the ercc6 gene, which encodes the csb protein. csa and csb are involved in transcription-coupled ner (tc-ner), which is involved in repairing dna; they ubiquitinate rna polymerase ii, halting its progress thus allowing the tc-ner mechanism to be carried out. the ubiquitinated rnap ii then dissociates and is degraded via the proteasome. mutations in ercc8, ercc6, or both mean dna is no longer repaired through tc-ner, and the accumulation of mutations leads to cell death, which may contribute to the symptoms of cockayne syndrome. xeroderma pigmentosum an eight-year-old girl from guatemala with xeroderma pigmentosum. children with xp are often colloquially referred to as children of the night. main article: xeroderma pigmentosum xeroderma pigmentosum (xp) is a rare autosomal recessive disorder, affecting about one per million in the united states and autochthonic europe populations but with a higher incidence rate in japan, north africa, and the middle east. there have been 830 published cases from 1874 to 1982. the disorder presents at infancy or early childhood. xeroderma pigmentosum mostly affects the eye and skin. individuals with xp have extreme sensitivity to light in the ultraviolet range starting from one to two years of age, and causes sunburn, freckling of skin, dry skin and pigmentation after exposure. when the eye is exposed to sunlight, it becomes irritated and bloodshot, and the cornea becomes cloudy. around 30% of affected individuals also develop neurological abnormalities, including deafness, poor coordination, decreased intellectual abilities, difficulty swallowing and talking, and seizures; these effects tend to become progressively worse over time. all affected individuals have a 1000-fold higher risk of developing skin cancer: half of the affected population develop skin cancer by age 10, usually at areas most exposed to sunlight (e.g. face, head, or neck). the risk for other cancers such as brain tumors, lung cancer and eye cancers also increase. there are eight types of xp (xp-a through xp-g), plus a variant type (xp-v), all categorized based on the genetic cause. xp can be caused by mutations in any of these genes: ddb2, ercc2, ercc3, ercc4, ercc5, xpa, xpc. these genes are all involved in the ner repair pathway that repairs damaged dna. the variant form, xp-v, is caused by mutations in the polh gene, which unlike the rest does not code for components of the ner pathway but produces a dna polymerase that allows accurate translesion synthesis of dna damage resulting from uv radiation; its mutation leads to an overall increase in uv-dependent mutation, which ultimately causes the symptoms of xp. trichothiodystrophy main article: trichothiodystrophy trichothiodystrophy (ttd) is a rare autosomal recessive disease whose symptoms span across multiple systems and can vary greatly in severity. the incidence rate of ttd is estimated to be 1.2 per million in western europe. milder cases cause sparse and brittle hair, which is due to the lack of sulfur, an element that is part of the matrix proteins that give hair its strength. more severe cases cause delayed development, significant intellectual disability, and recurrent infection; the most severe cases see death at infancy or early childhood. ttd also affects the mother of the affected child during pregnancy, when she may experience pregnancy-induced high blood pressure and develop hellp syndrome. the baby has a high risk of being born prematurely and will have a low birth weight. after birth, the child's normal growth is retarded, resulting in a short stature. other symptoms include scaly skin, abnormalities of the fingernails and toenails, clouding of the lens of the eye from birth (congenital cataracts), poor co-ordination, and ocular and skeletal abnormalities. half of affected individuals also experience photosensitivity to uv light. ttd is caused by mutations in one of three genes, ercc2, ercc3, or gtf2h5, the first two of which are also linked to xeroderma pigmentosum. however, patients with ttd do not show a higher risk of developing skin cancer, in contrast to patients with xp. the three genes associated with ttd encode for xpb, xpd and p8/ttda of the general transcription factor iih (tfiih) complex, which is involved in transcription and dna damage repair. mutations in one of these genes cause reduction of gene transcription, which may be involved in development (including placental development), and thus may explain retardation in intellectual abilities, in some