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The Molecular Basics of Cystinuria

By Matthew Lewis

Table of Contents
What is Cystinuria?
What Causes Cystinuria?
• The b0,+ Transporter System
• The Small Intestine
• The Kidneys
• Clinical Effects of a Nonfunctioning b0,+ Transporter System
The Inheritance of Cystinuria
• Our genome as a collection of individual genes
• Protein expression, genetic mutation, and inheritance
Types of Cystinuria, and the finer details of b0,+ transport system genes and proteins
• Type A
• Non-Type A (Type B)
• Type A/B (Combined Cystinuria)
Wrapping it all up

What is Cystinuria? :

When cystine, an amino acid, is found in the urine at concentrations above what is normal, that individual is said to have cystinuria (literally, “cystine in the urine”). Most patients will recognize cystinuria as a disease of chronic cystine kidney stone formation, as stones are likely to occur when cystine is found in the urine in significant amounts.

What causes Cystinuria?:

The b0,+ Transporter System

Cystinuria is caused by an inherited defect of amino acid transport. The human body contains many copies of a specialized protein complex that (when functioning normally) shuttles cystine and three other amino acids, lysine, ornithine, and arginine (known as the “dibasic amino acids”), across tissue barriers from one space in the body to another. This transporter complex, known as “system b0,+”, has been found in a handful of organs including the small intestine and the kidneys (discussed below), the liver, and the pancreas (not discussed in this article).

In short, the b0,+ transport system is composed of two separate proteins with specialized functions. One protein, named b0,+AT (for amino acid transporter of neutral and dibasic amino acids), is responsible for physically moving cystine and the dibasic amino acids from areas where they collect into adjacent tissues. The other, named rBAT (for related to basic amino acid transporter) is responsible for trafficking the b0,+AT protein to a location in the tissue where it is functional. Together, they form a complete and functional system. Without a properly functioning b0,+AT subunit, no cystine transport can occur, and without the rBAT subunit, b0,+AT is unable to get to where it needs to be in order to function properly. Thus, a defect in either subunit can result in reduced or absent transport of cystine, and thus cause cystinuria.

Before we discuss the how defects in system b0,+ cause cystinuria, we must first understand its undisturbed function in two of its "natural habitats".

The Small Intestine

In the small intestine, ingested protein is broken down via digestive processes into individual amino acids or small peptides (short chains of two or more amino acids). A number of transport systems are then responsible for transporting those amino acids and peptides across the intestinal tissue, where they are metabolized on site or passed into the bloodstream. Among these transporters, we find system b0,+ taking cystine from the intestinal lumen and moving it into the surrounding tissues. Within those cells lining the intestine, cystine is reduced to cysteine, and exported to the bloodstream via a separate transport system. The cystine then circulates via the blood stream to the liver and other organs.

The Kidneys

Amino acids circulating in the blood stream are removed via glomerular filtration by the kidneys, along with many other metabolic products and waste compounds. Much of that initial filtrate will be processed by the kidney to form urine, eliminating waste components that would otherwise accumulate to toxic levels in the blood . However, amino acids are valuable to the body and not considered a hazardous waste product. Therefore, the kidneys work to reclaim the filtered amino acids by transporting them from the lumen of the kidney tubules back into the surrounding tissue for immediate use or passage to the bloodstream. Again, we find the system b0,+ transporter working in these tissues, reclaiming cystine and the dibasic amino acids from the filtrate.

