Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
35,168
result(s) for
"Han J"
Sort by:
Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1
Marjolijn Ligtenberg and Suet Leung and colleagues report the identification of germline deletions in
TACSTD1
, a gene directly upstream of
MSH2
, in families with Lynch syndrome. The deletions result in transcriptional read-through of
TACSTD1
into
MSH2
, and methylation and silencing of the
MSH2
allele.
Lynch syndrome patients are susceptible to colorectal and endometrial cancers owing to inactivating germline mutations in mismatch repair genes, including
MSH2
(ref.
1
). Here we describe patients from Dutch and Chinese families with MSH2-deficient tumors carrying heterozygous germline deletions of the last exons of
TACSTD1
, a gene directly upstream of
MSH2
encoding Ep-CAM. Due to these deletions, transcription of
TACSTD1
extends into
MSH2
. The
MSH2
promoter
in cis
with the deletion is methylated in Ep-CAM positive but not in Ep-CAM negative normal tissues, thus revealing a correlation between activity of the mutated
TACSTD1
allele and epigenetic inactivation of the corresponding
MSH2
allele. Gene silencing by transcriptional read-through of a neighboring gene in either sense, as demonstrated here, or antisense direction
2
, could represent a general mutational mechanism. Depending on the expression pattern of the neighboring gene that lacks its normal polyadenylation signal, this may cause either generalized or mosaic patterns of epigenetic inactivation.
Journal Article
A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer
Roland Kuiper and colleagues identify a homozygous germline nonsense mutation in the base-excision repair gene
NTHL1
in three families with recessive inheritance of adenomatous polyposis.
The genetic cause underlying the development of multiple colonic adenomas, the premalignant precursors of colorectal cancer (CRC), frequently remains unresolved in patients with adenomatous polyposis. Here we applied whole-exome sequencing to 51 individuals with multiple colonic adenomas from 48 families. In seven affected individuals from three unrelated families, we identified a homozygous germline nonsense mutation in the base-excision repair (BER) gene
NTHL1
. This mutation was exclusively found in a heterozygous state in controls (minor allele frequency of 0.0036;
n
= 2,329). All three families showed recessive inheritance of the adenomatous polyposis phenotype and progression to CRC in at least one member. All three affected women developed an endometrial malignancy or premalignancy. Genetic analysis of three carcinomas and five adenomas from different affected individuals showed a non-hypermutated profile enriched for cytosine-to-thymine transitions. We conclude that a homozygous loss-of-function germline mutation in the
NTHL1
gene predisposes to a new subtype of BER-associated adenomatous polyposis and CRC.
Journal Article
Individual variation of the SARS‐CoV‐2 receptor ACE2 gene expression and regulation
The COVID‐19 coronavirus is now spreading worldwide. Its pathogen, SARS‐CoV‐2, has been shown to use angiotensin‐converting enzyme 2 (ACE2) as its host cell receptor, same as the severe acute respiratory syndrome coronavirus (SARS‐CoV) in 2003. Epidemiology studies found males although only slightly more likely to be infected than females account for the majority of the severely ill and fatality, which also bias for people older than 60 years or with metabolic and cardiovascular diseases. Here by analyzing GTEx and other public data in 30 tissues across thousands of individuals, we found a significantly higher level in Asian females, an age‐dependent decrease in all ethnic groups, and a highly significant decrease in type II diabetic patients of ACE2 expression. Consistently, the most significant expression quantitative loci (eQTLs) contributing to high ACE2 expression are close to 100% in East Asians, >30% higher than other ethnic groups. A shockingly common enrichment of viral infection pathways was found among ACE2 anti‐expressed genes, and multiple binding sites of virus infection related transcription factors and sex hormone receptors locate at ACE2 regulatory regions. Human and mice data analysis further revealed ACE2 expression is reduced in T2D patients and with inflammatory cytokine treatment and upregulated by estrogen and androgen (both decrease with age). Our findings revealed a negative correlation between ACE2 expression and COVID‐19 fatality at both population and molecular levels. These results will be instrumental when designing potential prevention and treatment strategies for ACE2 binding coronaviruses in general. This study revealed the negative correlation of high basal ACE2 level with CoVID‐19 severity/fatality at the population level and its anticorrelation with virus infection pathway expression levels, upregulation by sex hormones and suppression by inflammatory cytokine at the molecular level.
Journal Article
Cellular angiofibroma: analysis of 25 cases emphasizing its relationship to spindle cell lipoma and mammary-type myofibroblastoma
Cellular angiofibroma represents a rare benign mesenchymal tumor, occurring mainly in the superficial soft tissue of the genital region. The involvement of 13q14 in some cases confirmed the morphological suggested link with spindle cell lipoma and mammary-type myofibroblastoma. We analyzed the clinicopathological and immunohistochemical features of 25 cases, and performed in a number of cases additional molecular studies. There were 17 female and 8 male patients (age ranged from 27 to 83 years); females tended to be younger. A marked predilection for the vulva (
n
=13) was observed, and neoplasms in males were predominantly located in the inguinal region (
n
=4), and one case each in the scrotum, perianal, the knee, and the upper eyelid. The tumors arose most commonly in the superficial soft tissue and were well circumscribed in all but two cases. The tumor size ranged from 1 to 9 cm. All lesions were composed of spindle-shaped cells associated with numerous small- to medium-sized blood vessels; however, a broad morphological variation with foci of lipogenic differentiation in nine cases and sarcomatous transformation in one case was found. By immunohistochemistry, 11 out of 22 cases expressed CD34. A focal reaction for
α
-smooth muscle actin was observed in 9 out of 22 cases, and two cases each stained weak and focally positive for epithelial membrane antigen and CD99. In all seven cases tested, a monoallelic deletion of
RB1
was detected by FISH analysis. Follow-up, available in 14 patients, showed neither local recurrence nor metastasis. In conclusion, we affirm the link between cellular angiofibroma, spindle cell lipoma, and mammary-type myofibroblastoma, showing a spectrum of one entity with morphological variations dependent on anatomic location.
Journal Article
Diverse polarization angle swings from a repeating fast radio burst source
Fast radio bursts (FRBs) are millisecond-duration radio transients
1
,
2
of unknown origin. Two possible mechanisms that could generate extremely coherent emission from FRBs invoke neutron star magnetospheres
3
–
5
or relativistic shocks far from the central energy source
6
–
8
. Detailed polarization observations may help us to understand the emission mechanism. However, the available FRB polarization data have been perplexing, because they show a host of polarimetric properties, including either a constant polarization angle during each burst for some repeaters
9
,
10
or variable polarization angles in some other apparently one-off events
11
,
12
. Here we report observations of 15 bursts from FRB 180301 and find various polarization angle swings in seven of them. The diversity of the polarization angle features of these bursts is consistent with a magnetospheric origin of the radio emission, and disfavours the radiation models invoking relativistic shocks.
Polarization observations of the fast radio burst FRB 180301 with the FAST radio telescope show diverse polarization angle swings, consistent with a magnetospheric origin of the emission.
Journal Article