Genetic investigation of XPA gene: high frequency of the c.682C&gt;T mutation in Moroccan XP patients with moderate clinical profile

Kindil, Zineb; Senhaji, Mohamed Amine; Bakhchane, Amina; Charoute, Hicham; Chihab, Soumia; Nadifi, Sellama; Barakat, Abdelhamid

doi:10.1186/s13104-017-3042-6

Cited by 5 publications

(5 citation statements)

References 27 publications

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“…Since, we started studying XP we reported five complementation groups (XP-A, C, D, E, and V) in Tunisia. The mutations with founder effect responsible for the XP-C (Ben Rekaya et al, 2009) and XP-A phenotypes (Messaoud et al, 2010) have been also found in other North African countries (Soufir et al, 2010) such as Morocco (Senhaji et al, 2013; Kindil et al, 2017), Egypt (Amr et al, 2014), Algeria (Bensenouci et al, 2016), and Libya (unpublished data). The XP-D and XP-E forms have been recently identified thanks to whole exome sequencing (WES) technology (Ben Rekaya et al, 2018).…”

Section: Introductionmentioning

confidence: 76%

Identification of a ERCC5 c.2333T>C (L778P) Variant in Two Tunisian Siblings With Mild Xeroderma Pigmentosum Phenotype

et al. 2019

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Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder due to a defect in the nucleotide excision repair (NER) DNA repair pathway, characterized by severe sunburn development of freckles, premature skin aging, and susceptibility to develop cancers at an average age of eight. XP is an example of accelerated photo-aging. It is a genetically and clinically heterogeneous disease. Eight complementation groups have been described worldwide. In Tunisia, five groups have been already identified. In this work, we investigated the genetic etiology in a family with an atypically mild XP phenotype. Two Tunisian siblings born from first-degree consanguineous parents underwent clinical examination in the dermatology department of the Charles Nicolle Hospital on the basis of acute sunburn reaction and mild neurological disorders. Blood samples were collected from two affected siblings after written informed consent. As all mutations reported in Tunisia have been excluded using Sanger sequencing, we carried out mutational analysis through a targeted panel of gene sequencing using the Agilent HaloPlex target enrichment system. Our clinical study shows, in both patients, the presence of achromic macula in sun exposed area with dermatological feature suggestive of Xeroderma pigmentosum disease. No developmental and neurological disorders were observed except mild intellectual disability. Genetic investigation shows that both patients were carriers of an homozygous T to C transition at the nucleotide position c.2333, causing the leucine to proline amino acid change at the position 778 (p.Leu778Pro) of the ERCC5 gene, and resulting in an XP-G phenotype. The same variation was previously reported at the heterozygous state in a patient cell line in Europe, for which no clinical data were available and was suggested to confer an XP/CS phenotype based on functional tests. This study contributes to further characterization of the mutation spectrum of XP in consanguineous Tunisian families and is potentially helpful for early diagnosis. It also indicates that the genotype-phenotype correlation is not always coherent for patients with mild clinical features. These data therefore suggest that targeted NGS is a highly informative diagnostic strategy, which can be used for XP molecular etiology determination.

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Section: Introductionmentioning

confidence: 76%

Identification of a ERCC5 c.2333T>C (L778P) Variant in Two Tunisian Siblings With Mild Xeroderma Pigmentosum Phenotype

et al. 2019

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“…We found a mutation (c.682C>T; p.Arg228Ter) present in exon six in one of the alleles of XPA. This mutation have been described in nine Moroccan patients suffering severe skin lesions while neurological disorders were also observed in three aged (>30 years old) patients (Kindil et al, 2017). This mutation causes a premature stop signal and results in a protein with a truncation in the C-terminal region of XPA where TFIIH, another component of the NER machinery, binds.…”

