A novel mutation in the <i>XPA</i>
 gene associated with unusually mild clinical features in a patient who developed a spindle cell melanoma

Sidwell, Rachel U; Sandison, A. J. P.; Wing, Jonathan F.; Fawcett, Heather; Seet, Ju‐Ee; Fisher, Cyril; Nardò, Tiziana; Stefanini, Miria; Lehmann, Alan R.; Cream, J. J.

doi:10.1111/j.1365-2133.2006.07272.x

Cited by 36 publications

(27 citation statements)

References 28 publications

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“…He has since had multiple skin cancers removed, mainly in the last decade. As previously discussed, it appears that a minimal amount of repair capability in XP-A patients is sufficient to prevent any neurodegeneration, although not to prevent the typical cutaneous features of XP (15,17).…”

Section: Resultsmentioning

confidence: 72%

“…All 10 have the mutation c.555+8A > G. This mutation has previously been reported for a 60-y-old Afghan woman of Punjabi origin, XP40BR (15). It generates a new splice donor site for intron 4, resulting in seven bases from intron 4 being incorporated between exons 4 and 5, resulting in a frameshift at this position.…”

Section: Resultsmentioning

confidence: 99%

“…It generates a new splice donor site for intron 4, resulting in seven bases from intron 4 being incorporated between exons 4 and 5, resulting in a frameshift at this position. A very low level of normal transcript was noted, which can account for the 5-10% of normal repair in these patients (15). All of the patients in this subgroup have mild dermatological features with no neurological abnormalities and low ocular scores for their age, as described in detail elsewhere (16).…”

Section: Resultsmentioning

confidence: 99%

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Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect

Fassihi

Sethi

Fawcett

et al. 2016

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

171

202

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Xeroderma pigmentosum (XP) is a rare DNA repair disorder characterized by increased susceptibility to UV radiation (UVR)-induced skin pigmentation, skin cancers, ocular surface disease, and, in some patients, sunburn and neurological degeneration. Genetically, it is assigned to eight complementation groups (XP-A to -G and variant). For the last 5 y, the UK national multidisciplinary XP service has provided follow-up for 89 XP patients, representing most of the XP patients in the United Kingdom. Causative mutations, DNA repair levels, and more than 60 clinical variables relating to dermatology, ophthalmology, and neurology have been measured, using scoring systems to categorize disease severity. This deep phenotyping has revealed unanticipated heterogeneity of clinical features, between and within complementation groups. Skin cancer is most common in XP-C, XP-E, and XP-V patients, previously considered to be the milder groups based on cellular analyses. These patients have normal sunburn reactions and are therefore diagnosed later and are less likely to adhere to UVR protection. XP-C patients are specifically hypersensitive to ocular damage, and XP-F and XP-G patients appear to be much less susceptible to skin cancer than other XP groups. Within XP groups, different mutations confer susceptibility or resistance to neurological damage. Our findings on this large cohort of XP patients under long-term follow-up reveal that XP is more heterogeneous than has previously been appreciated. Our data now enable provision of personalized prognostic information and management advice for each XP patient, as well as providing new insights into the functions of the XP proteins.UV radiation | nucleotide excision repair | skin cancer | ocular disease | neurodegeneration

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Section: Resultsmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect

Fassihi

Sethi

Fawcett

et al. 2016

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

171

202

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“…3 The presence of a small amount of normally spliced mRNA could explain the less severe phenotype. 16 To the best of our knowledge, patients with XP-A without obvious skin manifestations, as observed in patients 1 and 4, have not been described previously. Neurological and developmental syndromes allelic to DNA repair diseases have been reported before.…”

Section: Discussionmentioning

confidence: 82%

“…This primarily neurological clinical phenotype is defined by a total absence of cutaneous elements indicative of XP-A and mild and delayed neurological symptoms. Although unusually mild clinical presentations of XP-A have previously been published, 16 all the clinical descriptions show that skin manifestations are pronounced compared with the neurological signs. The majority of these cases bore splice-site mutations.…”

Section: Discussionmentioning

confidence: 94%

Identification of a primarily neurological phenotypic expression of xeroderma pigmentosum complementation group A in a Tunisian family

Messaoud

Rekaya

Kéfi

et al. 2010

British Journal of Dermatology

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Xeroderma pigmentosum (XP) is a rare genodermatosis predisposing to skin cancers. The disease is classified into eight groups. Among them, XP group A (XP-A) is characterized by the presence of neurological abnormalities in addition to cutaneous symptoms. In the present study, we report a particular family with XP-A in which some members showed an atypical clinical presentation, i.e. unexplained neurological abnormalities with discrete skin manifestations. Molecular investigation allowed identification of a novel XPA mutation and complete phenotype-genotype correlation for this new phenotypic expression of XP-A.

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Genotype-phenotype relationships in trichothiodystrophy patients with novel splicing mutations in theXPDgene

et al. 2008

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Trichothiodystrophy (TTD) is a rare, autosomal recessive neurodevelopmental disorder most commonly caused by mutations in ERCC2 (XPD), a gene that encodes a subunit of the transcription/repair factor IIH (TFIIH). Here, we describe two TTD cases in which detailed biochemical and molecular investigations offered a clue to explain their moderately affected phenotype. Patient TTD22PV showed new mutated XPD alleles: one contains a nonsense mutation (c.1984C>T) encoding a nonfunctional truncated product (p.Gln662X) whereas the second carries a genomic deletion (c.2191-18_c.2213del) that affects the splicing of intron 22 and generates multiple out-of-frame transcripts from codon 731. XPD mRNA from the second allele corresponds to 20% of the total. The predicted proteins, which are longer than normal, affect the cellular repair activity but only partially interfere with TFIIH stability, suggesting that the observed changes in the C-ter region of XPD cause minor structural changes that do not drastically compromise the transcriptional activity of TFIIH. Patient TTD24PV was compound heterozygous for a typical TTD allele (c.2164C>T, p.Arg722Trp) and for a new XPD allele with a mutation that partially affects intron 10 splicing, resulting in both mutated and normal XPD transcripts (that together represent 15% of the total XPD mRNA). Compared to the previously described TTD compound heterozygotes for the Arg722Trp change, Patient TTD24PV's cells show similar level of TFIIH but increased repair activity, suggesting that even low amounts of normal XPD subunits are able to partially rescue the functionality of TFIIH complexes.

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A novel mutation in the XPA gene associated with unusually mild clinical features in a patient who developed a spindle cell melanoma

Abstract: The small amount of normally spliced mRNA detected may be sufficient to explain the relatively mild clinical features in our patient.

Cited by 36 publications

References 28 publications

Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect

Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect

Identification of a primarily neurological phenotypic expression of xeroderma pigmentosum complementation group A in a Tunisian family

Genotype-phenotype relationships in trichothiodystrophy patients with novel splicing mutations in theXPDgene

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