Instituto Valenciano de Microbiología
(IVAMI)

Masía El Romeral
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Atypical hemolytic-uremic syndrome ... (Atypical hemolytic uremic syndrome-) - Genes CFH, CFI, CD46, C3, CFB, CFHR5 and THBD.

Information 15/11/30.

Atypical hemolytic-uremic syndrome is a disease that primarily affects kidney function due to thrombus formation in small blood vessels in the kidneys. These clots may cause serious medical problems if they restrict or block blood flow. This disease is characterized by three main features related to abnormal coagulation: hemolytic anemia, thrombocytopenia and renal failure.

Hemolytic anemia is due to premature hemolysis destroying erythrocytes without the body can replace them . This alteration can cause pallor, jaundice, fatigue, shortness of breath, and rapid heart rate. Moreover, thrombocytopenia can cause bruising and abnormal bleeding. Following the formation of clots in blood vessels small, people with atypical hemolytic uremic syndrome- existing kidney damage and acute renal failure caused by renal failure in about half of all cases. These life - threatening complications hampers the kidneys perform their purifying function effectively.

Atypical hemolytic-uremic syndrome should be distinguished from more frequent condition called typical HUS. Both conditions have different causes and different signs and symptoms. Unlike the atypical form, typically it is caused by infection with certain strains of E. coli that produce toxic substances called Shiga toxins. The typical form is characterized by severe diarrhea and most often affects children under 10 years old. In contrast to the typical HUS, the atypical form have a worse prognosis, with high mortality rates and frequent progression of end - stage kidney disease.

Often the atypical hemolytic uremic syndrome is the result of a combination of environmental and genetic factors. Mutations in at least seven genes appear to increase the risk of developing the disease. These genes include CFH, CFI, CD46, C3, CFB, and THBD CFHR5. Mutations in the CFH gene are the most common and account for approximately 30% of all cases of atypical hemolytic uremic syndrome. Mutations in other genes have been identified in a lower percentage of cases. Genes associated with atypical hemolytic uremic syndrome encoding proteins involved in a part of the body 's immune response known as the complement system. This system is a group of proteins that act 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 that only address remove unwanted elements and not attack the healthy cells of the organism. Regulatory proteins associated with atypical hemolytic-uremic syndrome protect healthy cells by preventing activation of the complement system when not needed.

Mutations in genes associated with HUS atypical result in the uncontrolled activation of the complement system. The system hyperactive complement attacks the cells that line blood vessels in the kidneys, causing inflammation and the formation of abnormal blood clots. These abnormalities result in kidney damage and, in many cases, renal failure and end stage renal disease. Although genetic mutations increase the risk of atypical hemolytic-uremic syndrome, it is believed that often are not enough to express the disease. In people with certain genetic changes, signs and symptoms of disease can be triggered by factors including certain drugs, as drugs used against cancer, chronic diseases, bacterial or viral infections, cancers, organ transplantation, or pregnancy . Some people with atypical hemolytic-uremic syndrome have no known genetic changes or environmental triggers for the disease. In these cases, the disease is described as idiopathic.

The CFH gene, located on the long arm of chromosome 1 (1q32), encodes a protein called complement factor H. This protein helps regulate the complement system. They have been described at least 143 mutations in the CFH gene. The mutations described so far have been: missense mutations (115), and cutting mutations -splicing- connection (4), regulatory mutations (2), small deletions (12), small insertions (3), major deletions (4) , larger inserts / duplications (1) and complex rearrangements (2). Mutations in this gene increase the risk of a severe form of the disease that usually occurs early in life. Most CFH gene mutations associated with atypical hemolytic-uremic syndrome affecting a region of the protein complement factor H known as the C-terminal domain. These mutations result in abnormal or non - functional version of the protein. A deficiency of complement factor H can cause uncontrolled activation of the complement system on the surface of cells.

