Recurrent Missense Mutations in the STAT3 Gene in LGL Leukemia Provide Insights to Pathogenetic Mechanisms and Suggest Potential Diagnostic and Therapeutic Applications

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 936-936
Author(s):  
Hanna Koskela ◽  
Samuli Eldfors ◽  
Henrikki Almusa ◽  
Emma Andersson ◽  
Pekka Ellonen ◽  
...  
Keyword(s):  
T Cell ◽  
Exome Sequencing ◽  
Missense Mutation ◽  
Whole Exome Sequencing ◽  
Somatic Mutations ◽  
Index Patient ◽  
Missense Mutations ◽  
Whole Exome ◽  
Stat3 Mutations ◽  
Lgl Leukemia

Abstract Abstract 936 BACKGROUND: T-cell large granular lymphocyte (LGL) leukemia is an uncommon lymphoproliferative disorder characterized in most cases by expansion of mature, clonal CD3+CD8+ cytotoxic T lymphocytes (CTLs). The pathogenesis of LGL-leukemia is unknown, and leukemic cells closely resemble normal terminally differentiated effector memory CTLs. While resistance to apoptotic pathways (Fas/Fas ligand, sphingolipid) and activation of survival signaling pathways (Ras) have been implicated in LGL leukemia, the underlying genetic defects have not yet been elucidated. We aimed to identify somatic mutations in LGL leukemia by whole exome sequencing of leukemic and matched healthy control cells. METHODS: Our index patient is a 70 year-old male with untreated CD8+ LGL leukemia diagnosed in 2009 with a clonal rearrangement in the T-cell receptor (TCR) delta and gamma gene. He has been asymptomatic with grade 2 neutropenia and an absolute lymphocyte count of 4–15 ×109/L. The patient had one large predominant T-cell clone: 94% of CD8+ cells consisted of a single Vβ16 clone, as assessed by flow cytometry. No clonal expansions were observed in the CD4+ fraction. DNA was extracted from FACS-sorted CD8+ (leukemic) and CD4+ (control) cells and sequenced by exome capture using an Agilent SureSelect All exon 50 MB capture kit and the Illumina GAII sequencing platform. Candidate somatic mutations were identified with a bioinformatics pipeline consisting of BWA for sequence alignment, Samtools for alignment filtering and Varscan for somatic mutation calling. Mutations were manually reviewed in IGV for alignment artifacts and validated by capillary sequencing. DNA samples from 8 additional untreated LGL-leukemia patients were used for further screening of confirmed somatic mutations by capillary sequencing. From six of these patients DNA was extracted from CD8 sorted cells and from two patients from whole blood. RESULTS: Whole exome sequencing of CD8+ leukemic DNA from the index patient identified a missense mutation in the STAT3 gene (D661V), which was subsequently confirmed by capillary sequencing. As STAT3 signaling has been associated with LGL leukemia pathogenesis previously, we next designed primers for the secondary screening of the six exomes of STAT3 SH2 region from the remaining patients. Another recurrent somatic missense mutation (STAT3 Y640F) was identified in two additional patients. Thus, three out of nine LGL patients (33%) showed evidence of mutations in the STAT3 SH2 region. Both missense mutations found (D661V and Y640F) were located in the area of the SH2 domain known to mediate STAT3 protein dimerization and activation. The Y640F mutation alters a conserved tyrosine residue leading to a hyperactivating STAT protein (Scarzello et al. Mol Biol Cell, 2007) and was recently found in a human inflammatory hepatocellular adenoma causing cytokine-independent tyrosine phosphorylation and activation as well as cytokine-dependent hyperactivation of STAT3 (Pitali et al., J Exp Med, 2011). The D661V mutation has not been described previously. CONCLUSIONS: Our data imply for the first time that STAT3 is a common mutational target in LGL leukemia, revealing insights to the molecular pathogenesis of this rare disease. Known structural and functional data on STAT biology imply that the mutations are leading to STAT3 hyperactivation and could also confer ligand-independent signaling. While confirmatory data from a larger series of patients are necessary, our results pinpoint STAT3 mutations and aberrations in the STAT3 pathway as key pathogenetic events in true clonal LGL leukemia. Detection of STAT3 mutations could therefore be applied in the diagnostic assessment, disease stratification and therapeutic monitoring of LGL patients. Disclosures: Koskela: Novartis: Honoraria. Kuittinen:Roche: Consultancy. Porkka:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Mustjoki:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria.

