Adult-Onset Neurological Degeneration in a Patient with Cockayne Syndrome and a Null Mutation in the CSB Gene

Hashimoto, Satoru; Suga, Tomohiro; Kudo, Erina; Ihn, Hironobu; Uchino, Makoto; Tateishi, Seiichiro

doi:10.1038/sj.jid.5701210

Cited by 25 publications

(29 citation statements)

References 12 publications

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“…Moreover, a mild form of CS with late onset of symptoms has been described in a 47-year-old individual with a mutation that results in a stop codon at amino acid position 82. No CSB polypeptide could be detected in extracts from this individual's cells (11), a situation reminiscent of that described by Horibata et al (9), mentioned above. They raised the possibility that UV S S patients with mutations that result in very short, undetectable CSB protein might develop CS-like symptoms as they age (11).…”

supporting

confidence: 53%

A UV-sensitive syndrome patient with a specific CSA mutation reveals separable roles for CSA in response to UV and oxidative DNA damage

Nardò

Oneda

Spivak

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

114

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UV-sensitive syndrome (UV S S) is a recently-identified autosomal recessive disorder characterized by mild cutaneous symptoms and defective transcription-coupled repair (TC-NER), the subpathway of nucleotide excision repair (NER) that rapidly removes damage that can block progression of the transcription machinery in actively-transcribed regions of DNA. Cockayne syndrome (CS) is another genetic disorder with sun sensitivity and defective TC-NER, caused by mutations in the CSA or CSB genes. The clinical hallmarks of CS include neurological/developmental abnormalities and premature aging. UV S S is genetically heterogeneous, in that it appears in individuals with mutations in CSB or in a still-unidentified gene. We report the identification of a UV S S patient (UV S S1VI) with a novel mutation in the CSA gene (p.trp361cys) that confers hypersensitivity to UV light, but not to inducers of oxidative damage that are notably cytotoxic in cells from CS patients. The defect in UV S S1VI cells is corrected by expression of the WT CSA gene. Expression of the p.trp361cys-mutated CSA cDNA increases the resistance of cells from a CS-A patient to oxidative stress, but does not correct their UV hypersensitivity. These findings imply that some mutations in the CSA gene may interfere with the TC-NERdependent removal of UV-induced damage without affecting its role in the oxidative stress response. The differential sensitivity toward oxidative stress might explain the difference between the range and severity of symptoms in CS and the mild manifestations in UV s S patients that are limited to skin photosensitivity without precocious aging or neurodegeneration.

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supporting

confidence: 53%

A UV-sensitive syndrome patient with a specific CSA mutation reveals separable roles for CSA in response to UV and oxidative DNA damage

Nardò

Oneda

Spivak

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

114

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“…Laugel et al [85] recently showed that complete absence of CSB expression due to a promoter mutation leads to the classic features of CS. Also, Hashimoto et al [86] reported a Japanese patient, KPSX6 with late-onset CS neurologic disease. Strikingly, the mutation in KPSX6 is a premature termination near the N-terminus of CSB (codon 82), similar to that in 1KOSV (codon 77).…”

Section: Does the Complete Absence Of Csb Results In Cs Neurologic Dismentioning

confidence: 99%

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

2008

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The classic model for neurodegeneration due to mutations in DNA repair genes holds that DNA damage accumulates in the absence of repair, resulting in the death of neurons. This model was originally put forth to explain the dramatic loss of neurons observed in patients with xeroderma pigmentosum neurologic disease, and is likely to be valid for other neurode-generative diseases due to mutations in DNA repair genes. However, in trichiothiodystrophy (TTD), Aicardi-Goutières syndrome (AGS), and Cockayne syndrome (CS), abnormal myelin is the most prominent neuropathological feature. Myelin is synthesized by specific types of glial cells called oligodendrocytes. In this review, we focus on new studies that illustrate two disease mechanisms for myelin defects resulting from mutations in DNA repair genes, both of which are fundamentally different than the classic model described above. First, studies using the TTD mouse model indicate that TFIIH acts as a co-activator for thyroid hormone-dependent gene expression in the brain, and that a causative XPD mutation in TTD results in reduction of this co-activator function and a dysregulation of myelin-related gene expression. Second, in AGS, which is caused by mutations in either TREX1 or RNASEH2, recent evidence indicates that failure to degrade nucleic acids produced during S-phase triggers activation of the innate immune system, resulting in myelin defects and calcification of the brain. Strikingly, both myelin defects and brain calcification are both prominent features of CS neurologic disease. The similar neuropathology in CS and AGS seems unlikely to be due to the loss of a common DNA repair function, and based on the evidence in the literature, we propose that vascular abnormalities may be part of the mechanism that is common to both diseases. In summary, while the classic DNA damage accumulation model is applicable to the neuronal death due to defective DNA repair, the myelination defects and brain calcification seem to be better explained by quite different mechanisms. We discuss the implications of these different disease mechanisms for the rational development of treatments and therapies.

