C3 Glomerulopathy

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This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/condition/c3-glomerulopathy

C3 glomerulopathy is a group of related conditions that cause the kidneys to malfunction. The major features of C3 glomerulopathy include high levels of protein in the urine (proteinuria), blood in the urine (hematuria), reduced amounts of urine, low levels of protein in the blood, and swelling in many areas of the body. Affected individuals may have particularly low levels of a protein called complement component 3 (or C3) in the blood.

genetic conditions

1. Introduction

The kidney problems associated with C3 glomerulopathy tend to worsen over time. About half of affected individuals develop end-stage renal disease (ESRD) within 10 years after their diagnosis. ESRD is a life-threatening condition that prevents the kidneys from filtering fluids and waste products from the body effectively.

Researchers have identified two major forms of C3 glomerulopathy: dense deposit disease and C3 glomerulonephritis. Although the two disorders cause similar kidney problems, the features of dense deposit disease tend to appear earlier than those of C3 glomerulonephritis, usually in adolescence. However, the signs and symptoms of either disease may not begin until adulthood.

One of the two forms of C3 glomerulopathy, dense deposit disease, can also be associated with other conditions unrelated to kidney function. For example, people with dense deposit disease may have acquired partial lipodystrophy, a condition characterized by a lack of fatty (adipose) tissue under the skin in the upper part of the body. Additionally, some people with dense deposit disease develop a buildup of yellowish deposits called drusen in the light-sensitive tissue at the back of the eye (the retina). These deposits usually appear in childhood or adolescence and can cause vision problems later in life.

2. Frequency

C3 glomerulopathy is very rare, affecting 1 to 2 per million people worldwide. It is equally common in men and women.

3. Causes

C3 glomerulopathy is associated with changes in many genes. Most of these genes provide instructions for making proteins that help regulate a part of the body's immune response known as the complement system. This system is a group of proteins that work together to destroy foreign invaders (such as bacteria and viruses), trigger inflammation, and remove debris from cells and tissues. The complement system must be carefully regulated so it targets only unwanted materials and does not damage the body's healthy cells.

A specific mutation in one of the complement system-related genes, CFHR5, has been found to cause C3 glomerulopathy in people from the Mediterranean island of Cyprus. Mutation in the C3 and CFH genes, as well as other complement system-related genes, have been found to cause the condition in other populations. The known mutations account for only a small percentage of all cases of C3 glomerulopathy. In most cases, the cause of the condition is unknown.

Several normal variants (polymorphisms) in complement system-related genes are associated with an increased likelihood of developing C3 glomerulopathy. In some cases, the increased risk is related to a group of specific variants in several genes, a combination known as a C3 glomerulopathy at-risk haplotype. While these polymorphisms increase the risk of C3 glomerulopathy, many people who inherit these genetic changes will never develop the condition.

The genetic changes related to C3 glomerulopathy "turn up," or increase the activation of, the complement system. The overactive system damages structures called glomeruli in the kidneys. These structures are clusters of tiny blood vessels that help filter waste products from the blood. Damage to glomeruli prevents the kidneys from filtering waste products normally and can lead to ESRD. Studies suggest that uncontrolled activation of the complement system also causes the other health problems that can occur with dense deposit disease, including acquired partial lipodystrophy and a buildup of drusen in the retina. Researchers are working to determine how these associated health problems are related to overactivity of the complement system.

Studies suggest that C3 glomerulopathy can also result from the presence of specialized proteins called autoantibodies. Autoantibodies cause the condition by altering the activity of proteins involved in regulating the complement system.

4. Inheritance

Most cases of C3 glomerulopathy are sporadic, which means they occur in people with no history of the disorder in their family. Only a few reported families have had more than one family member with C3 glomerulopathy. However, many affected people have had close relatives with autoimmune diseases, which occur when the immune system malfunctions and attacks the body's tissues and organs. The connection between C3 glomerulopathy and autoimmune diseases is not fully understood.

