Xeroderma pigmentosum defines a class of autosomal recessive inherited diseases that are characterized clinically by sun sensitivity that results in progressive degeneration of sun exposed areas of the skin and eyes. Often these changes will result in neoplasia. Some XP patients also manifest with progressive neurologic degeneration. There are currently eight alleles whose mutations result in manifestation of XP. Seven of the genes are involved in processes of nucleotide excision repair, NER. These seven complementation groups are identified as XPA, XPB, XPC, XPD, XPE, XPF, and XPG. An additional class of XP patients referred to as XP variants (XPV) result from deficiencies in a gene involved in semi-conservative replication of previously damaged sites in DNA.
In most XP patients the initial symptoms are an abnormal reaction to sun exposure which includes severe sunburn with blistering and persistent erythema with minimal exposure to the sun. These symptoms most often manifest between 1 to 2 years although some patients do not exhibit symptoms until the teens. Most XP patients will develop xerosis (dry skin) and poikiloderma (referring to areas of increased pigment alternating with areas of reduced pigment, atrophy and telangiectasias). Telangiectasias are areas of the skin under which there are dilated superficial vessels resulting in an appearance similar to that in patients with rosacea or scleroderma. These constellation of skin manifestations gave rise to the name of this disease. The skin of affected patients will appear similar to that of a person exposed to the sun for many years, such as a farmer, even though they are very young. Additional benign lesions in the skin include actinic keratoses (scaly crusty bumps), keratocanthomas (well-differentiated squamous cell carcinoma), angiomas (benign tumors composed of blood vessels at or near the surface of the skin) and fibromas (benign tumors of connective tissue). Patients with XP who are younger than 20 years old have a greater than 1000-fold increase in developing cancer at uv-exposed areas of the skin relative to unaffected individuals. Non-melanoma skin cancer in XP patients appears with a median age of 10 years.
In addition to photophobia, XP-related ocular symptoms are restricted to the sun exposed anterior portion of the eye. The anterior portion of the eye includes the lid, cornea, and conjunctiva and these protect the posterior eye (uveal tract and retina) from uv radiation. Only visible light reaches the photosensitive areas of the retina. The ocular symptoms include conjunctivitis, ectropion (eyelids that turn outward) due to atrophy of the skin of the eyelids, exposure keratitis, and benign and malignant neoplasms of the eyelids.
In XP patients with neurologic symptoms there is variation in age of onset and severity. However, all are characterized by progressive deterioration. Frequently observed symptoms are sensorineural deafness and diminished deep tendon reflexes. In some patients progressive mental retardation is evident but usually is not evident until the second decade of life.
XPA: The XPA gene is located on chromosome 9q22.3 and is composed of 10 exons spanning 25 kb encoding a 273 amino acid protein. The protein contains a zinc finger consistent with a DNA-binding protein structure. In addition there is a glutamic acid cluster encoded in exon 2 that, in addition to the zinc finger domain, is critical for the DNA repair activity of the protein. The protein product of the XPA gene functions in a complex with several other proteins involved in repair of DNA damage. These proteins include ERCC1 (ERCC1 = excision repair cross complementing 1 gene; the ERCC genes are also called excision repair, complementing defective, in Chinese hamster). The ERCC genes are members of DNA repair enzymes that were identified based upon their ability to complement DNA excision repair in Chinese hamster ovary (CHO) cells defective in this process. As indicated below, several of the XP alleles encode ERCC genes. Additional proteins in the XPA complex are the XPC gene product, human single strand-binding protein (HSSB) and TFIIH (transcription factor H of RNA polymerase II) TFIIH acts as the nucleation protein for the formation of the functional complex. Exon 1 of the XPA gene enocodes the nuclear localization signal, exon 2 encodes the ERCC1-binding domain, exon 3 contains the zinc-finger domain that binds HSSB, exons 4 and 5 encode the DNA-binding domain and exon 6 encodes the TFIIH interacting domain.
