Cockayne syndrome is a rare autosomal recessive condition comprising microcephaly, "cachectic dwarfism" and progressive neurological degeneration. CS is characterized by progressive multisystem degeneration and is classified as a segmental premature-aging syndrome.
A prevalent feature of Cockayne syndrome (CS) is photosensitivity, without the pigmentary disturbances or other skin problems that are characteristic of XP. The mean age of death of patients with CS is about 12 years and the few patients who have survived to early adulthood do not manifest skin or other types of cancer.
The photosensitivity of individuals with CS prompted the early idea that they might be defective in DNA repair. Skin fibroblasts from these individuals are, indeed, more sensitive to killing by UV radiation than normal cells. However, measurements of global NER were normal.
Cells from individuals with CS recover from an inhibition of RNA synthesis that accompanies exposure to UV light much more slowly than normal cells do.
Further studies established that this cellular phenotype reflects defective transcription-coupled NER (TCNER), establishing CS as a DNA-repair-defective disorder.
It is now recognized that TCNER specifically requires the products of two genes called CSA and CSB and that defects in either gene can lead to the disease. The molecular pathogenesis of this disease remains uncertain as the precise functions of the CSA and CSB gene products are not known.
The combined XP/CS syndrome presents an equal challenge. So far, only a small number of patients have been identified as having the syndrome, and all of these have mutations in either the XPB, XPD or XPG genes. Skin cancer at a young age has been documented in some, but not all, of these cases.
Synopsis
sun sensitivity
mental retardation
microcephaly
dwarfism
systemic anomalies
- cachectic dwarfism
- intrauterine growth retardation (IUGR)
- severe postnatal growth deficiency
- normally no cancer is associated.
craniofacial anomalies
- micrognathia
- protruding ears
- dental overcrowding with caries
- prognathism
- loss of facial adipose tissue
- wizened face
- malformed ears
- slender nose
- dental caries
- delayed eruption of deciduous teeth
- malocclusion
- Absent/hypoplastic teeth
sensorineural hearing loss
ocular anomalies
- salt and pepper retinal pigmentation
- pigmentary retinopathy
- optic atrophy
- strabismus
- hyperopia
- corneal opacity
- decreased lacrimation
- nystagmus
- cataracts
cardiac arrhythmias
hypertension
hepatomegaly
splenomegaly
cryptorchidism
micropenis
proteinuria
renal failure
skeletal anomalies
- thickened calvarium
- kyphosis
- vertebral body abnormalities
- small, squared off pelvis
- hypoplastic iliac wings
- mild to moderate joint limitation
- sclerotic ivory phalangeal epiphyses
cutaneous anomalies
- precociously senile appearance
- photosensitivity (increased cellular sensitivity to UV light)
- scarring
- pigmentation
- cutaneous atrophy
- anhidrosis
- dry skin
- decreased subcutaneous adipose tissue
- thin, dry hair
nervous system anomalies
- mental retardation
- normal pressure hydrocephalus
- dementia
- basal ganglia calcifications
- patchy demyelination of subcortical white matter
- cerebral atrophy
- dysarthric speech
- dysmyelination
- gait disturbance
- ataxia
- tremor
- weakness
- peripheral neuropathy
- abnormal myelination in sural nerve biopsies
- CNS demyelination
- progressive spastic quadriparesis
- progressive neurological degeneration.
- severe developmental regression
- bilateral calcification of the globus pallidus
- global cerebral atrophy
irregular menstrual cycles
hypogonadism
Etiology
mutations in the CSA gene
mutations in the CSB gene. The CS complementation group B (CSB) protein is at the interface of transcription and DNA repair and is involved in transcription-coupled and global genome-DNA repair, as well as in general transcription.
XPB
XPD
XPG
The second human nucleotide excision repair disease is Cockayne syndrome (CS). CS patients are also sun sensitive but show a distinctive array of congenital neurological and skeletal abnormalities, including mental deficiency and dwarfism (Nance and Berry, 1992). Cells from these patients are very sensitive to UV irradiation and have a defective RNA synthesis after UV. Mutations in CSA and CSB genes are responsible for the classical CS. However, the symptoms of the disease are also seen in rare XP patients belonging to the groups B, D and G (Vermeulen et al., 1993).
Pathogeny
The real function of CSA and CSB genes are not known, yet. However, there are some findings that associate these genes with the preferential repair of transcribed genes.
Cells from patients with CS are defective in preferential repair (Friedberg, 1996) and the sequence of CSB gene reveal some similarity to the Escherichia coli Mfd gene, a transcription repair coupling factor (TRFC) (Troelstra et al., 1992).
The homology in the ATPase/helicase motif is high and this motif is essential for the function of the Mfd gene. These observations have led to the suggestion that CSB protein, complexed with the CSA protein, may function as TRFC in human cells.
The following model is proposed for the action of these proteins: the CSB-CSA heterodimer recognizes the RNA polymerase II stalled at a lesion, backs off this polymerase without dissociating the ternary complex, and then the heterodimer recruits XPA and TFIIH to the lesion site, necessary for the repair of transcribed genes.
See also
Cockayne symdromes
- Cockayne syndrome type I (CKN1)
- Cockayne syndrome type II (CKN2)
References
Cleaver JE. Cancer in xeroderma pigmentosum and related disorders of DNA repair. Nat Rev Cancer. 2005 Jul;5(7):564-73. PMID: 16069818
Licht CL, Stevnsner T, Bohr VA. Cockayne syndrome group B cellular and biochemical functions. Am J Hum Genet. 2003 Dec;73(6):1217-39. PMID: 14639525