5. Other Names for This Condition

C3 glomerulonephritis
C3G
DDD
DDD/MPGNII
dense deposit disease
membranoproliferative glomerulonephritis type II

References

Abrera-Abeleda MA, Nishimura C, Frees K, Jones M, Maga T, Katz LM, Zhang Y,Smith RJ. Allelic variants of complement genes associated with dense depositdisease. J Am Soc Nephrol. 2011 Aug;22(8):1551-9. doi: 10.1681/ASN.2010080795.
Barbour TD, Ruseva MM, Pickering MC. Update on C3 glomerulopathy. Nephrol DialTransplant. 2016 May;31(5):717-25. doi: 10.1093/ndt/gfu317.Review.
Bu F, Borsa NG, Jones MB, Takanami E, Nishimura C, Hauer JJ, Azaiez H,Black-Ziegelbein EA, Meyer NC, Kolbe DL, Li Y, Frees K, Schnieders MJ, Thomas C, Nester C, Smith RJ. High-Throughput Genetic Testing for ThromboticMicroangiopathies and C3 Glomerulopathies. J Am Soc Nephrol. 2016Apr;27(4):1245-53. doi: 10.1681/ASN.2015040385.
Fakhouri F, Frémeaux-Bacchi V, Noël LH, Cook HT, Pickering MC. C3glomerulopathy: a new classification. Nat Rev Nephrol. 2010 Aug;6(8):494-9. doi: 10.1038/nrneph.2010.85.
Martín B, Smith RJH. C3 Glomerulopathy. 2007 Jul 20 [updated 2018 Apr 5]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A,editors. GeneReviews® [Internet]. Seattle (WA): University of Washington,Seattle; 1993-2020. Available from http://www.ncbi.nlm.nih.gov/books/NBK1425/
Medjeral-Thomas NR, O'Shaughnessy MM, O'Regan JA, Traynor C, Flanagan M, Wong L, Teoh CW, Awan A, Waldron M, Cairns T, O'Kelly P, Dorman AM, Pickering MC,Conlon PJ, Cook HT. C3 glomerulopathy: clinicopathologic features and predictors of outcome. Clin J Am Soc Nephrol. 2014 Jan;9(1):46-53. doi:10.2215/CJN.04700513.
Pickering MC, D'Agati VD, Nester CM, Smith RJ, Haas M, Appel GB, Alpers CE,Bajema IM, Bedrosian C, Braun M, Doyle M, Fakhouri F, Fervenza FC, Fogo AB,Frémeaux-Bacchi V, Gale DP, Goicoechea de Jorge E, Griffin G, Harris CL, HolersVM, Johnson S, Lavin PJ, Medjeral-Thomas N, Paul Morgan B, Nast CC, Noel LH,Peters DK, Rodríguez de Córdoba S, Servais A, Sethi S, Song WC, Tamburini P,Thurman JM, Zavros M, Cook HT. C3 glomerulopathy: consensus report. Kidney Int.2013 Dec;84(6):1079-89. doi: 10.1038/ki.2013.377.
Servais A, Noël LH, Roumenina LT, Le Quintrec M, Ngo S, Dragon-Durey MA,Macher MA, Zuber J, Karras A, Provot F, Moulin B, Grünfeld JP, Niaudet P, LesavreP, Frémeaux-Bacchi V. Acquired and genetic complement abnormalities play acritical role in dense deposit disease and other C3 glomerulopathies. Kidney Int.2012 Aug;82(4):454-64. doi: 10.1038/ki.2012.63.
Xiao X, Pickering MC, Smith RJ. C3 glomerulopathy: the genetic and clinicalfindings in dense deposit disease and C3 glomerulonephritis. Semin Thromb Hemost.2014 Jun;40(4):465-71. doi: 10.1055/s-0034-1376334.
Zipfel PF, Skerka C, Chen Q, Wiech T, Goodship T, Johnson S, Fremeaux-BacchiV, Nester C, de Córdoba SR, Noris M, Pickering M, Smith R. The role of complementin C3 glomerulopathy. Mol Immunol. 2015 Sep;67(1):21-30. doi:10.1016/j.molimm.2015.03.012.

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Subjects: Genetics & Heredity

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Catherine Yang

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Entry Collection: MedlinePlus

Update Date: 24 Dec 2020

Table of Contents

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1. Introduction

2. Frequency

3. Causes

4. Inheritance

5. Other Names for This Condition

References

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1. Introduction

2. Frequency

3. Causes

3.1. The Genes Associated with C3 Glomerulopathy

3.2. Additional Information from NCBI Gene

4. Inheritance

5. Other Names for This Condition

References