There are two clinical classes of XPA. One class manifests only with skin sensitivity and cancer while the other class is also associated with severe neurologic disorder. The most severe cases of XPA are generally found to harbor mutated alleles that are both in the DNA-binding domain, whereas, milder presenting individuals harbor one allele mutated in the DNA-binding domain and the other allele harboring a mutation somewhere else, often in exon 6.
XPB (ERCC3): The XPB complementation group of XP is the result of defects in the ERCC3 gene. The ERCC3 gene is on chromosome 2q21 spanning 45kb and is composed of 15 exons that generate three alternatively spliced mRNAs. These three mRNAs encode two different isofoms of the enzyme. The ERCC3 protein is the p89 (protein of 89 kDa) subunit of the TFIIH transcription factor described above for XPA. The fact that ERCC3 is a component of a general transcription factor demonstrates that this protein functions in both transcription and DNA repair. ERCC3 functions as a 3' to 5' helicase and likely unwinds the DNA duplex upstream of the site of a damaged nucleotide. The ERCC3 protein interacts with the proteins encoded by both the XPD and XPG complementation groups via domains in the N-terminus. In the process of excision repair, the C-terminus of ERCC3 is required for 5' cleavage.
The occurrence of the XPB form of XP is extremely rare.
XPC: The XPC gene is located on chromosome 3p25.1 andis composed of 18 exons that encode a 940 amino acid protein that binds to single-stranded regions of DNA. The XPC protein is found in a complex with the human homolog of the of the yeast RAD25 gene identified as HHR23B. This complex exhibits selective repair of cyclobutane pyrimidine dimers (CPDs) rather than 6-4 photoproducts (6-4PPs). Related to this selectivity is the observation that the XPC-HHR23B complex interacts with thymine DNA glycosylase (TDG). In the process of DNA repair, the XPC-HHR23B complex plays an initial role in binding to damaged regions in the DNA but is released before strand incision occurs.
The XPC complementation group of XP patients represents the largest percentage of XP cases. These patients exhibit a high propensity for skin cancers without neurological involvement.
XPD (ERCC2): The XPD complementation group of XP results from mutations in the ERCC2 gene. The ERCC2 gene is located on chromosome 19q13.3 and is composed of 24 exons that generate two alternatively spliced mRNAs. The ERCC2 protein, like the XPB protein, is a subunit of TFIIH. ERCC2 specifically interacts with p44 which is another subunit of TFIIH. The interaction of ERCC2 and p44 stimulates the 5' to 3' helicase activity of ERCC2. Mutations in the C-terminal domain of ERCC2 is found in most XPD patients and these mutations prevent its interaction with p44. Both ERCC2 and ERCC3 are helicase subunits of TFIIH and as such mutations in either of these genes leads to clinically overlapping disorders. Mutations in ERCC2 result in complex phenotypes and patients with C-terminal mutations are associated with three different clinical disorders. These disorders include the XPD complementation group of XP, trichothiodystrophy (TTD), and the rare combination of XP and Cockayne syndrome (XP/CS). See below for more information on TTD and CS.
XPE (DDB2): The XPE complementation group of XP results from defects in a heterodimeric protein complex (identified as DNA damage binding protein: DDB) composed of p48 (DDB2) and p127 (DDB1) subunits. The DDB2 gene encodes the p48 subunit and is located on chromosome 11p12–p11. The DDB2 protein is required for DNA-binding of the heterodimeric complex in response to uv damage of DNA. Expression of the DDB2 gene is increased following DNA damage in response to increased activity of the p53 tumor suppressor protein.
XPF (ERCC4): The XPF complementation group of XP results from mutations in the ERCC4 gene. The ERCC4 gene is located on chromosome 16p13.13 spanning 28 kb and is composed of 14 exons encoding a 916 amino acid protein. The ERCC4 protein functions in a complex with the ERCC1 protein. The activity of ERCC4 is to introduce 3' incisions relative to the site of DNA damage, whereas, the ERCC1 protein introduces the 5' incision.