Clinical Effects of a Nonfunctioning b0,+ Transporter System

In each case (intestine and kidney), cystine is absorbed from an excretory pathway into the surrounding tissues. When the system b0,+ transporter is defective, as it is within cystinuric patients, that transport is reduced or absent, causing an accumulation of cystine, lysine, ornithine, and arginine. No detrimental clinical effect has been shown for the urinary (or intestinal) accumulation of lysine, ornithine, and arginine. Cystine, however, is poorly soluble in urine and therefore has a high potential for precipitating from solution when present in large quantity and forming solid crystals. These crystals may be passed in the urine as sediment or gravel, or they may aggregate to form larger cystine stones, called cystine calculi. If these calculi grow large enough, they may be too large to pass and require surgical removal. The major clinical importance of stone growth occurs when a stone blocks the normal production of urine in the small tubes of the kidney, causing potentially harmful backpressure that may eventually decrease kidney function (the ability of the kidneys to filter the blood and create urine). The overall loss of these amino acids from the body has not been shown to have any other clinical significance.

The Inheritance of Cystinuria:

Cystinuria is an inherited disease, meaning it can be passed on from parents to their children. To understand how non-functioning b0,+ transporters can run in families, we must first understand a bit about our genetic material and how proteins are made.

Our genome as a collection of individual genes

All endogenous proteins, including the two involved in the b0,+ transport system, are synthesized by the body. The instructions for creating each individual protein are written in large collections of genes (our DNA), known as "genomes". Genomes among individual people are similar enough to make us humans (rather than other animals or plants and, therefore, they are generically referred to as the "Human Genome"), but diverse enough to help give us our individual looks, traits, and diseases. A single human body contains trillions of fundamentally identical copies of his or her genome. Cells, the building blocks of all tissues (skin, muscle, etc.) each contain a single copy of a person's genome. As tissues change or grow, the cells from which they are made replicate, and thus more identical genome copies are created.

Protein expression, genetic mutation, and inheritance

In any given cell, proteins are being made using that cell's genetic information as a template. The gene coding for a specific protein is read, the protein is made, and that protein is then shipped away to perform its function. At any step in this process errors can occur that will produce a non-functioning protein. However, as the process is repeated, many more functioning copies of the protein are made, and the few non-functioning copies generally have no net effect on the global function of that protein group. On the other hand, if a gene coding for a specific protein is flawed, all proteins made from that template gene can be non-functional, often resulting in dramatic physiological effects.

There are a number of ways for errors to appear in the genetic code. Some are the results of mistakes in genome-copying when cells replicate, leaving localized cells with flawed genes. In these cases, the affected cells often recognize that they have made errors, and those errors are quickly corrected. Other genetic errors are induced by chemical and ultraviolet modification of the genetic code. Again, these are localized effects that are often corrected by the cell's genome "proofreading" capability. Any uncorrected gene errors may result in localized physiological perturbations (skin tumors are a reasonably good example). However, errors in a human’s genetic code can also be passed on from parents to their offspring. If this is the case, a bad copy of a gene is inherited from the genetic material given by a mother and father at conception. That gene will proliferate as the embryo grows and develops, eventually carrying that error into every copy of the genome in the resulting child’s body. Because the error was a part of the child's genome from conception (and not mutated at a later date), the cell will not recognize it as a gene mutation and no correction can be made. Depending on the dominance of the gene (discussed below), the severity of the specific gene error and the function of the protein it codes for, the physiological result in the offspring can range from unnoticed to fatal. Inherited diseases lie between those two extremes – they are often not fatal, but will impact the life of the offspring.

The gene-errors that cause inherited diseases differ from the gene-errors that can cause localized changes (like skin tumors) because they are not localized to a specific area (ie. a spot on the skin). Rather, they have been completely proliferated throughout the body. However, the resulting inherited diseases often appear to be localized to certain organs or body-parts. This is because different genes are selectively expressed in different parts of the body. While it is true that virtually all cells in the body contain the same set of genes, only certain genes are needed in certain areas. Therefore, the genes that make a human hand are present - but silenced - in a human foot, and vice versa. Likewise, the genes for the b0,+ transport system are found throughout the body, but they are only (to our current knowledge) expressed in the organs mentioned above, including the lining tissues of the small intestine and kidney tubules. Therefore, cystinuric patients who have mutations in the genes coding for the b0,+ transport system proteins, b0,+AT and rBAT, only experience clinical effects in those areas where the gene is expressed, and where the resulting change in physiology (lack of cystine and dibasic amino acid transport) is noticed.