Section: Discussionmentioning

confidence: 93%

Case Report: Identification of a Heterozygous XPA c.553C>T Mutation Causing Neurological Impairment in a Case of Xeroderma Pigmentosum Complementation Group A

et al. 2021

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We aimed to determine if an adolescent patient presenting with neurological impairment has xeroderma pigmentosum (XP). For this purpose, whole-exome sequencing was performed to assess mutations in XP genes. Dermal fibroblasts were established from a skin biopsy and XPA expression determined by immunoblotting. Nucleotide excision repair (NER) capacity was measured by detection of unscheduled DNA synthesis (UDS) in UVC-irradiated patient fibroblasts. Genetic analysis revealed two recessive mutations in XPA, one known c.682C>T, p.Arg228Ter, and the other c.553C>T, p.Gln185Ter, only two cases were reported. XPA protein was virtually undetectable in lysates from patient-derived fibroblast. The patient had significantly lower UV-induced UDS (3.03 ± 1.95%, p < 0.0001) compared with healthy controls (C5RO = 100 ± 12.2; C1UMN = 118 ± 5.87), indicating significant NER impairment. In conclusion, measurement of NER capacity is beneficial for the diagnosis of XP and in understanding the functional impact of novel mutations in XP genes. Our findings highlight the importance of neurologists considering XP in their differential diagnosis when evaluating patients with atypical neurodegeneration.

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“…In an Algerian series, the XPA mutation (c.682C> T) was present in 2 of 19 patients (10.5%) and the XPC mutation (1643 1644delTG) was present in 17 of 19 patients (89.5%) in the homozygous state [11]. In a study conducted in Casablanca, the XPC mutation (c 1643 1644delTG) was estimated to account for more than 76% of cases of XP in Moroccan patients [12]. Another study conducted at the same institution involving XP patients with neurological involvement revealed the presence of the nonsense mutation (c.682C> T) in the homozygous state at the level of the XPA gene in 78 patients [3].…”

Section: Discussionmentioning

confidence: 97%

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Background: Xeroderma pigmentosum (XP) is a rare hereditary disease characterized by hypersensitivity to UV radiation due to alterations in the nucleotide excision repair (NER) pathway. The XPA and XPC gene mutations are most common in North African countries. Our goal was to perform a molecular study on patients with XP followed in our northeastern Moroccan region to determine their genetic profile. Materials and methods: We explored the nonsense (c.682C> T, p.Arg228X) mutation at the XPA gene and a two-base pair deletion (c.1643_1644delTG or p.Val548Ala fsX25) at the XPC gene level with the molecular PCR sequencing technique. Subsequently, the relationship between the mutations found and the symptomatic and progressive features was analyzed. Results: In the course of our work, the alterations of the two XPA and XPC genes responsible for xeroderma pigmentosum in a sample of 24 index cases belonging to 22 unrelated families were characterized, revealing 14 cases of XPC and 6 cases of XPA. The study on the correlation between genotypes and phenotypes in our study showed that neurological involvement was significant in XPA patients and that these XPA patients develop malignant skin tumors earlier than XPC patients. Conclusions: In our XP population, the alterations of the XPA and XPC genes responsible for xeroderma pigmentosum in a sample of 24 index cases belonging to 22 unrelated families were characterized, revealing 14 cases of XPC and 6 cases of XPA. Neurological involvement was significant in XPA patients and these XPA patients were found to develop malignant skin tumors earlier than XPC patients.

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Genetic investigation of XPA gene: high frequency of the c.682C>T mutation in Moroccan XP patients with moderate clinical profile

Cited by 5 publications

References 27 publications

Identification of a ERCC5 c.2333T>C (L778P) Variant in Two Tunisian Siblings With Mild Xeroderma Pigmentosum Phenotype

Identification of a ERCC5 c.2333T>C (L778P) Variant in Two Tunisian Siblings With Mild Xeroderma Pigmentosum Phenotype

Case Report: Identification of a Heterozygous XPA c.553C>T Mutation Causing Neurological Impairment in a Case of Xeroderma Pigmentosum Complementation Group A

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