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Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2022

Open Access 01-12-2022 | Cockayne Syndrome | Research

Heterogeneous clinical features in Cockayne syndrome patients and siblings carrying the same CSA mutations

Authors: Asma Chikhaoui, Ichraf Kraoua, Nadège Calmels, Sami Bouchoucha, Cathy Obringer, Khouloud Zayoud, Benjamin Montagne, Ridha M’rad, Sonia Abdelhak, Vincent Laugel, Miria Ricchetti, Ilhem Turki, Houda Yacoub-Youssef

Published in: Orphanet Journal of Rare Diseases | Issue 1/2022

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Abstract

Background

Cockayne syndrome (CS) is a rare autosomal recessive disorder caused by mutations in ERCC6/CSB or ERCC8/CSA that participate in the transcription-coupled nucleotide excision repair (TC-NER) of UV-induced DNA damage. CS patients display a large heterogeneity of clinical symptoms and severities, the reason of which is not fully understood, and that cannot be anticipated in the diagnostic phase. In addition, little data is available for affected siblings, and this disease is largely undiagnosed in North Africa.

Methods

We report here the clinical description as well as genetic and functional characterization of eight Tunisian CS patients, including siblings. These patients, who belonged to six unrelated families, underwent complete clinical examination and biochemical analyses. Sanger sequencing was performed for the recurrent mutation in five families, and targeted gene sequencing was done for one patient of the sixth family. We also performed Recovery RNA Synthesis (RRS) to confirm the functional impairment of DNA repair in patient-derived fibroblasts.

Results

Six out of eight patients carried a homozygous indel mutation (c.598_600delinsAA) in exon 7 of ERCC8, and displayed a variable clinical spectrum including between siblings sharing the same mutation. The other two patients were siblings who carried a homozygous splice-site variant in ERCC8 (c.843+1G>C). This last pair presented more severe clinical manifestations, which are rarely associated with CSA mutations, leading to gastrostomy and hepatic damage. Impaired TC-NER was confirmed by RRS in six tested patients.