cases; these mutations also lead to reduction in dna repair, causing photosensitivity. a form of ttd without photosensitivity also exists, although its mechanism is unclear. the mplkip gene has been associated with this form of ttd, although it accounts for only 20% of all known cases of the non-photosensitive form of ttd, and the function of its gene product is also unclear. mutations in the ttdn1 gene explain another 10% of non-photosensitive ttd. the function of the gene product of ttdn1 is unknown, but the sex organs of individuals with this form of ttd often produce no hormones, a condition known as hypogonadism. defects in lamin a/c lamin is required at the inner nuclear membrane to ensure the nucleus keeps its shape. mutations in lmna causes dysfunctional lamin, and the nucleus can no longer keeps its shape. this leads to mislocalisation of heterochromatin, which normally lie in close proximity, or with, the nuclear matrix, nuclear blebbing and misregulation of gene expression. further information on other diseases caused by defects in lamin: laminopathy hutchinson–gilford progeria syndrome (hgps) and restrictive dermopathy (rd) are two ps caused by a defect in lamin a/c, which is encoded by the lmna gene. lamin a is a major nuclear component that determines the shape and integrity of the nucleus, by acting as a scaffold protein that forms a filamentous meshwork underlying the inner nuclear envelope, the membrane that surrounds the nucleus. hutchinson–gilford progeria syndrome girl with hgps (left). this condition is caused by dysfunctional lamin which is unable to maintain the nuclear shape (normal at top, abnormal at bottom). main article: progeria hutchinson–gilford progeria syndrome is an extremely rare developmental autosomal dominant condition, characterized by premature and accelerated aging (~7 times the normal rate) beginning at childhood. it affects 1 in ~4 million newborns; over 130 cases have been reported in the literature since the first described case in 1886. the mean age of diagnosis is ~3 years and the mean age of death is ~13 years. the cause of death is usually myocardial infarction, caused by the severe hardening of the arteries (arteriosclerosis). there is currently no treatment available. individuals with hgps typically appear normal at birth, but their growth is severely retarded, resulting in short stature, a very low body weight and delayed tooth eruption. their facial/cranial proportions and facial features are abnormal, characterized by larger-than-normal eyes, a thin, beaked nose, thin lips, small chin and jaw (micrognathia), protruding ears, scalp hair, eyebrows, and lashes, hair loss, large head, large fontanelle and generally appearing aged. other features include skeletal alterations (osteolysis, osteoporosis), amyotrophy (wasting of muscle), lipodystrophy and skin atrophy (loss of subcutaneous tissue and fat) with sclerodermatous focal lesions, severe atherosclerosis and prominent scalp veins. however, the level of cognitive function, motor skills, and risk of developing cancer is not affected significantly. hgps is caused by sporadic mutations (not inherited from parent) in the lmna gene, which encodes for lamin a. specifically, most hgps are caused by a dominant, de novo, point mutation p.g608g (ggc > ggt). this mutation causes a splice site within exon 11 of the pre-mrna to come into action, leading to the last 150 base pairs of that exon, and consequently, the 50 amino acids near the c-terminus, being deleted. this results in a truncated lamin a precursor (a.k.a. progerin or laminaδ50). after being translated, a farnesol is added to prelamin a using protein farnesyltransferase; this farnesylation is important in targeting lamin to the nuclear envelope, where it maintains its integrity. normally, lamin a is recognized by zmpste24 (face1, a metalloprotease) and cleaved, removing the farnesol and a few other amino acids. in the truncated lamin a precursor, this cleavage is not possible and the prelamin a cannot mature. when the truncated prelamin a is localized to the nuclear envelope, it will not be processed and accumulates, leading to "lobulation of the nuclear envelope, thickening of the nuclear lamina, loss of peripheral heterochromatin, and clustering of nuclear pores", causing the nucleus to lose its shape and integrity. the prelamin a also maintains the farnesyl and a methyl moiety on its c-terminal cysteine residue, ensuring their continued localization at the membrane. when this farnesylation