The CD46 gene, located on the long arm of chromosome 1 (1q32) encoding a membrane protein and is a type I regulating portion of the complement system. The encoded protein has a cofactor activity to inactivate components C3b and C4b by factor I serum that protects the cell from damage by complement. In addition, the encoded protein can act as a receptor for Edmonston measles virus, herpesvirus-6 human, and Neisseria type IV pili. In addition, the protein encoded by this gene may be involved in the fusion of sperm and egg during fertilization. They have been described at least 43 mutations in the CD46 gene. The mutations described so far have been: missense mutations (24), and cutting mutations -splicing- connection (7), regulatory mutations (1), small deletions (6), small insertions (1), insertions / deletions small ( 2), larger deletions (1) and complex rearrangements (1). Individuals with mutations in the CD46 gene appear to have a better prognosis compared with individuals carrying mutations in the CFH gene.

C3 gene, located on the short arm of chromosome 19 (19p13.3-p13.2), encoding the protein complement component 3 (C3). This protein plays a key role in the complement system, because it is essential for activation. The presence of foreign invaders makes the C3 protein is cleaved into two smaller pieces. One of these parts, C3b, interacts with other proteins on the cell surface to activate the complement system response. They have identified two protein allotypes of C3: C3S and C3F. In the general population, C3S is more common than C3F. The two allotypes differ in one amino acid, although it is unclear if work differently. They have been described at least 41 mutations in the C3 gene. The mutations described so far have been: missense mutations (31), and cutting mutations -splicing- connection (4), small deletions (3), small insertions (1), larger deletions (1) and variations of repetition (1 ). It is believed that many of these genetic changes alter the capacity of the C3 protein to bind other proteins, leading to abnormal activation of the complement system. Hyperactive system attacks the endothelial cells lining small blood vessels in the kidneys.

The CFB gene, located on the short arm of chromosome 6 (6p21.3) encoding the complement factor B, a component of the alternative pathway of complement activation. The B factor circulates in the blood as a single chain polypeptide. Upon activation of the alternative pathway, it is cleaved by complement factor D giving the Ba chain noncatalytic and the catalytic subunit Bb. The active subunit Bb is a serine protease that is associated with C3b to form C3 convertase of the alternative pathway. Bb subunit is involved in B cell proliferation preactivated while Ba inhibits their proliferation. They described so far 14 missense mutations in the C3 gene.

The CFHR5 gene, located on the long arm of chromosome 1 (1q31.3), encoding the H complement factor 5. Although the exact function of this protein is unknown, its structure is similar to that of the protein encoded from the gene CFH. They have been described at least 14 mutations in the gene CFHR5. The mutations described so far have been: missense mutations (8), regulatory mutations (2), small insertions (1) and insertions / higher duplications (3). These genetic changes lead to uncontrolled activation of the complement system.

The THBD gene, located on the short arm of chromosome 20 (20p11.2), encoding an endothelial - specific receptor type I membrane linking thrombin. This binding results in activation of protein C, which degrades the coagulation factors Va and VIIIa and reduces the amount of thrombin generated. They have been described at least 16 THBD gene mutations. The mutations described so far have been: missense mutations (11), regulatory mutations (2), small deletions (1) and insertions / deletions small (2).

Most cases of atypical hemolytic-uremic syndrome are sporadic, meaning that occur in people with no apparent history of the disease in your family. It is estimated that less than 20% of all cases have been described in families. When the alteration is familiar, the disease may have an autosomal dominant pattern of inheritance or autosomal recessive. Autosomal dominant inheritance means that a copy of an altered gene in each cell is sufficient to increase the risk of expressing the disease. In some cases, an affected person inherits the mutation from an affected parent. However, most people with autosomal dominant form of atypical hemolytic-uremic syndrome have no history of the disease in his family. Not all people who inherit a genetic mutation develop the signs and symptoms of the disease. Meanwhile, autosomal recessive inheritance means both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform the detection of mutations associated with atypical hemolytic uremic syndrome, by complete PCR amplification of the exons of CFH, CFI, CD46, C3, CFB, CFHR5 and THBD genes, respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).