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[PMID]: 29182774
[Au] Autor:Kullar PJ; Gomez-Duran A; Gammage PA; Garone C; Minczuk M; Golder Z; Wilson J; Montoya J; Häkli S; Kärppä M; Horvath R; Majamaa K; Chinnery PF
[Ad] Address:MRC-Mitochondrial Biology Unit, University of Cambridge, CB2 0XY, UK.
[Ti] Title:Heterozygous SSBP1 start loss mutation co-segregates with hearing loss and the m.1555A>G mtDNA variant in a large multigenerational family.
[So] Source:Brain;141(1):55-62, 2018 Jan 01.
[Is] ISSN:1460-2156
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:The m.1555A>G mtDNA variant causes maternally inherited deafness, but the reasons for the highly variable clinical penetrance are not known. Exome sequencing identified a heterozygous start loss mutation in SSBP1, encoding the single stranded binding protein 1 (SSBP1), segregating with hearing loss in a multi-generational family transmitting m.1555A>G, associated with mtDNA depletion and multiple deletions in skeletal muscle. The SSBP1 mutation reduced steady state SSBP1 levels leading to a perturbation of mtDNA metabolism, likely compounding the intra-mitochondrial translation defect due to m.1555A>G in a tissue-specific manner. This family demonstrates the importance of rare trans-acting genetic nuclear modifiers in the clinical expression of mtDNA disease.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1711
[Cu] Class update date: 180311
[Lr] Last revision date:180311
[St] Status:In-Data-Review
[do] DOI:10.1093/brain/awx295

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[PMID]: 29523635
[Au] Autor:Müller C; Krunic M; Wendt J; von Haeseler A; Okamoto I
[Ad] Address:Medical University of Vienna.
[Ti] Title:Germline Variants in the POT1-Gene in High-Risk Melanoma Patients in Austria.
[So] Source:G3 (Bethesda);, 2018 Mar 09.
[Is] ISSN:2160-1836
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Risk of melanoma is in part determined by genetic factors. Currently the only established high penetrance familial melanoma genes are CDKN2A and CDK4. Recent studies reported germline variants in POT1 in melanoma families. In the present study, we sequenced the entire POT1 gene in 694 patients from the M3-study. Patients with multiple primary melanomas (n=163) or with a positive family history (n=133) were classified as high-risk melanoma patients. Additionally, 200 single primary melanoma patients and 198 non-melanoma controls were sequenced. For prediction analysis 10 different tools were used. In total 53 different variants were found, of which 8 were detected in high-risk melanoma patients, only. Two out of these 8 variants were located in exons and were non-synonymous: g.124510982 G>A (p.R80C) and g.124491977 T>G (p.N300H). While g.124491977 T>G was predicted to be neutral, 80% of the prediction tools classified g.124510982 G>A as deleterious. The variant, g.124467236 T>C, which possibly causes a change in the splice site was identified in a case with a positive family history in the present study. Another variant in the 5-UTR, g.124537261 A>G, was found in 2 high-risk patients. So, in conclusion, melanoma associated POT1 germline variants seem to be rare. Further studies are required to evaluate the role of POT1 for genetic counselling.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher

  3 / 11164 MEDLINE  
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[PMID]: 29339161
[Au] Autor:El Nagar S; Zindy F; Moens C; Martin L; Plassard D; Roussel MF; Lamonerie T; Billon N
[Ad] Address:Université Côte d'Azur, CNRS, Inserm, iBV, Nice, France.
[Ti] Title:A new genetically engineered mouse model of choroid plexus carcinoma.
[So] Source:Biochem Biophys Res Commun;496(2):568-574, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Choroid plexus carcinomas (CPCs) are highly malignant brain tumours predominantly found in children and associated to poor prognosis. Improved therapy for these cancers would benefit from the generation of animal models. Here we have created a novel mouse CPC model by expressing a stabilised form of c-Myc (MycT58A) and inactivating Trp53 in the choroid plexus of newborn mice. This induced aberrant proliferation of choroid plexus epithelial cells, leading to aggressive tumour development and death within 150 days. Choroid plexus tumours occurred with a complete penetrance in all brain ventricles, with prevalence in the lateral and fourth ventricles. Histological and cellular analysis indicated that these tumours were CPCs resembling their human counterparts. Comparison of gene expression profiles of CPCs and non-neoplastic tissues revealed profound alterations in cell cycle regulation and DNA damage responses, suggesting that dysregulation of cell division and DNA checkpoint pathways may represent key vulnerabilities. This novel animal model of CPC provides an invaluable tool to elucidate the mechanism of CPC formation and to develop successful therapies against this devastating paediatric cancer.
[Mh] MeSH terms primary: Carcinoma/genetics
Carcinoma/pathology
Choroid Plexus Neoplasms/genetics
Choroid Plexus Neoplasms/pathology
Choroid Plexus/pathology
Proto-Oncogene Proteins c-myc/genetics
Tumor Suppressor Protein p53/genetics
[Mh] MeSH terms secundary: Animals
Carcinogenesis/genetics
Carcinogenesis/pathology
Cell Proliferation
DNA Damage
Disease Models, Animal
Humans
Mice
Mice, Transgenic
Mutation
Transcriptome
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (Proto-Oncogene Proteins c-myc); 0 (Tumor Suppressor Protein p53)
[Em] Entry month:1803
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[Js] Journal subset:IM
[Da] Date of entry for processing:180118
[St] Status:MEDLINE

  4 / 11164 MEDLINE  
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[PMID]: 29521748
[Au] Autor:Figueira JA; Batista FRS; Rosso K; Veltrini VC; Pavan AJ
[Ad] Address:Oral Oncology Center, Department of Pathology and Clinical Propedeutics, Araçatuba Dental School, São Paulo State University (UNESP).
[Ti] Title:Delayed Diagnosis of Gorlin-Goltz Syndrome: The Importance of the Multidisciplinary Approach.
[So] Source:J Craniofac Surg;, 2018 Mar 08.
[Is] ISSN:1536-3732
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Gorlin-Goltz syndrome (GGS), also known as nevoid basal cell carcinoma syndrome, is an autosomal dominant inherited disorder with high penetrance and variable expressivity. The classic triad originally described by Gorlin and Goltz in 1960 is composed of multiple nevoid basal cell carcinomas (NBCCs), odontogenic keratocysts (OKCs) in the jaws and bifid ribs. in 1977, this triad was modified by Rayner et al, and to GGS diagnosis, the OKCs had to appear in combination with calcification of the cerebellar falx or palmar and plantar pits. It may occur that although GGS syndrome is a well-known condition, only the specific symptom could be observed by different specialists. Therefore, the patient cannot be placed in an always complex clinical panel. The authors introduce an example in this report. In the present case, the patient had NBCCs, OKCs, and probably other signs of GGS since 1998, and has been treated for this conditions separated, without a diagnosis of a syndromic condition. A 54-year-old white woman was referred to the oral medicine service due to cyst located in the right mandibular body. She had history of skin cancer and undergone surgeries and radiotherapies for the lesions treatment, scars on the skin face due to the lesions removed, and a new ulcerated lesion on the back of was diagnosed. In addition, the patient presented frontal and parietal bossing leading to increased cranial circumference, hypertelorism, strabismus, broad base, and mandibular prognathism. To the image examination, skull radiography revealed calcification of the falx cerebri; on chest X-ray bifid rib was observed and spine radiography showed vertebral osteophytes. Panoramic radiograph showed a well-defined bilocular radiolucent image located in posterior and anterior mandibular region. The whole elements induced us to investigate the patient's past medical history, which revealed that since 1998 had the diagnosis of NBCC and OKC. A multidisciplinary approach becomes necessary for the diagnosis and follow-up of patients with GGS, considering the complexity of the clinical manifestations. Therefore, it is of primary importance for dental surgeons and dermatologists to know the signs and symptoms of GGS to perform early diagnosis and to avoid progression of the oral cysts or metastasis of the skin lesions.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[St] Status:Publisher
[do] DOI:10.1097/SCS.0000000000004438

