A kindred with Cockayne syndrome caused by multiple splicing variants of the <i>CSA</i> gene

A, Komatsu; Suzuki, Satoru; Inagaki, Takeshi; Yamashita, Koh; Hashizume, Kiyoshi

doi:10.1002/ajmg.a.30087

Cited by 21 publications

(21 citation statements)

References 12 publications

(15 reference statements)

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“…To the previously reported splicing mutation in CKN1 (Komatsu et al 2004) we now add IVS4 + 1-G > A and IVS7-1G > A. Previous findings of splicing mutations in CS-A patients, taken together with our finding of homozygosity for the altered splice donor and acceptor sequences in our cohort, indicates that abnormal splicing is an important subset of the molecular etiologies of this disorder.…”

Section: Discussionmentioning

confidence: 69%

Cockayne syndrome type A: novel mutations in eight typical patients

et al. 2006

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Cockayne syndrome is a rare autosomal recessive neurodegenerative disorder. It is considered to be a heterogeneous condition based on complementation in cell fusion studies, with two major forms, namely CS-A and CS-B. CKN1 is the gene responsible for CS-A, whose mutations disrupt the transcriptioncoupled repair system of the actively transcribed DNA. Mutation analysis of the CKN1 gene in eight typical CS-A Brazilian patients from six families showed a gene alteration in all of them. We found a total of five novel mutations that were absent from healthy control subjects. Six affected subjects were simple homozygotes and two affected siblings were each compound heterozygotes. While the findings extend the range of mutations in CS-A, there is no obvious genotypephenotype correlation across the mutational spectrum.

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Section: Discussionmentioning

confidence: 69%

Cockayne syndrome type A: novel mutations in eight typical patients

et al. 2006

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“…The main neuropathologic features of cases 3, 23 6,7,25,26 9, 28 and 14 31 were severe loss of both central and peripheral myelin, cerebellar atrophy, and basal ganglia calcification without evidence of gross brain malformation or major architectural alteration. The basis for thinning of the neocortex remains to be investigated.…”

Section: Neuropathologymentioning

confidence: 96%

“…Egly (quoted in Bohr et al 35 ) reported that mutation of XPD indirectly lowers the expression of reporter genes regulated by vitamin D, retinoic acid, and estrogen. It is also not clear whether the prominent joint contractures in cases 3, 23 5, 6 6, and 13 were caused by spasticity, neuropathic weakness, limited mobility, osteoporosis with degenerative changes in the spine and articulations, or all of them. Cases 5 6 and 6 were bald in their early thirties, and thinning of the hair is mentioned in many of the reports.…”

Section: Premature Aging and Cardiovascular Diseasementioning

confidence: 99%

“…Genetic studies have defined two Cockayne syndrome complementation groups: complementation group A owing to mutations of the CSA (CKN1, ERCC8) gene on chromosome 5q12, 5,6 which accounts for 20% of Cockayne cases, 7 and complementation group B, owing to mutations of the CSB (ERCC6) gene on chromosome 10q11, [8][9][10] which accounts for 80% of cases and at least four other clinically distinct disorders as well. 11 Exceptionally, mutations of genes for xeroderma pigmentosum (XPB, XPD, and XPG) result in a Cockayne syndrome phenotype (xeroderma pigmentosum-Cockayne syndrome complex), 12 although, thus far, only xeroderma pigmentosum B-Cockayne syndrome complex and xeroderma pigmentosum G-Cockayne syndrome complex have been associated with survival to adulthood.…”

