL4A1-related brain small-vessel disease. This condition is part of a group of conditions called COL4A1-related disorders that have overlapping signs and symptoms involving fragile blood vessels. COL4A1-related brain small-vessel disease is characterized by stroke and eye abnormalities. Most of the identified COL4A1 gene mutations that cause COL4A1-related brain small-vessel disease change one of the protein building blocks (amino acids) used to make the alpha1(IV) chain of type IV collagen. Specifically, the mutations replace the amino acid glycine with a different amino acid at one of various places in this collagen chain. The substitution of another amino acid for glycine in the alpha1(IV) chain prevents this chain from combining with other chains to form a complete type IV collagen molecule. This alteration in type IV collagen prevents protein networks from forming and basement membranes from developing properly, which causes the tissues they support to weaken. Blood vessels throughout the body become fragile, leading to the signs and symptoms of COL4A1-related brain small-vessel disease.

It is unclear how mutations in the COL4A1 gene can lead to different disorders. It is likely that mutations in different regions of this gene play a role in the development of the various signs and symptoms of the COL4A1-related disorders. Other genetic changes as well as environmental factors may also contribute to the features of the different COL4A1-related disorders.

2.2. Familial Porencephaly

Mutations in the COL4A1 gene have been found to cause familial porencephaly, another member of the group of vascular conditions called COL4A1-related disorders. Familial porencephaly is characterized by early stroke and brain cysts. Most of the identified COL4A1 gene mutations that cause familial porencephaly change one of the amino acids used to make the alpha1(IV) chain of type IV collagen. Specifically, the mutations replace the amino acid glycine with a different amino acid at one of various places in this collagen chain. The substitution of another amino acid for glycine in the alpha1(IV) chain prevents this chain from combining with other chains to form a complete type IV collagen molecule. This alteration in type IV collagen prevents protein networks from forming and basement membranes from developing properly, which causes the tissues they support to weaken. Blood vessels in the brain become fragile, leading to the signs and symptoms of familial porencephaly.

2.3. Hereditary Angiopathy with Nephropathy, Aneurysms, and Muscle Cramps Syndrome

Mutations in the COL4A1 gene have been found to cause hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome, a third member of the group of conditions called COL4A1-related disorders. HANAC syndrome is characterized by weakened blood vessels in the brain and throughout the body, kidney disease, muscle cramps, and eye abnormalities. Most of the identified COL4A1 gene mutations that cause HANAC syndrome change one of the amino acids used to make the alpha1(IV) chain of type IV collagen. Specifically, the mutations replace the amino acid glycine with a different amino acid at one of various places in this collagen chain. The substitution of another amino acid for glycine in the alpha1(IV) chain prevents this chain from combining with other chains to form a complete type IV collagen molecule. This alteration in type IV collagen prevents protein networks from forming and basement membranes from developing properly. As a result, the tissues they support weaken, particularly in the eyes and kidneys. Fragile blood vessels and weakened basement membranes lead to the signs and symptoms of HANAC syndrome.