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URL of this page: https://medlineplus.gov/genetics/gene/col4a4/

COL4A4 gene

collagen type IV alpha 4 chain

Normal Function

The COL4A4 gene provides instructions for making one piece of a protein called collagen IV. Specifically, this gene makes the alpha4(IV) chain of collagen IV. This chain combines with two other types of alpha (IV) chains (the alpha3 and alpha5 chains) to make alpha345(IV) collagen molecules. These molecules attach to each other to form complex protein networks that make up a large portion of basement membranes, which are thin, sheet-like structures that separate and support cells in many tissues. alpha345(IV) collagen networks play an especially important role in the basement membranes of the kidney, inner ear, and eye.

Health Conditions Related to Genetic Changes

Alport syndrome

Many variants (also called mutations) in the COL4A4 gene can cause Alport syndrome, a condition characterized by kidney disease, hearing loss, and eye abnormalities. Most of these variants change single protein building blocks (amino acids) in a region where the alpha4(IV) collagen chain combines with other collagen IV chains. Other variants in the COL4A4 gene severely decrease or prevent the production of alpha4(IV) chains. 

These changes in the structure or amount of alpha4(IV) chains severely impair the formation of alpha345(IV) collagen networks in the basement membranes of the kidney, inner ear, and eye. In the kidney, other types of collagen build up in the basement membranes, eventually  scarring the kidneys and leading to kidney failure. Variants in this gene can also lead to hearing loss and changes in the lens of the eye and the light-sensitive tissue at the back of the eye (retina).

Variants in a single copy of the COL4A4 gene can cause a form of the condition called autosomal dominant Alport syndrome. Individuals with this form typically have the kidney problems that are characteristic of Alport syndrome, including blood in the urine (hematuria), excess amounts of protein in the urine (proteinuria), and a gradual loss of kidney function. 

Variants in both copies of the COL4A4 gene cause autosomal recessive Alport syndrome. Individuals with this form of the condition can have hearing loss and eye abnormalities in addition to kidney problems.

More About This Health Condition

Keratoconus

MedlinePlus Genetics provides information about Keratoconus

More About This Health Condition

Other disorders

A variant in one of the two copies of the COL4A4 gene can cause thin basement membrane nephropathy. People with this condition typically have blood in their urine (hematuria) but no other signs or symptoms of kidney disease. In the past, this condition was often called benign familial hematuria. Thin basement membrane nephropathy rarely progresses to kidney failure.

Other Names for This Gene

  • alpha 4 type IV collagen
  • CA44
  • CO4A4_HUMAN
  • Collagen IV, alpha-4 polypeptide
  • collagen of basement membrane, alpha-4 chain
  • collagen type IV alpha 4
  • collagen, type IV, alpha 4

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

  • Buzza M, Dagher H, Wang YY, Wilson D, Babon JJ, Cotton RG, Savige J. Mutations in the COL4A4 gene in thin basement membrane disease. Kidney Int. 2003 Feb;63(2):447-53. doi: 10.1046/j.1523-1755.2003.00780.x. Citation on PubMed
  • Gregory MC. The clinical features of thin basement membrane nephropathy. Semin Nephrol. 2005 May;25(3):140-5. doi: 10.1016/j.semnephrol.2005.01.004. Citation on PubMed
  • Gross O, Netzer KO, Lambrecht R, Seibold S, Weber M. Novel COL4A4 splice defect and in-frame deletion in a large consanguine family as a genetic link between benign familial haematuria and autosomal Alport syndrome. Nephrol Dial Transplant. 2003 Jun;18(6):1122-7. doi: 10.1093/ndt/gfg157. Citation on PubMed
  • Kashtan CE. Alport Syndrome. 2001 Aug 28 [updated 2019 Feb 21]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK1207/ Citation on PubMed
  • Kashtan CE. Alport syndrome. An inherited disorder of renal, ocular, and cochlear basement membranes. Medicine (Baltimore). 1999 Sep;78(5):338-60. doi: 10.1097/00005792-199909000-00005. Citation on PubMed
  • Longo I, Porcedda P, Mari F, Giachino D, Meloni I, Deplano C, Brusco A, Bosio M, Massella L, Lavoratti G, Roccatello D, Frasca G, Mazzucco G, Muda AO, Conti M, Fasciolo F, Arrondel C, Heidet L, Renieri A, De Marchi M. COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome. Kidney Int. 2002 Jun;61(6):1947-56. doi: 10.1046/j.1523-1755.2002.00379.x. Citation on PubMed
  • Pescucci C, Mari F, Longo I, Vogiatzi P, Caselli R, Scala E, Abaterusso C, Gusmano R, Seri M, Miglietti N, Bresin E, Renieri A. Autosomal-dominant Alport syndrome: natural history of a disease due to COL4A3 or COL4A4 gene. Kidney Int. 2004 May;65(5):1598-603. doi: 10.1111/j.1523-1755.2004.00560.x. Citation on PubMed
  • Rana K, Wang YY, Buzza M, Tonna S, Zhang KW, Lin T, Sin L, Padavarat S, Savige J. The genetics of thin basement membrane nephropathy. Semin Nephrol. 2005 May;25(3):163-70. doi: 10.1016/j.semnephrol.2005.01.008. Citation on PubMed
  • Slajpah M, Gorinsek B, Berginc G, Vizjak A, Ferluga D, Hvala A, Meglic A, Jaksa I, Furlan P, Gregoric A, Kaplan-Pavlovcic S, Ravnik-Glavac M, Glavac D. Sixteen novel mutations identified in COL4A3, COL4A4, and COL4A5 genes in Slovenian families with Alport syndrome and benign familial hematuria. Kidney Int. 2007 Jun;71(12):1287-95. doi: 10.1038/sj.ki.5002221. Epub 2007 Mar 28. Citation on PubMed
  • Tazon Vega B, Badenas C, Ars E, Lens X, Mila M, Darnell A, Torra R. Autosomal recessive Alport's syndrome and benign familial hematuria are collagen type IV diseases. Am J Kidney Dis. 2003 Nov;42(5):952-9. doi: 10.1016/j.ajkd.2003.08.002. Citation on PubMed

The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.