scholarly journals Identification of a novel pathogenic missense mutation in PRPF31 using whole exome sequencing: a case report

2018 ◽  
Vol 103 (6) ◽  
pp. 761-767 ◽  
Author(s):  
Laura Bryant ◽  
Olga Lozynska ◽  
Anson Marsh ◽  
Tyler E Papp ◽  
Lucas van Gorder ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Whole Exome Sequencing ◽  
Protein Trafficking ◽  
Protein Misfolding ◽  
Autosomal Dominant ◽  
Null Alleles ◽  
Incomplete Penetrance ◽  
Missense Mutations ◽  
Whole Exome

BackgroundVariants in PRPF31, which encodes pre-mRNA processing factor 31 homolog, are known to cause autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance. However, the majority of mutations cause null alleles, with only two proven pathogenic missense mutations. We identified a novel missense mutation in PRPF31 in a family with adRP.MethodsWe performed whole exome sequencing to identify possible pathogenic mutations in the proband of a family with adRP. Available affected family members had a full ophthalmological evaluation including kinetic and two-colour dark adapted static perimetry, electroretinography and multimodal imaging of the retina. Two patients had evaluations covering nearly 20 years. We carried out segregation analysis of the probable mutation, PRPF31 c.590T>C. We evaluated the cellular localisation of the PRPF31 variant (p.Leu197Pro) compared with the wildtype PRPF31 protein.ResultsPRPF31 c.590T>C segregated with the disease in this four-generation autosomal dominant pedigree. There was intrafamilial variability in disease severity. Nyctalopia and mid-peripheral scotomas presented from the second to the fourth decade of life. There was severe rod >cone dysfunction. Visual acuity (VA) was relatively intact and was maintained until later in life, although with marked interocular asymmetries. Laboratory studies showed that the mutant PRPF31 protein (p.Leu197Pro) does not localise to the nucleus, unlike the wildtype PRPF31 protein. Instead, mutant protein resulted in punctate localisation to the cytoplasm.Conclusionsc.590T>C is a novel pathogenic variant in PRPF31 causing adRP with incomplete penetrance. Disease may be due to protein misfolding and associated abnormal protein trafficking to the nucleus.

Somatic PTPRT and ANGPT2 Mutations in Large Granulocyte Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1302-1302
Author(s):  
Emma I Andersson ◽  
Samuli Eldfors ◽  
Hanna L M Koskela ◽  
Pekka Ellonen ◽  
Thomas Olson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Exome Sequencing ◽  
Research Funding ◽  
Somatic Mutations ◽  
Cell Clone ◽  
Index Patient ◽  
T Cell Clone ◽  
Variant Frequency ◽  
Lgl Leukemia

