A summary of mutations in the UV‐sensitive disorders: Xeroderma pigmentosum,Cockayne syndrome,and trichothiodystrophy

The human diseases xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy are caused by mutations in a set of interacting gene products, which carry out the process of nucleotide excision repair. The majority of the genes have now been cloned and many mutations in the genes identified. The relationships between the distribution of mutations in the genes and the clinical presentations can be used for diagnosis and for understanding the functions and the modes of interaction among the gene products. The summary presented here represents currently known mutations that can be used as the basis for future studies of the structure, function, and biochemical properties of the proteins involved in this set of complex disorders, and may allow determination of the critical sites for mutations leading to different clinical manifestations. The summary indicates where more data are needed for some complementation groups that have few reported mutations, and for the groups for which the gene(s) are not yet cloned. These include the Xeroderma pigmentosum (XP) variant, the trichothiodystrophy group A (TTDA), and ultraviolet sensitive syndrome (UV^s) groups. We also recommend that the XP‐group E should be defined explicitly through molecular terms, because assignment by complementation in culture has been difficult. XP‐E by this definition contains only those cell lines and patients that have mutations in the small subunit, DDB2, of a damage‐specific DNA binding protein. Hum Mutat 14:9–22, 1999. © 1999 Wiley‐Liss, Inc.     

Xeroderma pigmentosum exhibiting neurological disorders and systemic lupus erythematosus

A patient is described who has a unique combination of symptoms that correspond with two sun-sensitive conditions: xeroderma pigmentosum (XP) and systemic lupus erythematows (SLE). Both of these conditions have been suggested as being associated with a defect in DNA repair, but this is only clearly established for XP. The patient described is the only known case among U.S. blacks, thus far, although African black cases are known. Her DNA repair levels are 20–30% of normal, within the range found for many XP cell cultures and consistent with her assignment to group C by other investigators. Unusual for group C cases, however, are the neurological disorders, some of which correspond to those found in the de Sanctis Cacchione form of XP, which is commonly assigned to group A. Whether the associated SLE is a consequence of some special aspect of this particular XP condition or whether it is fortuitous cannot be resolved at present.     

Intermittent hair loss in a child with PIBI(D)S syndrome and trichothiodystrophy with defective DNA repair-xeroderma pigmentosum group D

We describe a girl with photosensitivity (P), ichthyosis (I), brittle hair (B), impaired intelligence (I), possibly decreased fertility (D), and short stature (S). The clinical findings fit into the PIBI(D)S syndrome and trichothiodystrophy. A remarkable and probably unique observation for this disorder was the intermittent character of the scalp hair loss during infectious periods in this patient. Easy suntanning suggested photosensitivity and prompted DNA repair studies which demonstrated reduced UV-induced DNA repair synthesis. Subsequent studies have assigned this patient to xeroderma pigmentosum group D and suggested a specific deficiency of 6–4 photoproduct repair. An unaffected child was diagnosed in the next pregnancy of the mother. © 1994 Wiley-Liss, Inc.     

Pellagra‐like condition is xeroderma pigmentosum/Cockayne syndrome complex and niacin confers clinical benefit

An extremely rare pellagra‐like condition has been described, which was partially responsive to niacin and associated with a multisystem involvement. The condition was proposed to represent a novel autosomal recessive entity but the underlying mutation remained unknown for almost three decades. The objective of this study was to identify the causal mutation in the pellagra‐like condition and investigate the mechanism by which niacin confers clinical benefit. Autozygosity mapping and exome sequencing were used to identify the causal mutation, and comet assay on patient fibroblasts before and after niacin treatment to assess its effect on DNA damage. We identified a single disease locus that harbors a novel mutation in ERCC5, thus confirming that the condition is in fact xeroderma pigmentosum/Cockayne syndrome (XP/CS) complex. Importantly, we also show that the previously described dermatological response to niacin is consistent with a dramatic protective effect against ultraviolet‐induced DNA damage in patient fibroblasts conferred by niacin treatment. Our findings show the power of exome sequencing in reassigning previously described novel clinical entities, and suggest a mechanism for the dermatological response to niacin in patients with XP/CS complex. This raises interesting possibilities about the potential therapeutic use of niacin in XP.     