XPG (ERCC5): The XPG complementation group of XP results from mutations in the ERCC5 gene. The ERCC5 gene is located on chromosome 13q33 and is composed of 15 exons encoding an 1186 amino acid protein. The activity of ERCC5 is to introduce 3' incisions relative to the site of DNA damage. The ERCC5 protein is involved in both nucleotide excision repair and the repair of oxidative DNA damage. Binding of ERCC5 to DNA occurs on single-stranded regions that result due to the concerted actions of the XPB (ERCC3) and XPD (ERCC2) helicases that are subunits of TFIIH.
XPV (POLH): The XP variant form of XP results from mutations in the gene encoding DNA polymerase H (POLH) which is also called DNA polymerase eta (DNA pol ε) or Rad30 homolog A (HRAD30A). The POLH gene is located on chromosome 6p21.1 spanning 40 kb and composed of 11 exons that generate three alternatively spliced mRNAs. POLH is involved in the replication of oxidatively damaged DNA. Oxygen free radicals can cause oxidative alteration in guanine residues in DNA resulting in 7,8-dihydro-8-oxoguanine formation (8-oxoG). The normal eukaryotic replicative DNA polymerase (DNA polymerase delta, DNA pol δ) will insert an adenine residue when it encounters 8-oxoG in the template strand. This results in a GC to TA transversion. POLH can efficiently replicate DNA containing 8-oxoG by inserting a cytosine residue across from the lesion. POLH is also able to correctly replicate through cyclobutane pyrimidine dimers (CPDs).
Trichothiodystrophy is characterized by a variable phenotype that can include photosensitivity, ichthyosis (dry scaly skin), brittle hair, intellectual impairment, short stature, microcephaly (small head), characteristic facial features of protruding ears and micrognathia (small jaw), and decreased fertility. TTD has been shown to be caused by defects in ERCC2 (XPD), ERCC3 (XPB) and TTDA (trichothiodystrophy complementation group A, which encodes an additional TFIIH subunit identified as TFB5).
Cockayne syndrome is characterized by abnormal and slow growth evident within the first few years after birth. The classical distinguishing clinical feature in Cockayne syndrome is cachetic dwarfism. In addition patients exhibit cutaneous sensitive to sunlight, thin dry hair, short stature, , disproportionately long limbs with large hands and feet, sensorineural hearing loss, and have the appearance of premature aging. In the classical form of Cockayne syndrome (type A, CSA), the symptoms are progressive and typically become apparent after the age of 1 year. An early onset or congenital form of Cockayne syndrome (type B, CSB) is apparent at birth. CSA results from mutations in the ERCC8 gene and CSB results from mutations in the ERCC6 gene. Unlike other DNA repair diseases, Cockayne syndrome is not linked to cancer
Cerebrooculofacioskeletal syndrome (COFS syndrome type 1; Pena-Shokeir syndrome type 2) was originally defined within a group of Manitoba, Canada aboriginal peoples. There are several subtypes of COFS all of which are characterized by progressive neurologic disorder, microcephaly (small head) with intracranial calcifications, prominent noses, large ears, hypotonia, and growth failure. Ocular findings of microcornea, cataracts, and optic atrophy are present along with joint contractures. Photosensitivity may occur with a concurrent cellular phenotype of uv sensitivity. Individuals with type 1 COFS syndrome (COFS1) have mutations in the ERCC6 gene which is the same gene mutated in type B Cockayne syndrome (CSB). COFS2 results from mutations in the ERCC2 gene, the same gene mutated in XPD. COFS3, which is also known as XP complementation group G/Cockayne syndrome (XPG/CS), results from mutations in the ERCC5 gene. COFS4 results from mutations in the ERCC1 gene.