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491.
Recurrent DICER1 hotspot mutations in endometrial tumours and their impact on microRNA biogenesis 下载免费PDF全文
Jiamin Chen Yemin Wang Melissa K McMonechy Michael S Anglesio Winnie Yang Janine Senz Sarah Maines‐Bandiera Jamie Rosner Genny Trigo‐Gonzalez SW Grace Cheng Jaeyeon Kim Martin M Matzuk Gregg B Morin David G Huntsman 《The Journal of pathology》2015,237(2):215-225
DICER1 plays a critical role in microRNA (miRNA) biogenesis. Recurrent somatic 'hotspot' mutations at the four metal‐binding sites within the RNase IIIb domain of DICER1 were identified in ovarian sex cord‐stromal tumours and have since been described in other paediatric tumours. In this study, we screened the RNase IIIb domain of DICER1 in 290 endometrial tumours and identified six cases with hotspot mutations, including two cases affected by an atypical G1809R mutation directly adjacent to a metal‐binding site. Using Illumina and Sanger targeted resequencing, we observed and validated biallelic DICER1 mutations in several cases with hotspot mutations. Through in vitro DICER1 cleavage assays, small RNA deep sequencing and real‐time PCR, we demonstrated that mutations adding a positively charged side chain to residue 1809 have similar detrimental effects on 5p miRNA production to mutations at the metal‐binding sites. As expected, 5p miRNAs were globally reduced in tumours and cell lines with hotspot mutations. Pathway analysis of gene expression profiles indicated that genes de‐repressed due to loss of 5p miRNAs are strongly associated with pathways regulating the cell cycle. Using a Dicer1‐null mouse cell line model, we found that expression of DICER1 hotspot mutants promoted cell proliferation, whereas wild‐type (WT) DICER1 inhibited cell proliferation. Furthermore, targets of let‐7 family miRNAs are enriched among the up‐regulated genes, suggesting that loss of let‐7 may be impacting downstream pathways. Our results reveal that DICER1 hotspot mutations are implicated in common malignancies and may constitute a unique oncogenic pathway. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 相似文献
492.
Molecular analysis of the PDS gene in Pendred syndrome 总被引:18,自引:2,他引:18
Coyle B; Reardon W; Herbrick JA; Tsui LC; Gausden E; Lee J; Coffey R; Grueters A; Grossman A; Phelps PD; Luxon L; Kendall-Taylor P; Scherer SW; Trembath RC 《Human molecular genetics》1998,7(7):1105-1112
Pendred syndrome is an autosomal recessive disorder characterized by the
association between sensorineural hearing loss and thyroid swelling or
goitre and is likely to be the most common form of syndromic deafness.
Within the thyroid gland of affected individuals, iodide is incompletely
organified with variable effects upon thyroid hormone biosynthesis, whilst
the molecular basis of the hearing loss is unknown. The PDS gene has been
identified by positional cloning of chromosome 7q31, within the Pendred
syndrome critical linkage interval and encodes for a putative ion
transporter called pendrin. We have investigated a cohort of 56 kindreds,
all with features suggestive of a diagnosis of Pendred syndrome. Molecular
analysis of the PDS gene identified 47 of the 60 (78%) mutant alleles in 31
families (includes three homozygous consanguineous kindreds and one
extended family segregating three mutant alleles). Moreover, four recurrent
mutations accounted for 35 (74%) of PDS disease chromosomes detected and
haplotype analysis would favour common founders rather than mutational
hotspots within the PDS gene. Whilst these findings demonstrate molecular
heterogeneity for PDS mutations associated with Pendred syndrome, this
study would support the use of molecular analysis of the PDS gene in the
assessment of families with congenital hearing loss.
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493.