Diagnosis of Xeroderma Pigmentosum (XP) ... (2/2)

People with XP are extremely prone to skin cancer. Without sun protection, about ½ of children with XP develop their first skin cancer by the age of 10. Most people with XP develop multiple skin cancers during their lifetime. These cancers occur most often on the face, lips and eyelids. Cancer can also develop on the scalp, in the eyes and on the tip of the tongue. Apart from skin cancer they may also develop other types of cancer including brain tumors.

The eyes of the people with XP may be painfully sensitive to UV rays of Sun. If the eyes are not protected from the sun, they may become bloodshot and irritated and the clear front covering the eyes (the cornea) may become cloudy. In some people the eyelashes fall out and the eyelids may be thin and turn abnormally inward/outward. In addition to increased risk of eye cancer, XP is associated with numerous noncancerous growths on eyes which can impair vision.

About 30% of people with XP develop progressive neurological abnormalities, in addition to the problems in skin & eyes, including hearing loss, poor coordination, difficulty in walking, movement problem, loss of intellectual functions, difficulty in swallowing and talking and seizures.

Diagnosis of Xeroderma Pigmentosum (XP) ... (1/2)

Usually the Xeroderma Pigmentosum is detected in early infancy ¾within 1-2 Years.

A child having severe sunburn after their first exposure to sun may be a clue to the diagnosis of Xeroderma Pigmentosum (XP). XP can usually be conclusively diagnosed by measuring the DNA Repairing Factor from skin/blood sample.

Some affected children do not get sunburned with minimal sun exposure, but instead tan normally. By the age 2, almost all children with XP develop freckling of skin in sun-exposed areas (such as face, arms & lips); this type of freckling rarely occurs in children without the disorder.

XP associated Genes and their Roles in NER

NER Factor	Subunits	Function
XPC	XPC, HR23B	Damage Recognition Molecular Matchmaker
TFIIH	XPB, XPD, p34, p44, p62, p52, Mat1, Cdk7, Cyclin H	DNA unwinding, Helicase 3¢-5¢ helicase, 5¢-3¢ helicase
XPA	XPA	Damage Recognition
RPA	RPA70, RPA 32, RPA 14	Damage Recognition DNA Re-synthesis
XPG	XPG	3¢ incision
ERCC1-XPF	ERCC1, XPF	5¢ incision

Neucleotide Excision Repair !!! ... (3/4)

Neucleotide Excision Repair !!! ... (2/4)

Neucleotide Excision Repair (NER) is a particularly important excision mechanism which removes DNA damage induced by ultraviolet (UV) light. UV DNA damage results in bulky DNA adducts (a DNA adduct is a piece of DNA covalently bonded to cancer-causing chemical. This process could be the start of a cancerous cell or carcinogenesis) ¾ mostly pyrimidine/thymine dimmers, 6, 4- photoproducts.

Recognition of the damage leads to removal of a short single stranded DNA segment which contains the lesions. The undamaged single stranded DNA remains and DNA polymerase use it as a template to synthesize a short complementary sequence. Final ligation to complete NER and form a double stranded DNA is carried out by DNA ligase. NER can be divided into 2 sub-pathways ¾

E Global Genomic NER (GG-NER)

E Transcription Coupled NER (TC-NER)

The two sub-pathways differ in how they recognize DNA damage but they share the same process for lesions incision, repair and ligation.

In TCR, stalled RNA Polymerase, at DNA damage position, is the signal to initiate NER whereas in GGR, the signal is the helix distortion by the damage.

The assembly of the NER complex starts with DNA damage recognition, followed by binding of addition factors including the basal transcription factor ‘TFIIH’. This factor contains the XPB & XPD genes.

The incision step is carried out by two endonuclease ¾ XPF-ERRC1 and XPG ¾ leading to excision of DNA lesion.

XP indicate the 7 NER genes mutated in XP patient.

Source: Disorders of nucleotide excision repair: the genetic and molecular basis of heterogeneity

www.nature.com/nrg/journal/v10/n11/box/nrg2663_BX1.html 

Neucleotide Excision Repair !!! ... (1/4)

From the beginning of life, DNA stores the genetic information but has faced a fundamental problem of not being chemically inert. DNA damaged occurs constantly because of

E Chemicals (i.e. intercalating agents)

E Radiation

E Other Mutagen

To protect this ‘Achilles heel’ (a deadly weakness in spite of overall strength), an intricate network of DNA Repair System has evolved early in the evolution, comprising of three excision repair pathways to repair single stranded DNA damage:

E Neucleotide Excision Repair (NER)

E Base Excision Repair (BER)

E DNA mismatch Repair (MMR)

Cause of XP

We just came to know that Xeroderma Pigmentosum (XP) is a ‘autosomal recessive’ disorder. But the genetic disorder is caused due to a faulty DNA Repair Mechanism of the skin.

Ultraviolet Ray (UV Rays) from the Sum, damages the DNA of the skin cells. Normally the body repairs this damage through the process called ‘Nucleotide Excision Repair (NER)’ (we will discuss the process later). But a defect in NER results in an inefficient DNA repair mechanism in XP. As the cells are unable to repair it, the DNA remains damaged which leads to cells death making the skin very thin and patchy (splotchy pigmentation) and develop carcinoma (cancerous) cells.

XP also causes spidery blood vessels in the skin (telangiectasia) and skin cancer, occurs before the child became 5 yrs old.

How XP is inherited?

As we already discussed several times in my previous pots for the other disorder that every cell has 2 copies of each gene: one inherited from the mother and one from father.

Xeroderma Pigmentosum (XP) follows as ‘autosomal recessive’ inheritance pattern in which a mutation must be present in both copies of the gene in order to show its symptoms in the affected individual ¾ which indicates that both parents must pass on a genetic mutation for a child to be affected. A person who has only one copy of the gene mutation is called a carrier. When both the parents are carriers of recessive mutation in the same gene, there is a 25% chance for a child to inherit 2 mutations to be affected.

Types of Xeroderma Pigmentosum

There are 8 inherited forms of Xeroderma Pigmentosum (XP) have been identified ¾ Group (XP-A) to Group G (XP-G) plus one variant type (XP-V).

The types are distinguished by their genetic cause. All of the types are prone to skin cancer although some are more likely than others to be associated with neurological abnormalities.

Type	Disease Database	OMIM	Gene	Locus
Type A I (XP-A)	29877	27800	XPA	9q22.3
Type B II (XP-B)	29878	133510	XPB	2q21
Type C III (XP-C)	29879	278720	XPC	3p25
Type D IV (XP-D)	29880	278730 278800	XPD ERCC6	19q13.2-q13.3 10q11
Type E V (XP-E)	29881	278740	DDB2	11p12-p11
Type F VI (XP-F)	29882	278760	ERCC4	16p13.3-p13.13
Type G VII (XP-G)	29883	278780 133530	RAD2 ERCC5	13q33
Type V VIII (XP-V)		278750	POLH	6p21.1-p12

The Name

Xeroderma Pigmentosum, commonly known as XP, is as inherited condition characterized by an extreme sensitivity to Ultraviolet (UV) Rays from the Sunlight. The condition mostly affects the eyes and areas of skin exposed to the sun. In affected individuals, exposure to sunlight often causes ‘Dry Skin’ (Xeroderma) and changes in ‘Skin Coloring’ (Pigmentosum). Due to this types of combination of features this rare disorder named as ¾ ‘Xeroderma Pigmentosum’.