Ataxia telangiectasia syndrome: moonlighting ATM

Introduction: Ataxia-telangiectasia (A-T) a multisystem disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility and radiation sensitivity. Identification of the gene defective in this syndrome, ataxia-telangiectasia mutated gene (ATM), and further characterization of the disorder together with a greater insight into the function of the ATM protein have expanded our knowledge about the molecular pathogenesis of this disease.

Area covered: In this review, we have attempted to summarize the different roles of ATM signaling that have provided new insights into the diverse clinical phenotypes exhibited by A-T patients.

Expert commentary: ATM, in addition to DNA repair response, is involved in many cytoplasmic roles that explain diverse phenotypes of A-T patients. It seems accumulation of DNA damage, persistent DNA damage response signaling, and chronic oxidative stress are the main players in the pathogenesis of this disease.     

Cockayne syndrome: Review of 140 cases

To define diagnostic criteria for Cockayne Syndrome (CS) and to identify in detail the complications of the condition, a comprehensive review of 140 cases of CS was performed. Criteria required for the diagnosis include poor growth and neurologic abnormality; other very common manifestations include sensorineural hearing loss, cataracts, pigmentary retinopathy, cutaneous photosensitivity, and dental caries. The mean age of death in reported cases is 12³/12 years, though a few affected individuals have lived into their late teens and twenties. Prenatal growth failure, congenital structural eye anomalies, severe neurologic dysfunction from birth, and the presence of cataracts within the first 3 years of life are predictors of severe disease and early death. In contrast with other disorders of chromosome or DNA repair, cancer has never been reported in a classical CS patient, and there appears to be no predisposition to infectious complications. The wide spectrum of symptoms and severity of the disease suggest that biochemical and genetic heterogeneity exist. CS is an uncommon but devastating genetic condition which will be better understood as the biochemical interrelationships between DNA replication and repair, and between growth, homeostasis, and oncogenesis are unraveled.     

Characterisation of novel mutations in Cockayne syndrome type A and xeroderma pigmentosum group C subjects

We report that a subject with Cockayne syndrome type A (CS3BE) was a compound heterozygote for mutations in CKN1, the gene encoding the CSA protein (MIM 216400). CS3BE displayed a novel missense mutation (A160V) and a previously described nonsense mutation (E13X). Although residing between the second and third WD-40 repeats characteristic of the CSA protein, A160 is completely conserved in all species that possess a CKN1 homologue. We also describe a mutation in a previously uncharacterised xeroderma pigmentosum group C subject (XP8CA) in the XPC gene (MIM 278720). XP8CA was homozygous for a 2 bp TG deletion in codon 547 resulting in premature termination at codon 572. Immunoblotting of XP8CA extracts confirmed the absence of full-length XPC protein that was present in unaffected cell lines.     

Exome sequencing revealed a novel deletion in the ERCC8 gene in an Iranian family with Cockayne syndrome

Cockayne syndrome (CS) is one the rare DNA‐repair deficiency disorders with autosomal recessive inheritance. Failure to thrive and microcephaly are the major criteria of diagnosis. Owing to genetic heterogeneity of CS, whole exome sequencing is promising way to determine the genetic basis of the disease. Here, we present c.1053delT in ERCC8 gene in an Iranian family with symptom of CS using whole exome sequencing. The deletion was novel and was not previously reported elsewhere.     

<Emphasis Type="Italic">CKN1</Emphasis> (MIM 216400): mutations in Cockayne syndrome type A and a new common polymorphism

We found that a subject with Cockayne syndrome type A was a compound heterozygote for two new mutations in CKN1 (MIM 216400): a missense mutation (A205P) and a nonsense (E13X) mutation. We also identified and characterized a new common single nucleotide polymorphism in CKN1 in five groups.