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confidence: 99%

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Cockayne Syndrome in Adults: Review With Clinical and Pathologic Study of a New Case

et al. 2006

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Cockayne syndrome and xeroderma pigmentosum-Cockayne syndrome complex are rare autosomal recessive disorders with poorly understood biology. They are characterized by profound postnatal brain and somatic growth failure and by degeneration of multiple tissues resulting in cachexia, dementia, and premature aging. They result in premature death, usually in childhood, exceptionally in adults. This study compares the clinical course and pathology of a man with Cockayne syndrome group A who died at age 31½ years with 15 adequately documented other adults with Cockayne syndrome and 5 with xeroderma pigmentosum-Cockayne syndrome complex. Slowing of head and somatic growth was apparent before age 2 years, mental retardation and slowly progressive spasticity at 4 years, ataxia and hearing loss at 9 years, visual impairment at 14 years, typical Cockayne facies at 17 years, and cachexia and dementia in his twenties, with a retained outgoing personality. He experienced several transient right and left hemipareses and two episodes of status epilepticus following falls. Neuropathology disclosed profound microencephaly, bilateral old subdural hematomas, white-matter atrophy, tigroid leukodystrophy with string vessels, oligodendrocyte proliferation, bizarre reactive astrocytes, multifocal dystrophic calcification that was most marked in the basal ganglia, advanced atherosclerosis, mixed demyelinating and axonal neuropathy, and neurogenic muscular atrophy. Cellular degeneration of the organ of Corti, spiral and vestibular ganglia, and all chambers of the eye was severe. Rarely, and for unexplained reasons, in some patients with Cockayne syndrome the course is slower than usual, resulting in survival into adulthood. The profound dwarfing, failure of brain growth, cachexia, selectivity of tissue degeneration, and poor correlation between genotypes and phenotypes are not understood. Deficient repair of DNA can increase vulnerability to oxidative stress and play a role in the premature aging, but why patients with mutations in xeroderma pigmentosum genes present with the Cockayne syndrome phenotype is still not known.

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“…Similarly, the presence of multiple abnormal splicing variants in the CSA gene has been previously reported in a patient with Cockayne syndrome, although the causative mutation was not identified in that case. 13 A number of diseases associated with mutations that affect pre-mRNA splicing have been described before, 14,15 including intronic mutations leading to inclusion of cryptic exons. 8,16 We conclude that the analysis of RNA by RT-PCR and sequencing is an important step to characterize the precise impact of detected splice variants, and in some cases to detect deep intronic mutation.…”

Section: Discussionmentioning

confidence: 99%

Myotubular myopathy caused by multiple abnormal splicing variants in the MTM1 RNA in a patient with a mild phenotype

et al. 2012

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Mutations impacting on the splicing of pre-mRNA are one important cause of genetically inherited diseases. However, detection of splice mutations, that are mainly due to intronic variations, and characterization of their effects are usually not performed as a first approach during genetic diagnosis. X-linked recessive myotubular myopathy is a severe congenital myopathy due to mutations in the MTM1 gene encoding myotubularin. Here, we screened a male patient showing an unusually mild phenotype without respiratory distress by western blot with specific myotubularin antibodies and detected a strong reduction of the protein level.The disease was subsequently linked to a hemizygous point mutation affecting the acceptor splice site of exon 8 of MTM1, proven by protein, transcript and genomic DNA analysis. Detailed analysis of the MTM1 mRNA by RT-PCR, sequencing and quantitative PCR revealed multiple abnormal transcripts with retention of a truncated exon 8, and neighboring exons 7 and 9 but exclusion of several other exons, suggesting a complex effect of this mutation on the splicing of non-adjacent exons. We conclude that the analysis of RNA by RT-PCR and sequencing is an important step to characterize the precise impact of detected splice variants. It is likely that complex splice aberrations due to a single mutation also account for unsolved cases in other diseases.

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A kindred with Cockayne syndrome caused by multiple splicing variants of the CSA gene

Cited by 21 publications

References 12 publications

Cockayne syndrome type A: novel mutations in eight typical patients

Cockayne syndrome type A: novel mutations in eight typical patients

Cockayne Syndrome in Adults: Review With Clinical and Pathologic Study of a New Case

Myotubular myopathy caused by multiple abnormal splicing variants in the MTM1 RNA in a patient with a mild phenotype

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