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[PMID]: 29490943
[Au] Autor:Martín-Lorenzo A; Auer F; Chan LN; García-Ramírez I; Gonzalez-Herrero I; Rodríguez-Hernández G; Bartenhagen C; Dugas M; Gombert M; Ginzel S; Blanco O; Orfao A; Alonso-López D; De Las Rivas J; Begoña García-Cenador M; Javier García Criado F; Müschen M; Sánchez-García I; Borkhardt A; Vicente-Dueñas C; Hauer J
[Ad] Address:Experimental Therapeutics and Translational Oncology Program, Instituto de Biologia Molecular y Celular del Cancer, CSIC/Universidad de Salamanca.
[Ti] Title:Loss of Pax5 exploits Sca1-BCR-ABLp190 susceptibility to confer the metabolic shift essential for pB-ALL.
[So] Source:Cancer Res;, 2018 Feb 28.
[Is] ISSN:1538-7445
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Preleukemic clones carrying BCR-ABLp190 oncogenic lesions are found in neonatal cord blood, where the majority of preleukemic carriers do not convert into precursor B-cell acute lymphoblastic leukemia (pB-ALL). However, the critical question of how these preleukemic cells transform into pB-ALL remains undefined. Here we model a BCR-ABLp190 preleukemic state and show that limiting BCR-ABLp190 expression to hematopoietic stem/progenitor cells (HS/PC) in mice (Sca1-BCR-ABLp190) causes pB-ALL at low penetrance, which resembles the human disease. pB-ALL blast cells were BCR-ABL-negative and transcriptionally similar to pro-B/pre-B cells, suggesting disease onset upon reduced Pax5 functionality. Consistent with this, double Sca1-BCR-ABLp190+Pax5+/- mice developed pB-ALL with shorter latencies, 90% incidence, and accumulation of genomic alterations in the remaining wild-type Pax5 allele. Mechanistically, the Pax5-deficient leukemic pro-B cells exhibited a metabolic switch towards increased glucose utilization and energy metabolism. Transcriptome analysis revealed that metabolic genes (IDH1, G6PC3, GAPDH, PGK1, MYC, ENO1, ACO1) were upregulated in Pax5-deficient leukemic cells, and a similar metabolic signature could be observed in human leukemia. Our studies unveil the first in vivo evidence that the combination between Sca1-BCR-ABLp190 and metabolic reprogramming imposed by reduced Pax5 expression is sufficient for pB-ALL development. These findings might help to prevent conversion of BCR-ABLp190 preleukemic cells.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[St] Status:Publisher

  6 / 11164 MEDLINE  
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[PMID]: 29457785
[Au] Autor:Lee Y; Jonson PH; Sarparanta J; Palmio J; Sarkar M; Vihola A; Evilä A; Suominen T; Penttilä S; Savarese M; Johari M; Minot MC; Hilton-Jones D; Maddison P; Chinnery P; Reimann J; Kornblum C; Kraya T; Zierz S; Sue C; Goebel H; Azfer A; Ralston SH; Hackman P; Bucelli RC; Taylor JP; Weihl CC; Udd B
[Ad] Address:Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, Missouri, USA.
[Ti] Title:TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations.
[So] Source:J Clin Invest;128(3):1164-1177, 2018 Mar 01.
[Is] ISSN:1558-8238
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Multisystem proteinopathy (MSP) involves disturbances of stress granule (SG) dynamics and autophagic protein degradation that underlie the pathogenesis of a spectrum of degenerative diseases that affect muscle, brain, and bone. Specifically, identical mutations in the autophagic adaptor SQSTM1 can cause varied penetrance of 4 distinct phenotypes: amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Paget's disease of the bone, and distal myopathy. It has been hypothesized that clinical pleiotropy relates to additional genetic determinants, but thus far, evidence has been lacking. Here, we provide evidence that a TIA1 (p.N357S) variant dictates a myodegenerative phenotype when inherited, along with a pathogenic SQSTM1 mutation. Experimentally, the TIA1-N357S variant significantly enhances liquid-liquid-phase separation in vitro and impairs SG dynamics in living cells. Depletion of SQSTM1 or the introduction of a mutant version of SQSTM1 similarly impairs SG dynamics. TIA1-N357S-persistent SGs have increased association with SQSTM1, accumulation of ubiquitin conjugates, and additional aggregated proteins. Synergistic expression of the TIA1-N357S variant and a SQSTM1-A390X mutation in myoblasts leads to impaired SG clearance and myotoxicity relative to control myoblasts. These findings demonstrate a pathogenic connection between SG homeostasis and ubiquitin-mediated autophagic degradation that drives the penetrance of an MSP phenotype.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[St] Status:In-Data-Review

