Abstract:
:Prolactinomas are the most frequent type of pituitary tumors, which represent 10-20% of all intracranial neoplasms in humans. Prolactinomas develop in mice lacking the prolactin receptor (PRLR), which is a member of the cytokine receptor superfamily that signals via Janus kinase-2-signal transducer and activator of transcription-5 (JAK2-STAT5) or phosphoinositide 3-kinase-Akt (PI3K-Akt) pathways to mediate changes in transcription, differentiation and proliferation. To elucidate the role of the PRLR gene in human prolactinomas, we determined the PRLR sequence in 50 DNA samples (35 leucocytes, 15 tumors) from 46 prolactinoma patients (59% males, 41% females). This identified six germline PRLR variants, which comprised four rare variants (Gly57Ser, Glu376Gln, Arg453Trp and Asn492Ile) and two low-frequency variants (Ile76Val, Ile146Leu), but no somatic variants. The rare variants, Glu376Gln and Asn492Ile, which were in complete linkage disequilibrium, and are located in the PRLR intracellular domain, occurred with significantly higher frequencies (P < 0.0001) in prolactinoma patients than in 60 706 individuals of the Exome Aggregation Consortium cohort and 7045 individuals of the Oxford Biobank. In vitro analysis of the PRLR variants demonstrated that the Asn492Ile variant, but not Glu376Gln, when compared to wild-type (WT) PRLR, increased prolactin-induced pAkt signaling (>1.3-fold, P < 0.02) and proliferation (1.4-fold, P < 0.02), but did not affect pSTAT5 signaling. Treatment of cells with an Akt1/2 inhibitor or everolimus, which acts on the Akt pathway, reduced Asn492Ile signaling and proliferation to WT levels. Thus, our results identify an association between a gain-of-function PRLR variant and prolactinomas and reveal a new etiology and potential therapeutic approach for these neoplasms.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Gorvin CM,Newey PJ,Rogers A,Stokes V,Neville MJ,Lines KE,Ntali G,Lees P,Morrison PJ,Singhellakis PN,Malandrinou FC,Karavitaki N,Grossman AB,Karpe F,Thakker RVdoi
10.1093/hmg/ddy396subject
Has Abstractpub_date
2019-03-15 00:00:00pages
1023-1037issue
6eissn
0964-6906issn
1460-2083pii
5184334journal_volume
28pub_type
杂志文章abstract::Actinic keratosis (AK) is a pre-malignant skin disease, highly prevalent in elderly Europeans. This study investigates genetic susceptibility to AK with a genome-wide association study (GWAS). A full body skin examination was performed in 3194 elderly individuals from the Rotterdam Study (RS) of exclusive north-wester...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv076
更新日期:2015-06-01 00:00:00
abstract::Duchenne muscular dystrophy (DMD) is a lethal, muscle degenerative disease causing premature death of affected children. DMD is characterized by mutations in the dystrophin gene that result in a loss of the dystrophin protein. Loss of dystrophin causes an associated reduction in proteins of the dystrophin glycoprotein...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz044
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journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:2017-10-15 00:00:00
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journal_title:Human molecular genetics
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doi:10.1093/hmg/3.10.1795
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journal_title:Human molecular genetics
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journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy021
更新日期:2018-04-01 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy315
更新日期:2018-12-15 00:00:00
abstract::The cone photoreceptor cyclic nucleotide-gated (CNG) channel is essential for central and color vision and visual acuity. Mutations in the channel subunits CNGA3 and CNGB3 are associated with achromatopsia and cone dystrophy. We investigated the gene expression profiles in mouse retina with CNG channel deficiency usin...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt245
更新日期:2013-10-01 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm028
更新日期:2007-04-01 00:00:00
abstract::Glycosylation with O-linked β-N-acetylglucosamine (O-GlcNAc) is one of the protein glycosylations affecting various intracellular events. However, the role of O-GlcNAcylation in neurodegenerative diseases such as Alzheimer's disease (AD) is poorly understood. Mitochondrial adenosine 5'-triphosphate (ATP) synthase is a...
journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:2015-11-15 00:00:00
abstract::The gene encoding heterogeneous ribonucleoprotein (hnRNP) G recently has been mapped to the X chromosome. All mammals have a Y chromosome-encoded homologue of HNRNP G called RBMY, which is implicated with a role in male fertility and is a candidate for the azoospermia factor gene. We have identified a new member of th...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/9.14.2117
更新日期:2000-09-01 00:00:00
abstract::Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disease that has been linked to deletions within a tandem array of 3.2 kb repeats adjacent to the telomere of 4q. These repeats are also present in other locations in the human genome, including the short arms of all the acrocentric c...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/5.10.1567
更新日期:1996-10-01 00:00:00
abstract::There is considerable uncertainty and debate concerning the application of linkage disequilibrium (LD) mapping in common multifactorial diseases, including the choice of population and the density of the marker map. Previously, it has been shown that, in the large cosmopolitan population of the UK, the established typ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/9.20.2967
更新日期:2000-12-12 00:00:00
abstract::Duchenne and Becker muscular dystrophies (DMD/BMD) are caused by mutations in the human dystrophin gene. About two-thirds of DMD/BMD patients exhibit gross rearrangements in the gene whereas the mutations in the remaining one third are thought to be point mutations or minor structural lesions. By means of various prog...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.11.1877
更新日期:1993-11-01 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/8.10.1875
更新日期:1999-01-01 00:00:00
abstract::X-linked myotubular myopathy (MTM) is a severe neuromuscular disease of infancy caused by mutations of MTM1, which encodes the phosphoinositide lipid phosphatase, myotubularin. The Mtm1 knockout (KO) mouse has a severe phenotype and its short lifespan (8 weeks) makes it a challenge to use as a model in the testing of ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr512
更新日期:2012-02-15 00:00:00
abstract::The rapid increase in the prevalence of type 2 diabetes (T2D) represents a major challenge for health care delivery worldwide. Identification of genes influencing individual susceptibility to disease offers a route to better understanding of the molecular mechanisms underlying pathogenesis, a necessary prerequisite fo...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddh057
更新日期:2004-04-01 00:00:00
abstract::Differential allelic expression has been shown to be common in mice, humans and maize, and variability in the expression of polymorphic alleles has been associated with human disease. Here, we describe the differential expression pattern of Paraoxonase-1, a gene involved in lipid metabolism and implicated in the forma...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn222
更新日期:2008-11-01 00:00:00
abstract::Arrhythmogenic cardiomyopathy (ACM) is a disorder characterized by a progressive ventricular myocardial replacement by fat and fibrosis, which lead to ventricular arrhythmias and sudden cardiac death. Mutations in the desmosomal gene Plakophilin-2 (PKP2) accounts for >40% of all known mutations, generally causing a tr...
journal_title:Human molecular genetics
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更新日期:2016-09-01 00:00:00
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journal_title:Human molecular genetics
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journal_title:Human molecular genetics
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doi:10.1093/hmg/6.5.753
更新日期:1997-05-01 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds247
更新日期:2012-10-01 00:00:00
abstract::Grb10-Interacting GYF Protein 2 (GIGYF2) was initially identified through its interaction with Grb10, an adapter protein that binds activated IGF-I and insulin receptors. The GIGYF2 gene maps to human chromosome 2q37 within a region linked to familial Parkinson's disease (PARK11 locus), and association of GIGYF2 mutat...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp430
更新日期:2009-12-01 00:00:00
abstract::Huntington's disease is neurodegenerative disorder caused by a polyglutamine expansion in the N-terminal region of the huntingtin protein (N17). Here, we analysed the relative contribution of each phosphorylatable residue in the N17 region (T3, S13 and S16) towards huntingtin exon 1 (HTTex1) oligomerization, aggregati...
journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:2017-10-01 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp015
更新日期:2009-04-01 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz057
更新日期:2019-07-15 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章,评审
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更新日期:2013-10-15 00:00:00
abstract::The HLA class II (DRB1 and DQB1) associations with sarcoidosis have been studied by several groups but often without consistent results. In this paper, we consider the hypothesis that observed inconsistencies relate to distinct, genetically encoded disease phenotypes which differ in prevalence between centres. We ther...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq325
更新日期:2010-10-15 00:00:00
abstract::The gene which is defective in Duchenne muscular dystrophy (DMD) is the largest known gene. The product of the gene in muscle, dystrophin, is a 427 kDa protein. The same gene encodes at least six additional products: two non-muscle dystrophin isoforms transcribed from promoters located in the 5'-end region of the gene...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/7.4.581
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