Autosomal dominant Alport syndrome

Alport syndrome is caused by mutations in three possible genes: COL4A3, COL4A4, or COL4A5. These genes each provide instructions for making one component of a protein called type IV collagen, which plays an important role in the glomeruli of the kidneys. Glomeruli are clusters of specialized blood vessels that remove water and waste products from the blood and create urine. Mutations in the genes associated with Alport syndrome result in abnormalities of the type IV collagen in glomeruli, which prevent the kidneys from properly filtering the blood. As a result, blood and protein pass into the urine. Over time, the kidneys become scarred, which leads to kidney failure.^[1][2]

Type IV collagen is also an important component of the organ of Corti, the inner ear structure that transforms sound waves into nerve impulses for the brain. Alterations in type IV collagen may result in abnormal inner ear functions, which can lead to hearing loss. In addition, type IV collagen plays a role in the eye, where it helps maintain the shape of the lens and the cells of the retina. Mutations found in Alport syndrome may affect the retina and the shape of the lens.^[1] 

Alport syndrome can be inherited in three different ways. About 80 percent of cases are caused by mutations in the COL4A5 gene and are inherited in an X-linked recessive pattern. The COL4A5 gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the COL4A5 gene in each cell is sufficient to cause kidney failure and other severe symptoms of the disorder. In females (who have two X chromosomes), a mutation in only one copy of the COL4A5 gene usually only results in hematuria. However, some women experience more severe symptoms such as kidney failure or hearing loss. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.^[1]

In approximately 15 percent of cases, Alport syndrome results from mutations in both copies of the COL4A3 or COL4A4 gene and is inherited in an autosomal recessive pattern. The parents of an individual with the autosomal recessive form of this condition each have one copy of the mutated gene and are called carriers. Some carriers are unaffected, and others develop a less severe condition called thin basement membrane nephropathy, which is characterized by hematuria. Males and females are equally affected by the autosomal recessive form of Alport syndrome.^[1]

Alport syndrome is rarely inherited as an autosomal dominant condition. People with this form of Alport syndrome have one mutation in either COL4A3 or COL4A4 in each cell. It remains unclear why some individuals with one mutation in the COL4A3 or COL4A4 gene have autosomal dominant Alport syndrome and others have thin basement membrane nephropathy or no symptoms at all.^[1][3]

Approximately 10%-15% of affected individuals have X-linked Alport syndrome as the result of a de novo (new) mutation. While these individuals did not inherit the genetic mutation, they can pass the mutated gene onto their children. Affected males transmit the disease-causing mutation to all of their daughters and to none of their sons.^[4]

Most individuals diagnosed with an autosomal dominant Alport syndrome have an affected parent. In some cases, the disorder may result from a de novo gene mutation. The proportion of cases of autosomal dominant Alport syndrome that result from de novo gene mutations in unknown. Each child of an individual with autosomal dominant Alport syndrome has a 50% chance of inheriting the mutation.^[4]

Additional information about the different ways that Alport syndrome may be inherited (and how other family members might be impacted) can be accessed through GeneReviews. A genetics professional can help to better understand the risks for individuals and family members to develop Alport syndrome.

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from Genetics Home Reference.