Gene Dominance and the finer details of inheritance

As stated above, the clinical effects of cystinuria are the result of a defective or absent b0,+ transport system which is composed of two protein parts, b0,+ AT and rBAT. If an individual has sufficient mutation to the gene coding for either of these proteins, that individual may not be able to produce functional b0,+ transporters. These two proteins are coded by two distinct genes named SLC3A1 (coding for rBAT) and SLC7A9 (coding for b0,+ AT). A person may have mutations in either of those two genes seperatly, or in both. Whether or not that person is unable to produce active transporters and displays the clinical signs of cystinuria, however, is a matter of how genetic information is utilized.

It is important to understand that each person's genome is, in a sense, redundant, meaning we all have two copies of genes that code for a single protein. These gene copies are not identical, as one was inherited from the mother's genome, and the other from the father's. Rather, they can be thought of as complimentary. Under normal circumstances, they preform the same function, but perhaps with some slight variation. For example, we all have two copies of the gene that codes for eye color - one from mom, and one from dad. It is possible that each codes for a eye color of green, but it is also possible that one codes for blue eyes, and the other codes for brown eyes. In this sense, we have redundant but distinct genetic information. How the body sorts out which genes to use is the final chapter in understanding the genetics of cystinuria.

If the latter scenario is true (a child that inherits brown and blue genes from their mother and father, respectivly), does the child end up with an eye color that is a mixture of brown and green? The answer is no. The child will either have blue eyes, brown eyes, or possibly an eye color that the parents did not have.

 

 

 

parent may carry mutated copies of either of these genes individually, or both genes together.

 

 

and therefore have clinical cystinuria. It is important to realize that cystinuria can arise from defects in a single transporter complex protein, or defects in both.

However, to seperate the underlying genetic cause (defect in b0,+ AT vs. defect in rBAT) the disease can be classified as two distinct types (and a third type which is a combination of the first two). Current accepted convention names these: Type A, Non-Type A (Type B), and Type A/B (combined type).

As stated above, the clinical effects of cystinuria can be caused by a defective or absent b0,+ transport system which is composed of two protein parts, b0,+ AT and rBAT. If an individual has sufficient mutation to the gene coding for either b0,+ AT or rBAT, that individual can have cystinuria.

Types of Cystinuria, and the finer details of b0,+ transport system genes and proteins

As stated above, the clinical effects of cystinuria can be caused by a defective or absent b0,+ transport system which is composed of two protein parts, b0,+ AT and rBAT. If an individual has sufficient mutation to the gene coding for either b0,+ AT or rBAT, that individual can have cystinuria. However, to seperate the underlying genetic cause (defect in b0,+ AT vs. defect in rBAT) the disease can be classified as two distinct types (and a third type which is a combination of the first two). Current accepted convention names these: Type A, Non-Type A (Type B), and Type A/B (combined type).

SLC3A1 (rBAT)

SLC7A9 (b0,+ AT)

Wrapping it all up

Cystinuria, characterized by cystine loss in the urine, is a disease caused by absent or defective transport of dibasic amino acids (lysine, ornithine, and arginine) and cystine affecting a number of organs including the in the kidneys and small intestine. This lack amino acid transport prevents absorbtion of cystine and dibasic amino acids from excretory pathways. The insolubility of cystine in urine encourages the potential for stone formation in cystinuric patients, which may lead to other kidney-damaging complications.

Cystinuria, as a genetic defect, can be passed from parent to child. Mutated genes causing cystinuria are inherited from one or both parents (depending on the cystinuria type) and proliferated throughout the child's body as a part of their genome. These genes are then decoded into defective or absent b0,+ transporter proteins (b0,+ AT and rBAT), unable to preform system b0,+ amino acid transport, resulting in the clinical effects of cystinuria.

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