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“…As a result, many in this group are not suspected of having CS until adulthood and/or after they have visited many physician specialists-if they are diagnosed at all [Inoue et al, 1997;Rapin et al, 2006]. The literature describes mild CS/CS in adults as atypical or rare [Kennedy et al, 1980;Nance and Berry, 1992;Rapin et al, 2006;Morris et al, 2007;Hashimoto et al, 2008], yet the even distribution of severity group membership among survey subjects here (Table I) implies that mild CS may be under-diagnosed.…”

Section: Mild Csmentioning

confidence: 94%

“…Males (n ¼ 11), averaged 131 cm (50th centile for age 8 1 / 2 years) [Smits et al, 1982;Fryns et al, 1991;Nance and Berry, 1992;Miyauchi et al, 1994;Ellaway et al, 2000;Komatsu et al, 2004]. Females (n ¼ 8) averaged 127 cm (50th centile for age 8 years) [Brumback et al, 1978;Kennedy et al, 1980;Miyauchi et al, 1994;Inoue et al, 1997;Lahiri and Davies, 2003;Hashimoto et al, 2008].…”

Section: Fig 2 Patient 2 Very Mildmentioning

confidence: 98%

“…Information in this article will help clinicians make informal subdivisions, such as ''very severe'' or ''very mild.'' The first three groups (severe, moderate, and mild) may be thought of as juvenile-onset CS, as a further way of contrasting them with adult-onset CS.People with adult-onset CS may be photosensitive throughout their lives and may also show one or more other symptoms associated with CS, such as very short stature [Hashimoto et al, 2008]. However, based on the scant information available at this time, this group is distinguishable from the juvenile-onset group by virtue of not experiencing other CS-type health problems until adulthood.…”

mentioning

confidence: 96%

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A comprehensive description of the severity groups in Cockayne syndrome

Natale¹

2011

American J of Med Genetics Pt A

102

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Cockayne syndrome (CS) is a rare degenerative disorder with a common set of symptoms but a very wide variation in phenotype. The variation is sufficiently wide that CS patients have traditionally been described in three different severity groups. Unfortunately, there is no single source for information about the different severity groups. This problem can complicate not only diagnosis, but accurate prognosis as well. The goal of this study was to describe the phenotypic variation in CS as completely as possible. This article provides extensive descriptions of traits common to each group and their degree of severity in each group. Forty-five people with CS were surveyed and information from the published literature was used to increase the sample sizes for calculations. This study provides new information, including statistical data for each of the three severity groups (mean age at death, average head circumference, and average length or stature). The study includes cerebro-oculo-facial syndrome (COFS) as a severe form of CS, based on results of recently published genetic studies performed by other authors. This study proposes revised names for CS severity groups: severe, moderate, and mild. The groups were formerly called Type II/early onset CS, Type I/classical CS, and Type III/atypical/mild/late-onset CS, respectively. A fourth newly documented group, UV sensitivity only/adult onset, is also described. Average ages of death were calculated as 5.0 years (severe), 16.1 years (moderate), and 30.3 years (mild).

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Adult-Onset Neurological Degeneration in a Patient with Cockayne Syndrome and a Null Mutation in the CSB Gene

Cited by 25 publications

References 12 publications

A UV-sensitive syndrome patient with a specific CSA mutation reveals separable roles for CSA in response to UV and oxidative DNA damage

A UV-sensitive syndrome patient with a specific CSA mutation reveals separable roles for CSA in response to UV and oxidative DNA damage

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

A comprehensive description of the severity groups in Cockayne syndrome

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