Saturday, 12 April 2014

 All the genetic information that we need is inherited from our parents. The majority of the genes are present as two copies, one of which we have received from each parent. Genetic diseases can be inherited in a number of ways which are referred to as "Mendelian". Recessive diseases show up only when both copies of a pair of genes are abnormal. In dominant conditions, only one member of the pair needs to be abnormal for the disease to occur. A few diseases, of which IP is one, are caused by genes on the X-chromosome and are called "X-linked". This type of Mendelian inheritance is different because all females have two X-chromosomes, while males have only one X (and another, male-determining chromosome called the Y-chromosome). For most X-linked disorders, females are not affected since they have two X-chromosomes (one with the disease gene and one with a normal gene); the effect of the normal copy of the gene on one X overrides the effect of the abnormal copy on the other X. Males, however, do not have this second normal copy; they have only one X-chromosome, so they have no way to compensate for their only abnormal X-linked gene and thus they are affected with the disease. Some rare males can have two X chromosomes along with their Y--some males with IP have been found who have this chromosomal anomaly. 

IP is a dominant X-linked condition. This means that females with only one copy of the abnormal gene will show the disease, even though they have a normal gene on their other X-chromosome. Males who inherit the abnormal gene (and, of course, do not have a balancing normal copy) do not survive, which demonstrates that the normal copy of the IP gene is extremely important. With the identification of the NEMO gene in IP, we now know that males lacking a function copy of this gene will not survive due to liver failure, typically in the first trimester of pregnancy.

A woman who is affected with IP has one normal X-chromosome, and one X-chromosome carrying the abnormal gene. At each pregnancy she will give half of her genetic information to each fetus. Thus, for any pregnancy there is a 50-50 chance that she will transmit the X-chromosome with the abnormal IP gene, regardless of the sex of the fetus. On average, half of her daughters will inherit the normal X-chromosome and be unaffected, and half will receive the abnormal X and have IP like their mother. Half of the sons will inherit the normal X-chromosome and be normal, and the other half will receive the abnormal X. Since males typically do not survive without a normal copy of the gene, these "affected" males will either miscarry or be stillborn. In summary, half the daughters of an affected IP female will have IP and half will not, but nearly all the live-born sons will be normal. This 50-50 chance for affected females is true for each pregnancy, regardless of whether previous pregnancies have been affected or not.

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