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The Genetics and Inheritance of Cystinuria
By Dr. David GoldfarbAn excerpt from the 2006 ICF Symposium at Mercy Hospital, Chicago
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Transcript
Chromosome 19 has the other gene – SLC7A9, and this protein is the light component. It's an amino acid transporter – that's what “AT” stands for – of neutral and dibasic amino acids – that's what these superscripts mean. These are the two proteins that we're going to talk about. So these two - the heavy component and the light component – come together and form the cystine transporter. |
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 Now, this is a little complicated, but here's a father [top square], and here's a mother [top circle]. And... this is the more common kind of presentation in the United States – this cystinuria Type I or Type A – is an abnormality in that SLC3A1 [gene] – the rBAT protein. [So here we have] a father, and a mother, and they have four children. And this is really, whether they have four children or not, obviously this is a statistical issue – how many – what percent of their children will be affected. This arrow, this heavy red, indicates that this person has two abnormal genes: one from father, one from the mother. These [striped circles and squares] are heterozygotes. That's what the hatched filling means – the stripes. These are people who have one abnormal gene. Twenty-five percent of the children will have a high amount of cystine in the urine. But notice that the other children – this one [white circle] has no abnormal genes - 25% of their children. Fifty percent will be carriers, and they will not have abnormal amounts of cystine, just like their parents. Normal is less than 100 micromoles, or 25 milligrams of cystine in the urine. So, this is the more common, so-called “recessive” gene. Twenty-five percent of the children will be affected by cystinuria [dark red square]. They'll have two abnormal genes - a large amount of cystine in the urine. Carriers – parents - will not have abnormal amounts of cystine. |
This is an abnormality in the other gene, SLC7A9. Here, both the parents do not have stones, but they both have increased amounts of cystine. They're above 100 micromoles of cystine per gram of creatinine. So both the parents have abnormal amounts of cystine in the urine, but each of them has only one abnormal gene. If those two abnormal genes come together in one individual - 25% - that person is going to be abnormal [dark red square]. But the children who have one gene from the parents will also have high amounts of cystine in the urine [striped square and circle]. So that's why this is considered potentially a dominant gene in the sense that some people will have enough cystine in the urine to have a stone; they'll certainly have an abnormal amount of cystine. This is a different gene problem. And here, if you tested the parents and knew that they did not have cystine stones but had high amounts of cystine in the urine, you would know that this family was affected by a different genetic heritage than the other family that I showed you before.
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 And it's of course – it's possible that the whole family has different kinds of genes – that the parents have different genetic abnormalities. So this mother has a normal cystine gene and an abnormal cystine gene [top striped circle, red], but she winds up with a low amount because she is a Ttype 1 gene carrier – she has the rBAT mutation. But her husband [top striped square, black] has a high amount of cystine in the urine because he's a Type 2 or Type 3 carrier of a SLC7A9 mutation. So when they get together, 25% of their children will have these 2 abnormal genes coming together [solid black square]. This child now has 2 different abnormal genes, so it's mixed. This child [white circle] has no abnormal genes. This child [red striped circle] has one abnormal gene from the mother and has a normal amount of cystine. This child [black striped square] has the same as his father; he's got that abnormal gene that leads to cystine in the urine, but it's not high enough to give him stones. |
A gene is a section of DNA - a length of DNA that codes for a protein. A protein is a chain of amino acids, and there are two important genes that we're going to talk about. One is on chromosome 2p. This gene is called – the name of the gene is SLC3A1. “SLC” is “solute carrier”. It's going to transport something from one side of a membrane to the other side. SLC3A1 codes for a protein that's usually called “rBAT” – it's the heavy component of the cystine transporter, and “rBAT” stands for “related to basic amino acid transporter”. Originally it was “rat basic amino acid transporter”, and they wanted people to know that they had the same molecule too, so they took the rat part out and made the “r” stand for “related”, which was kind. 
The gene for cystinuria – or any one of these genes – is carried by about one out 170 people, and originally you may be familiar with the classification that these were Types I, II, and III. Probably now, we're going to talk about types A and B. This was based, not really on the patient, but on the patient's parents – the patient's parent's cystine excretion. The parents are heterozygotes. That means the parents have one abnormal gene and one normal gene. The patient with cystinuria has two abnormal genes. Since there are two abnormal genes, that's a homozygote. The patients are homozygotes, the parents must be heterozygotes. The heterozygotes [are a] carrier of one mutated gene, and have one normal gene. If the parent has normal urinary cystine, then the patient has Type I cystinuria. That's a recessive gene – it's recessive meaning that the parent who carries one gene has no abnormality in cystine transport – does not have [abnormal cystine in their] urine. But there are [also] parents who have high cystine values – high enough to be measurable as abnormal, but not high enough, in most cases, to cause stones. Those are type– what usually were called– what in the past were called Type II or Type III. So some people have classified now – the distinction between what was called Type II and Type III is not so easy to make, and maybe not even relevant, so people are calling this Type I and non-Type I, or A and B. There are different researchers who have used different classifications. The point is, let's call it A and B for now. 
The other type, the non-Type I or Type B, [is caused by] genes that could be considered dominant. It could be that one gene is enough to have stones. Most people will not have stones, but it's possible. And as far as I can tell – I haven't seen a patient who had one gene and had stones, so I think it's going to be relatively unusual. Cystinuria.org « Resources « Education « The Genetics and Inheritance of Cystinuria (video)