Functional and clinical relevance of novel mutations in a large cohort of patients with Cockayne syndrome

Calmels, Nadège; Botta, Elena; Nan, Jun; Fawcett, Heather; Nardò, Tiziana; Nakazawa, Yuka; Lanzafame, Manuela; Moriwaki, Shinichi; Sugita, Katsuo; Kubota, Masaya; Obringer, Cathy; Spitz, Marie‐Aude; Stefanini, Miria; Laugel, Vincent; Orioli, Donata; Ogi, Tomoo; Lehmann, Alan R.

doi:10.1136/jmedgenet-2017-104877

Cited by 63 publications

(69 citation statements)

References 57 publications

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“…Primary keratinocytes from patients with CS-A display premature senescence features and high levels of oxidative DNA damage Primary keratinocytes were established from skin biopsies of three patients with CS-A affected by the classical form (CSI). They are homozygous (CS15PV) or compound heterozygous (CS6PV and CS16PV) for distinct CSA mutations resulting in truncated products (Calmels et al, 2018) (Supplementary Table S1 online). The transition from keratinocyte stem to transient amplifying cells, named clonal evolution, is a unidirectional process that occurs during skin aging (Dellambra et al, 2000;Maurelli et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

Cockayne Syndrome Type A Protein Protects Primary Human Keratinocytes from Senescence

Cordisco

Tinaburri

Teson

et al. 2019

Journal of Investigative Dermatology

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Defects in Cockayne syndrome type A (CSA), a gene involved in nucleotide excision repair, cause an autosomal recessive syndrome characterized by growth failure, progressive neurological dysfunction, premature aging, and skin photosensitivity and atrophy. Beyond its role in DNA repair, the CSA protein has additional functions in transcription and oxidative stress response, which are not yet fully elucidated. Here, we investigated the role of CSA protein in primary human keratinocyte senescence. Primary keratinocytes from three patients with CS-A displayed premature aging features, namely premature clonal conversion, high steady-state levels of reactive oxygen species and 8-OH-hydroxyguanine, and senescence-associated secretory phenotype. Stable transduction of CS-A keratinocytes with the wild-type CSA gene restored the normal cellular sensitivity to UV irradiation and normal 8-OH-hydroxyguanine levels. Gene correction was also characterized by proper restoration of keratinocyte clonogenic capacity and expression of clonal conversion key regulators (p16 and p63), decreased NF-kB activity and, in turn, the expression of its targets (NOX1 and MnSOD), and the secretion of senescence-associated secretory phenotype mediators. Overall, the CSA protein plays an important role in protecting cells from senescence by facilitating DNA damage processing, maintaining physiological redox status and keratinocyte clonogenic ability, and reducing the senescence-associated secretory phenotypemediated inflammatory phenotype.

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Section: Resultsmentioning

confidence: 99%

Cockayne Syndrome Type A Protein Protects Primary Human Keratinocytes from Senescence

Cordisco

Tinaburri

Teson

et al. 2019

Journal of Investigative Dermatology

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“…It is also increasingly clear that the most severe presentations of all NER-related disorders do not meet the classical diagnostic criteria and are probably the most difficult to recognize. Furthermore, when the diagnosis can finally be reached, the prognosis of these conditions is still difficult to establish: the age of onset is grossly correlated with the mean life expectancy but there are numerous exceptions 22,23 and there have been contradictory reports on the prognostic factors that could be used in the early stages to provide reliable information to families and caregivers. 11,21 In this article, we will describe the phenotype and natural history of the most severe NER-related patients who have been reported to present with their first symptoms during the foetal, neonatal and early infancy period (before or at 12 months), based on a large review of the literature and on additional unreported patients from our own cohort.…”

Section: Introductionmentioning

confidence: 99%

Early‐onset nucleotide excision repair disorders with neurological impairment: Clues for early diagnosis and prognostic counseling

et al. 2020

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Nucleotide excision repair associated diseases comprise overlapping phenotypes and a wide range of outcomes. The early stages still remain under‐investigated and underdiagnosed, even although an early recognition of the first symptoms is of utmost importance for appropriate care and genetic counseling. We systematically collected clinical and molecular data from the literature and from newly diagnosed NER patients with neurological impairment, presenting clinical symptoms before the age of 12 months, including foetal cases. One hundred and eighty‐five patients were included, 13 with specific symptoms during foetal life. Arthrogryposis, microcephaly, cataracts, and skin anomalies are the most frequently reported signs in early subtypes. Non ERCC6/CSB or ERCC8/CSA genes are overrepresented compared to later onset cohorts: 19% patients of this cohort presented variants in ERCC1, ERCC2/XPD, ERCC3/XPB or ERCC5/XPG. ERCC5/XPG is even the most frequently involved gene in foetal cases (10/13 cases, [4/7 families]). In this cohort, the mutated gene, the age of onset, the type of disease, severe global developmental delay, IUGR and skin anomalies were associated with earlier death. This large survey focuses on specific symptoms that should attract the attention of clinicians towards early‐onset NER diagnosis in foetal and neonatal period, without waiting for the completeness of classical criteria.

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“…NER‐associated diseases include Xeroderma Pigmentosum, Cockayne Syndrome, and Trichothiodystrophy, the most severe end of spectrum being represented by COFS (Laugel et al, ). Besides participating to NER, these pleiotropic proteins are also involved in other DNA‐associated processes such as transcription, chromatin remodeling and DNA oxidative damage repair, as well as in mitochondrial DNA metabolism (Calmels et al, ; Ferri, Orioli, & Botta, ). While pediatric phenotype is commonly described by the literature, only one publication reports the fetal presentation of COFS syndrome in a Pakistani kindred of five fetuses harboring the same homozygous pathogenic variant in the ERCC5/XPG gene (Drury et al, ).…”

Section: Introductionmentioning

confidence: 99%

Prenatal diagnosis of cerebro‐oculo‐facio‐skeletal syndrome: Report of three fetuses and review of the literature

Quyen

Calmels

Bonnière

et al. 2020

American J of Med Genetics Pt A

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Cerebro-oculo-facio-skeletal syndrome (COFS) is a rare autosomal recessive neurodegenerative disease belonging to the family of DNA repair disorders, characterized by microcephaly, congenital cataracts, facial dysmorphism and arthrogryposis. Here, we describe the detailed morphological and microscopic phenotype of three fetuses from two families harboring ERCC5/XPG likely pathogenic variants, and review the five previously reported fetal cases. In addition to the classical features of COFS, the fetuses display thymus hyperplasia, splenomegaly and increased hematopoiesis.Microencephaly is present in the three fetuses with delayed development of the gyri, but normal microscopic anatomy at the supratentorial level. Microscopic anomalies reminiscent of pontocerebellar hypoplasia are present at the infratentorial level. In conclusion, COFS syndrome should be considered in fetuses when intrauterine growth retardation is associated with microcephaly, arthrogryposis and ocular anomalies. Further studies are needed to better understand XPG functions during human development. K E Y W O R D S COFS, ERCC5, fetal pathology, neuropathology, XPG

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Functional and clinical relevance of novel mutations in a large cohort of patients with Cockayne syndrome

Cited by 63 publications

References 57 publications

Cockayne Syndrome Type A Protein Protects Primary Human Keratinocytes from Senescence

Cockayne Syndrome Type A Protein Protects Primary Human Keratinocytes from Senescence

Early‐onset nucleotide excision repair disorders with neurological impairment: Clues for early diagnosis and prognostic counseling

Prenatal diagnosis of cerebro‐oculo‐facio‐skeletal syndrome: Report of three fetuses and review of the literature

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