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frameshift mutation

Satoshi Suzuki, Moriya Iwaizumi, Hidetaka Yamada, Tomohiro Sugiyama, Yasushi Hamaya, Takahisa Furuta, Shigeru Kanaoka, Haruhiko Sugimura, Hiroaki Miyajima, Satoshi Osawa, John M Carethers, Ken Sugimoto
Backgrounds: Trifluridine is an active antitumor component of TAS-102 that resembles 5-fluorouracil. Although patients with advanced colorectal cancer (CRC) exhibiting a mismatch repair (MMR) deficiency reportedly do not benefit from 5-fluorouracil-based chemotherapy and we previously reported that truncated methyl-CpG binding domain protein 4 (MBD4) enhances 5-fluorouracil cytotoxicity in MMR-deficient CRC cells, little is known regarding the effect of MMR deficiency on trifluridine cytotoxicity in CRC...
February 20, 2018: Oncotarget
Gözde Yeşil, Ayşe Aralaşmak, Enes Akyüz, Dilara İçağasıoğlu, Türkan Uygur Şahin, Yavuz Bayram
BACKGROUND: The KCNMA1 gene encodes the α-subunit of the large conductance, voltage and calcium-sensitive potassium channel (BK channels) which plays an important role in neuronal excitability. Heterozygous mutations in KCNMA1 were firstly described in a large family with generalized epilepsy and paroxysmal nonkinesigenic dyskinesia. Recently, homozygous KCNMA1 mutations were reported to cause a phenotype of cerebellar atrophy, developmental delay and seizures. CASE REPORT: Herein; we report a patient with a novel homozygous truncating mutation in KCNMA1 (p...
March 16, 2018: Balkan Medical Journal
Kotaro Yuge, Kazuhiro Iwama, Chihiro Yonee, Mayumi Matsufuji, Nozomi Sano, Tomoko Saikusa, Yukako Yae, Yushiro Yamashita, Takeshi Mizuguchi, Naomichi Matsumoto, Toyojiro Matsuishi
Rett syndrome (RTT) is a neurodevelopmental disorder mostly caused by mutations in Methyl-CpG-binding protein 2 (MECP2); however, mutations in various other genes may lead to RTT-like phenotypes. Here, we report the first case of a Japanese girl with RTT caused by a novel syntaxin-binding protein 1 (STXBP1) frameshift mutation (c.60delG, p.Lys21Argfs*16). She showed epilepsy at one year of age, regression of acquired psychomotor abilities thereafter, and exhibited stereotypic hand and limb movements at 3 years of age...
March 12, 2018: Brain & Development
Ceren D Durmaz, Gareth Evans, Miriam J Smith, Pelin Ertop, Bengü N Akay, Timur Tuncalı
Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a rare multisystemic autosomal dominant disorder typically presenting with cutaneous basal cell carcinomas, multiple keratocysts, and skeletal anomalies. NBCCS is caused by heterozygous mutations in the PTCH1 gene in chromosome 9q22, in the PTCH2 gene in 1p34, or the SUFU gene in 10q24.32. Here, we report on an 18-month-old boy presenting with medulloblastoma, frontal bossing, and multiple skeletal anomalies and his father who has basal cell carcinomas, palmar pits, macrocephaly, bifid ribs, calcification of falx cerebri, and a history of surgery for odontogenic keratocyst...
March 16, 2018: Cytogenetic and Genome Research
Ying Pang, Garima Gupta, Chunzhang Yang, Herui Wang, Thanh-Truc Huynh, Ziedulla Abdullaev, Svetlana D Pack, Melanie J Percy, Terence R J Lappin, Zhengping Zhuang, Karel Pacak
BACKGROUND: The role of the hypoxia signaling pathway in the pathogenesis of pheochromocytoma/paraganglioma (PPGL)-polycythemia syndrome has been elucidated. Novel somatic mutations in hypoxia-inducible factor type 2A (HIF2A) and germline mutations in prolyl hydroxylase type 1 and type 2 (PHD1 and PHD2) have been identified to cause upregulation of the hypoxia signaling pathway and its target genes including erythropoietin (EPO) and its receptor (EPOR). However, in a minority of patients presenting with this syndrome, the genetics and molecular pathogenesis remain unexplained...
March 13, 2018: BMC Cancer
Min Jae Kang, Soo Min Ahn, Il Tae Hwang
Cornelia de Lange syndrome (CdLS) is a developmental disorder which is characterized by typical facial features, upper extremity malformations, and growth and cognitive delays. The genes involved in CdLS encode the cohesin complex and its associated proteins; and NIPBL mutations, which account for half of the cases, result in severe CdLS phenotypes. We describe a girl with CdLS, presenting with typical facial dysmorphism, cleft palate, hypertrichosis, upper limb hypertonicity, flexion contracture of elbows, micromelia, bilateral hearing loss, gastroesophageal reflux, and severe pyloric stenosis...
