Alport Syndrome

Alport syndrome is caused by disease-causing variants in the DNA sequences of specific genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a disease-causing variant in the DNA sequence of genes of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.

Alport syndrome is inherited in an X-linked pattern and caused by COL4A5 gene mutations, although other inheritance patterns do exist. It can be inherited as an autosomal recessive or dominant pattern by mutations in COL4A3 or COL4A4 gene. Approximately 80% of men with the XLAS develop some degree of hearing loss till they reach teenage.[rx]

The COL4A5 gene is located on the X chromosome. The COL4A3 and the COL4A4 genes are located on chromosome 2. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes.

X-linked Alport syndrome is caused by disease-causing variants in the COL4A5 gene, which resides on the X chromosome. X-linked disorders cause more severe symptoms in affected males than in affected females. Females have two X chromosomes in their cells, but one of the X chromosomes is “turned off” or inactivated during development, a process termed “lyonization,” and all of the genes on that chromosome are inactivated. Lyonization is a random process, and varies from tissue to tissue; within tissues, it can also vary from cell to cell. Females who have a disease gene present on one X chromosome are heterozygous for that disorder, meaning they have one abnormal copy of the gene and one normal copy. As the result of the lyonization process, most heterozygous females have about 50% of the normal X and 50% of the mutant X expressed in each tissue, and usually display only milder symptoms of the disorder.

Because of the randomness of the lyonization process, exceptions to this rule exist, particularly if the inactivation of one copy of the X chromosome is significantly “skewed” in favor of one of the copies. If the normal copy prevails, then heterozygous females can be and remain completely asymptomatic. If the mutant copy prevails, then heterozygous females can be affected as severely as males.

Unlike females, males have only one X chromosome. If a male inherits an X chromosome that contains a disease gene, he will develop the disease. A male with an X-linked disorder passes the disease gene to all of his daughters, and the daughters will be heterozygous because they inherit a normal copy of the gene from their mothers. A male cannot pass an X-linked gene to his sons because the Y chromosome (not the X chromosome) is always passed to male offspring. A female who is heterozygous for an X-linked disorder has a 50% chance with each pregnancy of having a heterozygous daughter, a 50% chance of having a daughter with two normal copies of the gene, a 50% chance of having a son affected with the disease, and a 50% chance of having an unaffected son. Approximately 10-15% of males with XLAS have a variant that occurs randomly (spontaneously) for no known reason. In these cases, the mutation was not inherited from the mother.

Autosomal recessive Alport syndrome is caused by disease-causing variants in both copies of either the COL4A3 or the COL4A4 genes. Autosomes are the non-sex chromosomes that carry most of our genes. There are 22 autosomes and cells have two copies of each autosome, one inherited from the mother and the other inherited from the father. Each cell has two copies (alleles) of every autosomal gene. Autosomal recessive genetic disorders occur when an individual inherits an abnormal copy of a gene from each parent. If an individual receives one normal gene and one gene for the disease, the person will be heterozygous for the disease, and may or may not show symptoms. The risk for two heterozygous parents to both pass the altered gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is heterozygous like the parents are 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

Autosomal dominant Alport syndrome is caused by disease-causing variants in one copy of either the COL4A3 gene or the COL4A4 gene. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new variant (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.

Researchers have determined that the progression and severity of Alport syndrome tend to vary based upon the specific variant present in a gene as well as the specific location of the variant in the gene. This is known as genotype-phenotype correlation and allows physicians to predict individuals who are at risk of early-onset kidney failure? or are more likely to develop extra-renal? abnormalities. More than 1000 different disease-causing variants have been identified in XLAS.

Some individuals with Alport syndrome have a loss of genetic material (microdeletion) and loss of function of several adjacent genes (contiguous gene syndrome) on the long arm of the X chromosome, which affects both the COL4A5 and COL4A6 genes. In addition to the classic symptoms of Alport syndrome, affected individuals can develop leiomyomatosis (tumors of smooth muscle that are not malignant?). This is known as Alport syndrome with diffuse leiomyomatosis. Another disorder involving a contiguous gene syndrome associated with X-linked Alport syndrome is the AMME complex. For more information on these disorders, see the Related Disorders section below.

The COL4A3, COL4A4, and COL4A5 genes create (encode) proteins known as alpha chains of collagen IV, a protein family that serves as the major structural component of basement membranes, specifically those of the kidneys, ears, and eyes. Basement membranes are delicate protein matrices that separate the thin outer layer of tissue (epithelium) of a structure from the underlying tissue. The basement membrane anchors the epithelium to the loose connective tissue beneath it and also serves as a barrier. The COL4A3 gene encodes the collagen IV alpha-3 chain. The COL4A4 gene encodes the collagen IV alpha-4 chain. The COL4A5 gene encodes the collagen IV alpha-5 chain. Disease-causing variants in these genes impair the production of functional copies of the corresponding proteins, leading in turn to the improper health and maintenance of collagen IV. The negative effects of collagen IV abnormalities result in progressive damage to the basement membranes and ultimately the signs and symptoms of Alport syndrome.

For example, in the kidneys, the glomerular basement membrane (GBM) is a vital component of the walls of the small blood vessels (capillaries) that make up glomeruli. The glomeruli are the filtering units of the kidney. Blood flows through very small capillaries in each glomerulus where it is filtered through the GBM to form urine. Collagen IV acts to strengthen and hold the GBM together. In individuals with Alport syndrome the GBM is initially thin and can develop microscopic ruptures that allow blood cells to leak into the urine, causing hematuria?. The cells of the glomeruli respond to the abnormal collagen IV by laying down other proteins that lead to the thickening of the GBM while impairing the GBM’s ability to keep protein out of the urine. This results in proteinuria?. Further damage such as the formation of scar tissue (chronic? injury or inflammation. সহজ বাংলা: অতিরিক্ত দাগের মতো টিস্যু তৈরি হওয়া।" data-rx-term="fibrosis" data-rx-definition="Fibrosis means excess scar-like tissue formation after chronic injury or inflammation. সহজ বাংলা: অতিরিক্ত দাগের মতো টিস্যু তৈরি হওয়া।">fibrosis?) in the kidneys may also occur. Damage to the GBM and the kidneys is progressive, causing worsening kidney function and, in many cases, eventually kidney failure?.