Abstract Abstract 1302 Introduction: T-cell large granular lymphocyte (T-LGL) leukemia is a rare, clonal disease characterized by the expansion of mature CD3+CD8+ cytotoxic T-cells. It is often associated with autoimmune disorders and immune-mediated cytopenias. Our recent findings suggest that up to 40% of T-LGL patients harbor mutations in the STAT3 gene (Koskela et al, NEJM, 2012). In the remaining T-LGL patients, the pathogenetic mutations are not known. Methods: To identify additional somatic mutations, we chose two STAT3 mutation negative T-LGL leukemia patients for exome sequencing. CD8+ T-cells were used as test cells and matched CD4+ T-cells as control. The exome was captured with the Nimblegen SeqCap EZ Exome Library v2.0 and the sequencing was performed with the Illumina HiSeq2000 sequencing platform. Candidate somatic mutations were identified with a bioinformatics pipeline consisting of BWA for sequence alignment, Samtools for alignment filtering and Varscan for somatic mutation calling. Results: Index patient 1 was diagnosed with T-LGL leukemia at the age of 70 and a TCR repertoire assay revealed one minor T- cell clone in the leukemic sample (Vβ7.1: 28 %). Exome sequencing revealed 10 nonsynonymous nucleotide variants with p-values lower than 0.01, of which the tumor suppressor gene Protein tyrosine phosphatase (PTP) receptor T (PTPRT) had a variant frequency of 14%. PTPRT has previously been found to reverse Tyr705 phosphorylation on STAT3, a modification associated with STAT3 deactivation. In this novel mutation, a highly conserved hydrophobic valine residue is converted into methionine (V995M). The mutation occurs in the cytoplasmic part of the protein, within the tyrosine-protein phosphatase 1 domain. The PTPRT V995M mutation may thereby affect STAT3 activity by reducing dephosphorylation of Tyr705, thus increasing the expression of STAT3 target genes. Index patient 2 was a 40 year-old male with untreated T-LGL leukemia. A TCR repertoire assay showed one predominant T-cell clone in the leukemic T-cells (Vβ13.2: 70%). Exome sequencing revealed 8 nonsynonymous nucleotide variants with p-values lower than 0.01. The missense mutation K436E in Angiopoietin-2 (ANGPT2), presenting with the lowest somatic p-value (1,06−09) and highest variant frequency (34%), was the most relevant candidate involved in the pathogenesis of leukemia. The mutation occurs on the surface of ANGPT2 within the well-conserved fibrinogen C-terminal domain. This domain binds the receptor TIE2 and the change in the polarity induced by K436E mutation is likely to affect the binding of TIE2 by ANGPT2. Overexpression of ANGPT2 has previously been shown to confer an adverse prognostic factor in other forms of leukemia. While these mutations appear biologically relevant and exciting, we have not yet seen them in other LGL patients screened so far (n=80). Conclusions: Somatic mutations in the PTPRT and ANGPT2 genes may represent rare genetic causes for T-LGL leukemia. Screening for these mutations in a larger cohort of patients is warranted. The mutation in the PTPRT gene is particularly exciting as it may directly impact the STAT3 pathway, which is a common pathogenetic event in T-LGL leukemia. Inactivating mutations of the PTPRT gene may have the same functional consequence as activating mutations of STAT3 in LGL patients. Disclosures: Koskela: Novartis: Honoraria; BMS: Honoraria; Janssen-Cilag: Honoraria. Kallioniemi:TEKES-FiDiPro: Research Funding. Porkka:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Maciejewski:NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding. Mustjoki:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria.

Whole Exome Sequencing of Flow Purified Tumour Cells Reveals Recurrently Mutated Genes and Pathways in Adult T-Cell Lymphoma/Leukaemia (ATLL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1469-1469
Author(s):  
Richard Dillon ◽  
Lucy Cook ◽  
Alka Saxena ◽  
Rosamond Nuamah ◽  
Ghazala Mirza ◽  
...  
Keyword(s):  
T Cell ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
T Cell Activation ◽  
Japanese Population ◽  
Cell Activation ◽  
Somatic Mutations ◽  
Point Mutations ◽  
Tumour Cells ◽  
Whole Exome

