期刊
FRONTIERS IN GENETICS
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fgene.2021.717361
关键词
xeroderma pigmentosum group A; neurode generation; DNA repair activity; nucleotide excision repair; mutation; rare diseases
资金
- Servicio Murciano de Salud (Spain)
- NIH [U01ES029603]
- Irene Diamond Fund/American Federation on Aging Research Postdoctoral Transition Award (US)
The study aimed to diagnose neurological impairment in adolescent patients, identifying xeroderma pigmentosum (XP) through whole-exome sequencing. Genetic analysis revealed recessive mutations in XPA affecting nucleotide excision repair (NER) capacity. The significantly impaired NER in the patient underscores the importance of considering XP in differential diagnosis for atypical neurodegeneration.
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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