  7 / 11164 MEDLINE  
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[PMID]: 29424105
[Au] Autor:Tan SC
[Ad] Address:UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
[Ti] Title:Low penetrance genetic polymorphisms as potential biomarkers for colorectal cancer predisposition.
[So] Source:J Gene Med;, 2018 Feb 08.
[Is] ISSN:1521-2254
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Colorectal cancer is a leading form of cancer in both males and females. Early detection of individuals at risk of colorectal cancer allows proper treatment and management of the disease to be implemented, which can potentially reduce the burden of colorectal cancer incidence, morbidity and mortality. In recent years, the role of genetic susceptibility factors in mediating predisposition to colorectal cancer has become more and more apparent. Identification of high-frequency, low-penetrance genetic polymorphisms associated with the cancer has therefore emerged as an important approach which can potentially aid prediction of colorectal cancer risk. However, the overwhelming amount of genetic epidemiology data generated over the past decades has made it difficult for one to assimilate the information and determine the exact genetic polymorphisms that can potentially be used as biomarkers for colorectal cancer. This review comprehensively consolidates, based primarily on results from meta-analyses, the recent progresses in the search of colorectal cancer-associated genetic polymorphisms, and discusses the possible mechanisms involved.
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Em] Entry month:1802
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[St] Status:Publisher
[do] DOI:10.1002/jgm.3010

  8 / 11164 MEDLINE  
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[PMID]: 29367466
[Au] Autor:Yu Z; Tang PL; Wang J; Bao S; Shieh JT; Leung AW; Zhang Z; Gao F; Wong SY; Hui AL; Gao Y; Dung N; Zhang ZG; Fan Y; Zhou X; Zhang Y; Wong DS; Sham PC; Azhar A; Kwok PY; Tam PP; Lian Q; Cheah KS; Wang B; Song YQ
[Ad] Address:School of Biomedical Sciences, Joint Laboratories of Matrix Biology and Diseases, The University of Hong Kong, Hong Kong, China.
[Ti] Title:Mutations in Hnrnpa1 cause congenital heart defects.
[So] Source:JCI Insight;3(2), 2018 Jan 25.
[Is] ISSN:2379-3708
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Incomplete penetrance of congenital heart defects (CHDs) was observed in a mouse model. We hypothesized that the contribution of a major genetic locus modulates the manifestation of the CHDs. After genome-wide linkage mapping, fine mapping, and high-throughput targeted sequencing, a recessive frameshift mutation of the heterogeneous nuclear ribonucleoprotein A1 (Hnrnpa1) gene was confirmed (Hnrnpa1ct). Hnrnpa1 was expressed in both the first heart field (FHF) and second heart field (SHF) at the cardiac crescent stage but was only maintained in SHF progenitors after heart tube formation. Hnrnpa1ct/ct homozygous mutants displayed complete CHD penetrance, including truncated and incomplete looped heart tube at E9.5, ventricular septal defect (VSD) and persistent truncus arteriosus (PTA) at E13.5, and VSD and double outlet right ventricle at P0. Impaired development of the dorsal mesocardium and sinoatrial node progenitors was also observed. Loss of Hnrnpa1 expression leads to dysregulation of cardiac transcription networks and multiple signaling pathways, including BMP, FGF, and Notch in the SHF. Finally, two rare heterozygous mutations of HNRNPA1 were detected in human CHDs. These findings suggest a role of Hnrnpa1 in embryonic heart development in mice and humans.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[St] Status:Publisher