Abstract Introduction ATLL is an aggressive lymphoid malignancy with a very poor prognosis arising in patients with HTLV-1 infection. Asymptomatic HTLV1+ individuals have a polyclonal expansion of CD4+ T-cells driven by the products of the HTLV-1 tax and HBZ genes. In ATLL, integration site analysis shows a monoclonal outgrowth (frequently associated with downregulation of tax) which is presumed to be driven by acquisition of oncogenic somatic mutations. Genome-wide studies identifying these mutations in patients of African or African Caribbean origin have not been reported; limited data are available on a Japanese population. Methods We obtained nine cryopreserved peripheral blood mononuclear cell samples from seven patients of African Carribean origin. ATLL cells (CD3+CD4+CD25+CCR4+) and healthy B- and myeloid cells (CD3-CD33+ and CD3-CD20+) were sorted to high purity (>99%) by flow cytometry. B- and myeloid populations were pooled and used as a germline control. DNA was extracted from the sorted populations and whole exome sequencing libraries were prepared using Sure Select XT v5 (Agilent) and sequenced using an Illumina HiSeq2500. Mean exome coverage was 145.3x in tumour samples and 131x in control samples with 96.3% and 96% respectively covered at >20x. Variants were called using GATK, germline variants were filtered out using VarScan, and all remaining variants were manually inspected using IGV. Copy number changes were called using ExomeDepth. Results We identified somatic mutations in all cases, including short insertions or deletions (InDels, median 3 per exome, range 2-12), single nucleotide variations (SNV) affecting the amino acid sequence (median 40, range 4-132) and noncoding SNV (median 35, range 12-114). Median variant allele frequency (VAF) was >20% in 8/9 tumour samples (overall median 40%, range 24-47%) indicating reliable isolation of substantially pure clonal tumour cells. We excluded one sample with a low VAF (18%) from further analysis. We identified two recurrent somatic point mutations: CCR4 Y331I (2 patients; a known activating mutation present in ~25% of ATLL cases) and NRG1 T232M (2 patients; a novel mutation). Both patients with CCR4 Y331I had large duplications encompassing the mutant CCR4 allele along with CCR1-CCR9; one of the two patients had been treated with the anti-CCR4 antibody Mogamulizumab and had been in complete remission for 20 months. We identified a further six genes harbouring somatic mutations in more than one patient: ANKRD30A, CDH7, PRKCB, RYR2, SETD5 and STAT3 (each mutated in two patients). In addition to these recurrently mutated genes, pathway analysis using ConsensusPath identified three pathways which were mutated in most or all patients. NOTCH pathway members were mutated in 6/6 cases (with 3/6 cases carrying two mutations) in one of the following genes: NOTCH1, NOTCH2, MAMLD1, DMXL2, PTCRA, NOTCH2NL, TBL1XR1, HDAC10. T-cell activation and costimulation pathway members were mutated in 5/6 patients (range 1-5 mutations). The following genes were affected: CARD11, CCR4, CD40LG, CHUK, DPP8, HLA-A, HLA-B, IFNAR2, NLRP2, P2RX7, PLCG1, RASSF5, SH2B3, ZEB1. Finally we observed multiple mutations affecting the FGFR/EGFR - PI3K signalling pathway (6/6 patients, 1-6 mutations per patient). The affected genes were ADCY1, APBB1B, FGFR2, HGF, LRRFIP1, NCAM1, NRG1, PDGFC, PI3KCD, PLCG1, PLCXD1, PRKCB, STAT3 and ZMYM2. In one patient, all 261 somatic mutations present in the blood were detected in a lymph node biopsy taken at the same time; an additional mutation (a frameshift deletion in FIP1L1) was present in the node but not detected in the blood. In another patient, a sample taken at the time of relapse five years after initial presentation was also analysed: all 97 mutations called at diagnosis were present at relapse, and 15 additional somatic mutations had been acquired. Conclusions Whole exome sequencing identified two recurrent somatic point mutations and six recurrently mutated genes which, given their co-occurrence in this small sample, are likely to be tumour drivers. Genes encoding components of the NOTCH, T-cell activation and FGFR/EGFR-PI3K pathways were mutated in most or all ATLL samples analysed, identifying these pathways as potential therapeutic targets. We now plan to validate these candidate genes in a large and longitudinal patient cohort and compare these with results from an ongoing study in the Japanese population. Disclosures No relevant conflicts of interest to declare.

scholarly journals AB0008 APPLYING WHOLE EXOME SEQUENCING TO FAMILIAL ANTIPHOSPHOLIPID SYNDROME: NEW PLAYERS IN A RARE DISEASE?

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1039.1-1039
Author(s):  
A. Barinotti ◽  
M. Radin ◽  
I. Cecchi ◽  
S. G. Foddai ◽  
E. Rubini ◽  
...  
Keyword(s):  
Immune Response ◽  
Ischemic Stroke ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Antiphospholipid Syndrome ◽  
Missense Mutations ◽  
Literature Research ◽  
Missense Variants ◽  
Vein Thrombosis ◽  
Whole Exome

