A genetic illness

 

Xeroderma Pigmentosum :

 Transmission of the disease :

Xeroderma pigmentosum (XP or in short xeroderma) is not acquired through an infection, it is not a contagious disease but a genetic illness that is transmitted from parents to children. The question is the following : how ??

As you probably know our genome is the nucleus of our cells, distributed over 23 different the chromosomes, each carruing numerous protein-coding genes. In total the humain genome carries 20,313 different protein coding genes (for more infomations, click here). Everybody has two copies of the genome, one from the father and the other from the mother. They do the same job but they are not identical because each of the genomes have evolved in a different way (over many generations). 

Xeroderma is the consequence of a mutation in the protein genes that constitute our genome. It is a recessive illness, which means that both genes have to carry mutations in order to get the symptoms. This is why the parents of affected children are not necessarly ill. A person who has a mutated and a normal gene is called a carrier and two carries can give rise to a diseased child. (see figure 2)

Figure 2

When Xeroderma has been diagnosed in families couples generally seek prenatal diagnosis to assert whether the foetus two mutated genes or not. As figure 2 shows, when both parents are carriers the chance of an affected child is 1 in 4. Couples can then decide to terminate pregnancy.

Xeroderma is not caused by a single mutations, all in all, scientists have found 7 genes located on different chromosomes that, when mutated, can bring about disease.

 The source of the problem :


Normally, when small part of the DNA is damaged or altered (for instance through UV radiation, through errors in replication, or the presence of free radicals), the cell is able to repair its DNA. It mobilizes numerous protein that first spot and then fix the anomaly. In short, the damaged DNA strand removed and a complementary DNA strand is produces. When both DNA strand are affected the repair machinery can use the similar gene on the matching chomosome as a template for repair. The DNA repair process briefly discribed is referred to as Nucleotide Excision Repair. (see video below for more informations click here )

Sometimes anomalies are not noticed or not properly corrected and leads to a mutation in the genome. Mutations in the protein-coding genome can bring about three things (see figure 3) :
- A Nonsense which is a mutation that creates a translation"stop" codon (giving rise to a shortened or "truncated" protein)
- A Missense which is a mutation that changes the protein (with sometimes a change in inactivity or in a subcellular localization or both)
- A Silent mutation which is a mutation that does not change the amino-acid composition of the protein.  
               

Figure 3

                         

The problem :  when someone has xeroderma pigmentosum, the mutations have occured in the genes that code for the proteins that constitute the DNA repair mechanism described above. This means that mutations will occur more frequently because of faulty repair or lack or repair of damaged DNA. In short, people with the disease carry a mutation that causes the increase of mutations and as a consequence enhance the chance of other acquiring other diseases among which cance.

Proteins involved in DNA repair that may be mutated in XP :

There are 7 major proteins involved in nuclear excision repair that are also associated with Xeroderma when mutated, there are : XPA, XPB, XPC, XPD, XPE, XPF, and XPG. What this means is that when one of the seven proteins is mutated the efficiency of the repair mechanism will be reduced. Not all mutations have the same impact on DNA repaire, some are associated with mild and others with severe forms of the disease. These proteins names have been given disease-related names such as other proteins involved in DNA repair are named after the Cockayne syndrom, characterized by insufficient growth, facial dysmorphia and abnormal sensitivity to light, such as CSA and CSB. Additionally, proteins are ERCC1, RPA, RAD23A and RAD23B (rad for radiation sensitive).

The order of events in nucleotide excision repair can be described as follows : When a part of DNA is damaged, WPA, XPC-HR23 and RPA recruits the Transcription factor II (TFIIH) that incorporates two helicases which are XPB and XPD playing a role in unwinding the damaged fragment of DNA. After that, damaged-DNA strand is excised by XPG and XPF-ERRC1 complex, then the strand is removed and replaced by re-synthesizing a complementary DNA by a DNA-polymerase complex.

In the following page ("genes and mutations") we list more specifically the genes and their protein products (their structure and function) involved in Xeroderma Pigmentosum : click here