Genes and mutations

Several mutations can cause the illness, the most common touchs the XPa gene, the effects are different depending on which genes is touched but there is always an alteration of NER.

 

Six genes mutations that cause XP :

Type XPE :

Frequency : rare

Gene : DDB2           

Locus : 11p12-p11 

Function : 

Bind to an other protein to form  UV-DDB complex, which is able to recognize damages linked to UV. It can also recruits proteins to initiate the DNA repair.
 

Disease description : 

Impairs DNA-biding of the UV-DDB complex. There isn’t any recognization of the damages made by the UV.

Type XPF :

Frequency : 6 %

Gene : ERCC4

Locus : 16p13.3-p13.13

Function :  

It is a gene that is implied in incision during the DNA repair and that helps during the removal of interstrand cross-link.

Disease description : 

Inhibits the catalytic site. Exhibits residual excision activity, thus the protein insn’t able to realise the incision of the DNA and the removal.

Type XPG :

Frequency : 6 %

Cockayne syndrom

Gene : ERCC5

Locus : 13q33

Function : 

Single-stranded structure that is involved in DNA excision repair. It makes one incision on the DNA nucleotide. It may also be involved in transcription-coupled repair of this kind of damage, in transcription by RNA polymerase II, and perhaps in other processes too.

Disease description : 

Reduces stability and greatly impairs endonuclease activity. Decreases XPG activity to repair DNA damages in a XP patient.

Type XPC :

Frequency : 25 %

Nail and hair problems.

Locus : 3p35 

Function : 

It is implied in the pre-incision or the initial recognition complex. It can recognize a large spectrum of damaged DNA.

Disease description:

Decreases repair activity and impairs DNA binding. The protein is unable to bind the DNA and  to recruits TFIIH complex, which is very important for the excision repair.

Type : XPB

Frequency : Rare

Gene:XPB

Locus 9q22.3

Function :
XPB is a component of the TFIIH, which means it's used in the NER of DNA. It acts by opening DNA either around the RNA transcription start site or around the damage.

Disease description :

One of the worst consequences of the mutation that affect XPB is that it disables the NER activity. It also  prevents from binding to UV-damaged, and repair damaged DNA, and can also disrupt the TFIIH activity.

Type : XPD

Frequency : 15%

Gene:XPD/ERCC6

Locus 19q13

Function :

XPB is a component of the TFIIH, which acts in nucleotide excision repair (NER) of DNA by opening DNA around the damage, and in RNA transcription by RNA polymerase II. It might have a role in aging process and could play a role in the generation of skin cancers.

Disease description :
This mutation can impair DNA binding.

XPA : The most frequent one

 

XPA is a gene which creates a protein (XPA) involved in DNA excision repair. Indeed, it initiates the repair by binding to damaged sites allowing other proteins to cut and repair the mutated zone of the DNA.

The xpa protein, with its zinc fingers that bind to the DNA

When this gene is mutated, it can't create a functional protein, thus the DNA can't be repaired properly.

Different mutations can occur on this gene. You can find some examples in the following table and picture :

 

The mutations all have a different incidence on the symptoms.

On this picture, the mutation that imports for XP is the one on position 108. Indeed, this mutation is within the zone of Zn-binding, aka the zone which codes for the binding function of the XPA protein.