Conclusions

This study provides the first deep characterization of case series of CS patients carrying CSA mutations in North Africa. These mutations have been described only in this region and in the Middle-East. We also provide the largest characterization of multiple unrelated patients, as well as siblings, carrying the same mutation, providing a framework for dissecting elusive genotype–phenotype correlations in CS.
Appendix
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Literature
1.
2.
3.
4.
Calmels N, Botta E, Jia N, Fawcett H, Nardo T, Nakazawa Y, et al. Functional and clinical relevance of novel mutations in a large cohort of patients with Cockayne syndrome. J Med Genet. 2018;55(5):329–43.PubMedCrossRef
5.
Wilson BT, Stark Z, Sutton RE, Danda S, Ekbote AV, Elsayed SM, et al. The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care. Genet Med. 2016;18(5):483–93.PubMedCrossRef
6.
Kleijer WJ, Laugel V, Berneburg M, Nardo T, Fawcett H, Gratchev A, et al. Incidence of DNA repair deficiency disorders in western Europe: Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. DNA Repair. 2008;7(5):744–50.PubMedCrossRef
7.
Zghal M, El-Fekih N, Fazaa B, Fredj M, Zhioua R, Mokhtar I, et al. Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 49 Tunisian cases. Tunis Med. 2005;83(12):760–3.PubMed
8.
9.
Vessoni AT, Guerra CCC, Kajitani GS, Nascimento LLS, Garcia CCM. Cockayne syndrome: the many challenges and approaches to understand a multifaceted disease. Genet Mol Biol. 2020;43(1):e20190085.PubMedPubMedCentralCrossRef
10.
Zayoud K, Kraoua I, Chikhaoui A, Calmels N, Bouchoucha S, Obringer C, et al. Identification and characterization of a novel recurrent ERCC6 variant in patients with a severe form of Cockayne syndrome B. Genes. 2021;12(12):1922.PubMedPubMedCentralCrossRef
11.
12.
Groisman R, Polanowska J, Kuraoka I, Sawada J-I, Saijo M, Drapkin R, et al. The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage. Cell. 2003;113(3):357–67.PubMedCrossRef
13.
Fischer ES, Scrima A, Bohm K, Matsumoto S, Lingaraju GM, Faty M, et al. The molecular basis of CRL4DDB2/CSA ubiquitin ligase architecture, targeting, and activation. Cell. 2011;147(5):1024–39.PubMedCrossRef
14.
Laugel V, Dalloz C, Durand M, Sauvanaud F, Kristensen U, Vincent MC, et al. Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome. Hum Mutat. 2010;31(2):113–26.PubMedCrossRef
15.
Blin-Rochemaure N, Allani-Essid N, Carlier R, Laugel V, Quijano-Roy S. The place of neuropathy in the early diagnosis of Cockayne syndrome: report on two siblings. Arch Pediatr. 2017;24(4):353–9.PubMedCrossRef
16.
Chebly A, Corbani S, Abou Ghoch J, Mehawej C, Megarbane A, Chouery E. First molecular study in Lebanese patients with Cockayne syndrome and report of a novel mutation in ERCC8 gene. BMC Med Genet. 2018;19(1):161.PubMedPubMedCentralCrossRef
17.
Desmet F-O, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C. Human splicing finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res. 2009;37(9):e67-e.CrossRef
18.
Laugel V. Cockayne syndrome: the expanding clinical and mutational spectrum. Mech Ageing Dev. 2013;134(5–6):161–70.PubMedCrossRef
19.
Khayat M, Hardouf H, Zlotogora J, Shalev SA. High carriers frequency of an apparently ancient founder mutation p. Tyr322X in the ERCC8 gene responsible for Cockayne syndrome among Christian Arabs in Northern Israel. Am J Med Genet Part A. 2010;152(12):3091–4.CrossRef
20.
Ben Chehida A, Ghali N, Ben Abdelaziz R, Ben Moussa F, Tebib N. Renal involvement in 2 siblings with Cockayne syndrome. Iran J Kidney Dis. 2017;11(3):253–5.PubMed
21.
Tinsa F, Bellalah M, Brini I, Bousnina D, Lehmann A, Boussetta K, et al. Infantile onset of Cockayne syndrome without photosensitivity in a Tunisian girl. Tunis Med. 2009;87(12):877–9.PubMed
22.
Kaissi A, Safi H, Ghachem M, Hendaoui L, Chehida F. Congenital dysplastic hips, spinal column abnormalities, fractures and progressive neurological manifestations in Tunisian family with cockayne syndrome. Ann Afr Med. 2005;4(2):83–7.
23.
Saijo M. The role of Cockayne syndrome group A (CSA) protein in transcription-coupled nucleotide excision repair. Mech Ageing Dev. 2013;134(5–6):196–201.PubMedCrossRef
24.
Ivarsson K, Weijdegård B. Evaluation of the effects of DNase treatment on signal specificity in RT-PCR and in situ RT-PCR. Biotechniques. 1998;25(4):630–8.PubMedCrossRef
25.
Wang X, Huang Y, Yan M, Li J, Ding C, Jin H, et al. Molecular spectrum of excision repair cross-complementation group 8 gene defects in Chinese patients with Cockayne syndrome type A. Sci Rep. 2017;7(1):13686.PubMedPubMedCentralCrossRef
26.
Spitz MA, Severac F, Obringer C, Baer S, Le May N, Calmels N, et al. Diagnostic and severity scores for Cockayne syndrome. Orphanet J Rare Dis. 2021;16(1):63.PubMedPubMedCentralCrossRef
27.
Colella S, Nardo T, Mallery D, Borrone C, Ricci R, Ruffa G, et al. Alterations in the CSB gene in three Italian patients with the severe form of Cockayne syndrome (CS) but without clinical photosensitivity. Hum Mol Genet. 1999;8(5):935–41.PubMedCrossRef
28.