Background:Antiphospholipid Syndrome (APS) is an autoimmune disease whose precise aetiology is still unknown, but the high heterogeneity of its manifestations and clinical course is presumably due to the occurrence of different mechanisms and alterations at different levels and pathways [1]. The first genetic studies in APS focused primarily on the human leukocytes antigen system region, but more recent data highlighted a role of other genes in APS susceptibility, primarily those involved in the immune response and in the haemostatic process.Objectives:We aimed to deepen the investigation of APS genetic background starting from a case of familial APS, analysing two siblings with thrombotic APS (Table 1), both triple positive for antiphospholipid antibodies (aPL).Table 1.Main clinical and laboratory characteristics of the patients included in the study.PatientAgeaPL ProfileRelevant Clinical History1 (F)51Triple positive (LA, aCL IgG, aβ2GPI IgG)Two episodes of ischemic stroke, one episode of CAPS (renal thrombotic microangiopathy, visual impairment, ischemic stroke)2 (M)47Triple positive (LA, aCL IgG, aβ2GPI IgG)Three episodes of deep vein thrombosis, regardless ongoing well conducted therapy vitamin k antagonist and additional retinal vein thrombosisLA: lupus anticoagulant; aCL: anti-cardiolipin antibodies; aβ2GPI: anti- β2 glycoprotein I antibodies; CAPS: catastrophic APS.Methods:Genomic DNA was extracted from peripheral blood and the samples underwent Whole Exome Sequencing (WES). Sequencing was done on a 100X coverage, and reads have been aligned to the human reference genome (GRCh37/hg19 assembly) using the Burrows–Wheeler Alignment tool (BWA). The mean sequencing depth on target regions was 170X for patient 1, 205X for patient 2, moreover, 99.50% of the targeted bases had at least 10X coverage for all the three donors. The resulting single nucleotide polymorphisms (SNPs) have been analysed through a step-by-step process based on their frequency population (using Genome Aggregation Database), their predicted effects on the protein (using VarSome) and a literature research about the genes carrying them. Moreover, genes previously associated with a pro-thrombotic tendency and with APS have been analysed in the two patients.Results:Starting from more than 120000 SNPs for each patients, the analysis led to reduce the list of SNPs of interest to 27 missense mutations. The complete literature research regarding the genes carrying these mutations allowed to further reduce the number of selected genes, focusing on those that exert a role potentially involved in APS pathogenesis and development. In particular, these genes (PLA2G6, HSPG2, BCL3, ZFAT, ATP2B2, CRTC3 and ADCY3) take part in the immune response and the vascular homeostasis. The list of the DNA missense variants of interest found in our cases of familial APS is resumed in Figure 2.Figure 2.List of DNA missense variants of interest found in patient 1 and 2. Genes potentially involved in APS pathogenesis and development are highlighted in bold.No mutations on genes known to be associated with a pro-thrombotic state (F5, F2, MTHFR, F13A1, PROC, PROS1, FGB and SERPINE1), or on genes previously associated with APS (B2GPI, PF4V1, SELP, TLR2, TLR4, GP Ia, GP1BA, F2R, F2RL1, TFPI, F3, VEGFA, FLT1, and TNF) have been found in the WES analysis.Conclusion:To some extent, this can be seen as a proof of concept of the complexity of APS. Efforts to interpret the genetic risk factors involved in the heterogeneous clinical features of the syndrome, for instance, the integration of WES and network-based approaches might help to identify and stratify patients at risk of developing APS.References:[1]Iuliano A, Galeazzi M, Sebastiani GD. Antiphospholipid syndrome’s genetic and epigenetic aspects. Autoimmun Rev. 2019;18(9).Disclosure of Interests:None declared

scholarly journals Germline and somatic mutations in the pathology of pineal cyst: A whole‐exome sequencing study of 93 individuals

2021 ◽  
Author(s):  
Yuanqing Yan ◽  
Rebecca Martinez ◽  
Maria N. Rasheed ◽  
Joshua Cahal ◽  
Zhen Xu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Somatic Mutations ◽  
Pineal Cyst ◽  
Whole Exome

Whole-exome sequencing reveals potential germline and somatic mutations in 60 malignant ovarian germ cell tumors

2021 ◽  
Author(s):  
Juan Chen ◽  
Yan Li ◽  
Jianlei Wu ◽  
Yakun Liu ◽  
Shan Kang
Keyword(s):  
Germ Cell ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Peripheral Blood ◽  
Copy Number ◽  
Somatic Mutations ◽  
Germ Cell Tumors ◽  
Germline Mutations ◽  
Deletion Region ◽  
Whole Exome