  9 / 11164 MEDLINE  
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[PMID]: 29348176
[Au] Autor:Meng F; He Z; Tang X; Zheng J; Jin X; Zhu Y; Ren X; Zhou M; Wang M; Gong S; Mo JQ; Shu Q; Guan MX
[Ad] Address:From the Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310052, China.
[Ti] Title:Contribution of the tRNA 4317A→G mutation to the phenotypic manifestation of the deafness-associated mitochondrial 12S rRNA 1555A→G mutation.
[So] Source:J Biol Chem;293(9):3321-3334, 2018 Mar 02.
[Is] ISSN:1083-351X
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The 1555A→G mutation in mitochondrial 12S rRNA has been associated with aminoglycoside-induced and non-syndromic deafness in many individuals worldwide. Mitochondrial genetic modifiers are proposed to influence the phenotypic expression of m.1555A→G mutation. Here, we report that a deafness-susceptibility allele (m.4317A→G) in the tRNA gene modulates the phenotype expression of m.1555A→G mutation. Strikingly, a large Han Chinese pedigree carrying both m.4317A→G and m.1555A→G mutations exhibited much higher penetrance of deafness than those carrying only the m.1555A→G mutation. The m.4317A→G mutation affected a highly conserved adenine at position 59 in the T-loop of tRNA We therefore hypothesized that the m.4317A→G mutation alters both structure and function of tRNA Using lymphoblastoid cell lines derived from members of Chinese families (three carrying both m.1555A→G and m.4317A→G mutations, three harboring only m.1555A→G mutation, and three controls lacking these mutations), we found that the cell lines bearing both m.4317A→G and m.1555A→G mutations exhibited more severe mitochondrial dysfunctions than those carrying only the m.1555A→G mutation. We also found that the m.4317A→G mutation perturbed the conformation, stability, and aminoacylation efficiency of tRNA These m.4317A→G mutation-induced alterations in tRNA structure and function aggravated the defective mitochondrial translation and respiratory phenotypes associated with the m.1555A→G mutation. Furthermore, mutant cell lines bearing both m.4317A→G and m.1555A→G mutations exhibited greater reductions in the mitochondrial ATP levels and membrane potentials and increasing production of reactive oxygen species than those carrying only the m.1555A→G mutation. Our findings provide new insights into the pathophysiology of maternally inherited deafness arising from the synergy between mitochondrial 12S rRNA and tRNA mutations.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[St] Status:In-Data-Review
[do] DOI:10.1074/jbc.RA117.000530

  10 / 11164 MEDLINE  
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[PMID]: 29516370
[Au] Autor:Tabaro I; Reimondo G; Osella G; Aurizi C; Caraci P; Barbieri L; Giachino DF; Sirchia F; Terzolo M
[Ad] Address:Department of Clinical and Biological Sciences, Internal Medicine, San Luigi Gonzaga Hospital, Orbassano, University of Turin, Torino, Italy.
[Ti] Title:Novel mutation of PPOX gene in a patient with abdominal pain and syndrome of inappropriate antidiuresis.
[So] Source:Endocrine;, 2018 Mar 07.
[Is] ISSN:1559-0100
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:PURPOSE: Acute porphyrias are metabolic disorders of heme biosynthesis characterized by acute life-threatening attacks. The diagnosis is often missed since clinical presentation is aspecific mimicking other medical and surgical conditions. Variegate porphyria (VP) is an autosomal dominant inherited disease with incomplete penetrance due to decreased activity of the Protoporphyrinogen Oxydase (PPOX) gene; most VP mutations are family specific. We report the case of a 40 year-old woman who presented many times to the emergency department complaining of unexplained abdominal pain and laboratory investigations showed repeatedly hyponatremia. Syndrome of inappropriate antidiuresis (SIAD) was confirmed and measurement of urine porphobilinogen and delta-aminolevulinic acid disclosed the diagnosis of acute porphyria. The genetic analysis of PPOX gene was performed. METHODS: The entire coding sequence and exon/intron boundaries of PPOX gene were amplified in 5 different Polymerase Chain Reaction (PCR) fragments. In silico prediction of the pathogenicity of the mutation was determined by using different tools, Polyphen2, SNPs&GO, SNPs3D. RESULTS: The genetic analysis of PPOX gene revealed a novel missense variant c.1376 G > A (p.Cys459Tyr) in heterozygous state. The same variant was later found in one of her cousins with skin lesions and other three younger asymptomatic relatives. We provided evidence that this novel mutation is likely to be pathogenetic. CONCLUSIONS: Our case highlights the importance of considering VP in the differential diagnosis of SIAD and underlines the role of genetic screening in the management of such patients. The finding of a novel mutation of PPOX gene in our index case has allowed to recognize an affected family.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180308
[Lr] Last revision date:180308
[St] Status:Publisher
[do] DOI:10.1007/s12020-018-1569-5


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