Sonmez FM, Celep F, Ugur SA. Severe form of Cockayne syndrome with varying clinical presentation and no photosensitivity in a family. J Child Neurol. 2006;21(4):333–7.PubMedCrossRef
29.
Schmickel R, Chu E, Trosko J, Chang C. Cockayne syndrome: a cellular sensitivity to ultraviolet light. Pediatrics. 1977;60(2):135–9.PubMedCrossRef
30.
Mayne LV, Lehmann AR. Failure of RNA synthesis to recover after UV irradiation: an early defect in cells from individuals with Cockayne’s syndrome and xeroderma pigmentosum. Can Res. 1982;42(4):1473–8.
31.
32.
Nardo T, Oneda R, Spivak G, Vaz B, Mortier L, Thomas P, et al. A UV-sensitive syndrome patient with a specific CSA mutation reveals separable roles for CSA in response to UV and oxidative DNA damage. Proc Natl Acad Sci USA. 2009;106(15):6209–14.PubMedPubMedCentralCrossRef
33.
34.
Chatre L, Biard DS, Sarasin A, Ricchetti M. Reversal of mitochondrial defects with CSB-dependent serine protease inhibitors in patient cells of the progeroid Cockayne syndrome. Proc Natl Acad Sci. 2015;112(22):E2910–9.PubMedPubMedCentralCrossRef
35.
D’Errico M, Pascucci B, Iorio E, Van Houten B, Dogliotti E. The role of CSA and CSB protein in the oxidative stress response. Mech Ageing Dev. 2013;134(5–6):261–9.PubMedCrossRef
36.
Okur MN, Lee J-H, Osmani W, Kimura R, Demarest TG, Croteau DL, et al. Cockayne syndrome group A and B proteins function in rRNA transcription through nucleolin regulation. Nucleic Acids Res. 2020;48(5):2473–85.PubMedPubMedCentralCrossRef
37.
Piekarowicz K, Machowska M, Dzianisava V, Rzepecki R. Hutchinson-Gilford progeria syndrome-current status and prospects for gene therapy treatment. Cells. 2019;8(2):88.PubMedCentralCrossRef
38.
Schalk A, Greff G, Drouot N, Obringer C, Dollfus H, Laugel V, et al. Deep intronic variation in splicing regulatory element of the ERCC8 gene associated with severe but long-term survival Cockayne syndrome. Eur J Hum Genet. 2018;26(4):527–36.PubMedPubMedCentralCrossRef
39.
Natale V. A comprehensive description of the severity groups in Cockayne syndrome. Am J Med Genet Part A. 2011;155a(5):1081–95.PubMedCrossRef
40.
Karikkineth AC, Scheibye-Knudsen M, Fivenson E, Croteau DL, Bohr VA. Cockayne syndrome: clinical features, model systems and pathways. Ageing Res Rev. 2017;33:3–17.PubMedCrossRef
41.
Blin-Rochemaure N, Allani-Essid N, Carlier R, Laugel V, Quijano-Roy S. Place de la neuropathie dans le diagnostic précoce du syndrome de Cockayne : à propos de deux cas dans une fratrie. Arch Pediatr. 2017;24(4):353–9.PubMedCrossRef
42.
Ben Halim N, Nagara M, Regnault B, Hsouna S, Lasram K, Kefi R, et al. Estimation of recent and ancient inbreeding in a small endogamous tunisian community through genomic runs of homozygosity. Ann Hum Genet. 2015;79(6):402–17.PubMedCrossRef
43.
Romdhane L, Mezzi N, Hamdi Y, El-Kamah G, Barakat A, Abdelhak S. Consanguinity and inbreeding in health and disease in north African populations. Annu Rev Genom Hum Genet. 2019;20:155–79.CrossRef
44.
Betts RB. The Druze. London: Yale University Press; 1988.
45.
Falik-Zaccai TC, Kfir N, Frenkel P, Cohen C, Tanus M, Mandel H, et al. Population screening in a Druze community: the challenge and the reward. Genet Med. 2008;10(12):903–9.PubMedCrossRef
46.
Calmels N, Greff G, Obringer C, Kempf N, Gasnier C, Tarabeux J, et al. Uncommon nucleotide excision repair phenotypes revealed by targeted high-throughput sequencing. Orphanet J Rare Dis. 2016;11(1):1–16.CrossRef
47.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med Off J Am Coll Med Genet. 2015;17(5):405–24.
48.
Pedersen BS, Brown JM, Dashnow H, Wallace AD, Velinder M, Tristani-Firouzi M, et al. Effective variant filtering and expected candidate variant yield in studies of rare human disease. NPJ Genom Med. 2021;6(1):1–8.CrossRef
49.
Chikhaoui A, Elouej S, Nabouli I, Jones M, Lagarde A, Ben Rekaya M, et al. Identification of a ERCC5 c. 2333T> C (L778P) variant in two Tunisian siblings with mild xeroderma pigmentosum phenotype. Front Genet. 2019;10:111.PubMedPubMedCentralCrossRef
50.
Nakazawa Y, Yamashita S, Lehmann AR, Ogi T. A semi-automated non-radioactive system for measuring recovery of RNA synthesis and unscheduled DNA synthesis using ethynyluracil derivatives. DNA Repair. 2010;9(5):506–16.PubMedCrossRef
51.
Jia N, Nakazawa Y, Guo C, Shimada M, Sethi M, Takahashi Y, et al. A rapid, comprehensive system for assaying DNA repair activity and cytotoxic effects of DNA-damaging reagents. Nat Protoc. 2015;10(1):12–24.PubMedCrossRef
52.
Le May N, Calmels N, Abiayad Y, Boukli L, Semer M, Serradj A, et al. Xeroderma pigmentosum groups C and A in Algerian patients with deregulation of both transcription and DNA repair. J Case Rep Stud. 2018;6(4):1–9.
Metadata
Title
Heterogeneous clinical features in Cockayne syndrome patients and siblings carrying the same CSA mutations
Authors
Asma Chikhaoui
Ichraf Kraoua
Nadège Calmels
Sami Bouchoucha
Cathy Obringer
Khouloud Zayoud
Benjamin Montagne
Ridha M’rad
Sonia Abdelhak
Vincent Laugel
Miria Ricchetti
Ilhem Turki
Houda Yacoub-Youssef
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2022
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-022-02257-1

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