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Alu -Mediated MEN1 Gene Deletion and Loss of Heterozygosity in a Patient with Multiple Endocrine Neoplasia Type 1.

Journal of the Endocrine Society(2020)

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摘要
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder caused by mutations of the tumor suppressor gene . Most of the germline gene mutations have been small mutations, and the whole gene deletion is rarely observed. In the present study, we revealed retrotransposon-mediated germline deletion of the whole gene and somatic copy-neutral loss of heterozygosity (LOH) in a patient with MEN1. The patient is a 39-year-old woman who was referred to our department for the management of prolactinoma. She was also diagnosed with primary hyperparathyroidism and suspected of MEN1. Although nucleotide sequencing did not detect any gene mutations, multiplex ligation-dependent probe amplification (MLPA) revealed a large germline deletion of the gene. Subsequent quantitative polymerase chain reaction (qPCR)-based copy number mapping showed a monoallelic loss of approximately 18.5-kilobase region containing the whole gene. Intriguingly, the 2 breakpoints were flanked by repetitive elements, suggesting the contribution of /-mediated rearrangements (AAMR) to the whole gene deletion. Furthermore, copy number mapping using MLPA and qPCR in combination with single nucleotide polymorphism analysis revealed copy-neutral LOH as a somatic event for parathyroid tumorigenesis. In conclusion, copy number mapping revealed a novel combination of /-mediated germline deletion of the gene and somatic copy-neutral LOH as a cytogenetic basis for the MEN1 pathogenesis. Moreover, subsequent in silico analysis highlighted the possible predisposition of the gene to retrotransposon-mediated genomic deletion.
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关键词
Alu retrotransposon,Alu/Alu-mediated genomic rearrangement,loss of heterozygosity,multiple endocrine neoplasia type 1
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