is prevented using farnesyltransferase inhibitor (fti), the abnormalities in nuclear shape are significantly reduced. hgps is considered autosomal dominant, which means that only one of the two copies of the lmna gene needs to be mutated to produce this phenotype. as the phenotype is caused by an accumulation of the truncated prelamin a, only mutation in one of the two genes is sufficient. at least 16 other mutations in lamin a/c, or defects in the zmpste24 gene, have been shown to cause hgps and other progeria-like symptoms, although these are less studied. repair of dna double-strand breaks can occur by one of two processes, non-homologous end joining (nhej) or homologous recombination (hr). a-type lamins promote genetic stability by maintaining levels of proteins which have key roles in nhej and hr. mouse cells deficient for maturation of prelamin a show increased dna damage and chromosome aberrations and have increased sensitivity to dna damaging agents. in hgps, the inability to adequately repair dna damages due to defective a-type lamin may cause aspects of premature aging (see dna damage theory of aging). restrictive dermopathy main article: restrictive dermopathy restrictive dermopathy (rd), also called tight skin contracture syndrome, is a rare, lethal autosomal recessive perinatal genodermatosis. two known causes of rd are mutations in the lmna gene, which lead to the production of truncated prelamin a precursor, and insertions in the zmpste24, which lead to a premature stop codon. individuals with rd exhibit growth retardation starting in the uterus, tight and rigid skin with erosions, prominent superficial vasculature and epidermal hyperkeratosis, abnormal facial features (small mouth, small pinched nose and micrognathia), sparse or absent eyelashes and eyebrows, mineralization defects of the skull, thin dysplastic clavicles, pulmonary hypoplasia and multiple joint contractures. most affected individuals die in the uterus or are stillbirths, and liveborns usually die within a week. defects in fbn1 patients with marfan-progeroid-lipodystrophy syndrome typically exhibit congenital lipodystrophy and a neonatal progeroid appearance. sometimes identified as having neonatal progeroid syndrome, the term is a misnomer since they do not exhibit accelerated aging. the condition is caused by mutations near the 3'-terminus of the fbn1 gene. a common cause for premature aging hutchinson–gilford progeria syndrome, werner syndrome, and cockayne syndrome are the three genetic disorders in which patients have premature aging features. premature aging also develops on some animal models which have genetic alterations. although the patients with these syndromes and the animal models with premature aging symptoms have different genetic backgrounds, they all have abnormal structures of tissues/organs as a result of defective development. misrepair-accumulation aging theory suggests that the abnormality of tissue structure is the common point between premature aging and normal aging. premature aging is a result of mis-construction during development as a consequence of gene mutations, whereas normal aging is a result of accumulation of misrepairs for the survival of an organism. thus the process of development and that of aging are coupled by mis-construction and mis-re-construction (misrepair) of the structure of an organism. unknown causes wiedemann–rautenstrauch syndrome wiedemann–rautenstrauch (wr) syndrome, also known as neonatal progeroid syndrome, is an autosomal recessive progeroid syndrome. more than 30 cases have been reported. most affected individuals die by seven months of age, but some do survive into their teens. wr is associated with abnormalities in bone maturation, and lipids and hormone metabolism. affected individuals exhibit intrauterine and postnatal growth retardation, leading to short stature and an aged appearance from birth. they have physical abnormalities including a large head (macrocephaly), sparse hair, prominent scalp veins, inward-folded eyelids, widened anterior fontanelles, hollow cheeks (malar hypoplasia), general loss of fat tissues under the skin, delayed tooth eruption, abnormal hair pattern, beaked noses, mild to severe intellectual disability and dysmorphism. the cause of wr is unknown, although defects in dna repair have been implicated. rothmund–thomson syndrome classified as an autosomal recessive defect, but the pathology has still yet to be well researched. cancer some segmental progeroid syndromes, such