Abstract Background Malignant ovarian germ cell tumors (MOGCTs) are rare and heterogeneous ovary tumors. We aimed to identify potential germline mutations and somatic mutations in MOGCTs by whole-exome sequencing. Methods The peripheral blood and tumor samples from these patients were used to identify germline mutations and somatic mutations, respectively. For those genes corresponding to copy number alterations (CNA) deletion and duplication region, functional annotation of was performed. Immunohistochemistry was performed to evaluate the expression of mutated genes corresponding to CNA deletion region. Results In peripheral blood, copy number loss and gain were mostly found in yolk sac tumors (YST). Moreover, POU5F1 was the most significant mutated gene with mutation frequency > 10% in both CNA deletion and duplication region. In addition, strong cytoplasm staining of POU5F1 (corresponding to CNA deletion region) was found in 2 YST and nuclear staining in 2 dysgerminomas (DG) tumor samples. Genes corresponding to CNA deletion region were significantly enriched in the signaling pathway of regulating pluripotency of stem cells. In addition, genes corresponding to CNA duplication region were significantly enriched in the signaling pathways of RIG-I-like receptor, Toll-like receptor, NF-kappa B and Jak–STAT. KRT4, RPL14, PCSK6, PABPC3 and SARM1 mutations were detected in both peripheral blood and tumor samples. Conclusions Identification of potential germline mutations and somatic mutations in MOGCTs may provide a new field in understanding the genetic feature of the rare biological tumor type in the ovary.

scholarly journals PCNT point mutations and familial intracranial aneurysms

Neurology ◽  
2018 ◽  
Vol 91 (23) ◽  
pp. e2170-e2181 ◽  
Author(s):  
Oswaldo Lorenzo-Betancor ◽  
Patrick R. Blackburn ◽  
Emily Edwards ◽  
Rocío Vázquez-do-Campo ◽  
Eric W. Klee ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Intracranial Aneurysms ◽  
Point Mutations ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Interaction Domain ◽  
Knockout Mouse Model ◽  
Whole Exome ◽  
Primordial Dwarfism

ObjectiveTo identify novel genes involved in the etiology of intracranial aneurysms (IAs) or subarachnoid hemorrhages (SAHs) using whole-exome sequencing.MethodsWe performed whole-exome sequencing in 13 individuals from 3 families with an autosomal dominant IA/SAH inheritance pattern to look for candidate genes for disease. In addition, we sequenced PCNT exon 38 in a further 161 idiopathic patients with IA/SAH to find additional carriers of potential pathogenic variants.ResultsWe identified 2 different variants in exon 38 from the PCNT gene shared between affected members from 2 different families with either IA or SAH (p.R2728C and p.V2811L). One hundred sixty-four samples with either SAH or IA were Sanger sequenced for the PCNT exon 38. Five additional missense mutations were identified. We also found a second p.V2811L carrier in a family with a history of neurovascular diseases.ConclusionThe PCNT gene encodes a protein that is involved in the process of microtubule nucleation and organization in interphase and mitosis. Biallelic loss-of-function mutations in PCNT cause a form of primordial dwarfism (microcephalic osteodysplastic primordial dwarfism type II), and ≈50% of these patients will develop neurovascular abnormalities, including IAs and SAHs. In addition, a complete Pcnt knockout mouse model (Pcnt−/−) published previously showed general vascular abnormalities, including intracranial hemorrhage. The variants in our families lie in the highly conserved PCNT protein-protein interaction domain, making PCNT a highly plausible candidate gene in cerebrovascular disease.

scholarly journals Whole-Exome Sequencing Identifies Somatic Mutations Associated With Mortality in Metastatic Clear Cell Kidney Carcinoma

2019 ◽  
Vol 10 ◽  
Author(s):  
Alejandro Mendoza-Alvarez ◽  
Beatriz Guillen-Guio ◽  
Adrian Baez-Ortega ◽  
Carolina Hernandez-Perez ◽  
Sita Lakhwani-Lakhwani ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Somatic Mutations ◽  
Clear Cell ◽  
Kidney Carcinoma ◽  
Whole Exome
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