January 2018: Annals of Clinical and Laboratory Science
Savana C L Santos, Isabela M P O Rizzo, Reinaldo I Takata, Carlos E Speck-Martins, Jaime M Brum, Claudio Sollaci
BACKGROUND: Multiple osteochondromas is a dysplasia characterized by growth of two or more osteochondromas. It is genetically heterogeneous, caused by pathogenic variants in EXT1 or EXT2 genes in 70%-90% of patients. The EXT1 is more often mutated than EXT2 gene, with a variable prevalence between populations. There are no data about EXT1 and EXT2 pathogenic variants in patients with multiple osteochondromas in Brazilian population. The aim of this survey is to characterize these to determine the genotype profile of this population...
March 12, 2018: Molecular Genetics & Genomic Medicine
Dechao Xu, Yiyi Ma, Xiangchen Gu, Rongrong Bian, Yunhui Lu, Xiaohong Xing, Changlin Mei
BACKGROUND/AIMS: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder with mutations in PKD1 or PKD2. This study aimed to identify novel PKD1 and PKD2 mutations in Chinese patients with ADPKD. METHODS: Mutational analyses of both PKD genes were performed in 120 Chinese families with inherited ADPKD using long-range PCR and targeted next-generation sequencing approaches. Sanger sequencing was performed to check the positive mutations, while multiplex ligation-dependent probe amplification was adopted to examine those without mutations for the presence of large deletions...
March 6, 2018: Kidney & Blood Pressure Research
Laercio R Porto-Neto, Derek M Bickhart, Antonio J Landaeta-Hernandez, Yuri T Utsunomiya, Melvin Pagan, Esbal Jimenez, Peter J Hansen, Serdal Dikmen, Steven G Schroeder, Eui-Soo Kim, Jiajie Sun, Edward Crespo, Norman Amati, John B Cole, Daniel J Null, Jose F Garcia, Antonio Reverter, William Barendse, Tad S Sonstegard
Evolutionary adaptations are occasionally convergent solutions to the same problem. A mutation contributing to a heat tolerance adaptation in Senepol cattle, a New World breed of mostly European descent, results in the distinct phenotype known as slick, where an animal has shorter hair and lower follicle density across its coat than wild type animals. The causal variant, located in the 11th exon of prolactin receptor , produces a frameshift that results in a truncated protein. However, this mutation does not explain all cases of slick coats found in criollo breeds...
2018: Frontiers in Genetics
Wen-Li Deng, Mei-Ling Gao, Xin-Lan Lei, Ji-Neng Lv, Huan Zhao, Kai-Wen He, Xi-Xi Xia, Ling-Yun Li, Yu-Chen Chen, Yan-Ping Li, Deng Pan, Tian Xue, Zi-Bing Jin
Retinitis pigmentosa (RP) is an irreversible, inherited retinopathy in which early-onset nyctalopia is observed. Despite the genetic heterogeneity of RP, RPGR mutations are the most common causes of this disease. Here, we generated induced pluripotent stem cells (iPSCs) from three RP patients with different frameshift mutations in the RPGR gene, which were then differentiated into retinal pigment epithelium (RPE) cells and well-structured retinal organoids possessing electrophysiological properties. We observed significant defects in photoreceptor in terms of morphology, localization, transcriptional profiling, and electrophysiological activity...
February 28, 2018: Stem Cell Reports
Ceren D Durmaz, John McGrath, Lu Liu, Halil G Karabulut
Focal dermal hypoplasia (FDH), also known as Goltz-Gorlin syndrome, is a rare, multisystemic, X-linked dominant genodermatosis characterized by defective development of mesodermal and ectodermal tissues. Major clinical features of the disorder are skin manifestations, skeletal defects, and developmental eye abnormalities. FDH is caused by heterozygous mutations in the PORCN gene located at Xp11.23, and 90% of individuals with FDH are females. Here, we report a female patient with cutaneous changes, multiple eye anomalies, short stature, and ectrodactyly of the right foot...
March 10, 2018: Cytogenetic and Genome Research
Nianwei Zhou, Shengmei Qin, Yili Liu, Lu Tang, Weipeng Zhao, Cuizhen Pan, Zilong Qiu, Xiaolin Wang, Xianhong Shu
Most patients with hypertrophic cardiomyopathy have single-gene autosomal dominant mutations in loci that encode for sarcomeric proteins. The aim of this study was to determine whether pathogenic mutations were present by whole-exome sequencing (WES) in two families with hypertrophic cardiomyopathy (HCM) that presented during adolescence. Blood samples and clinical data were collected from individuals in two families with HCM. DNA was extracted. Mutations were identified using whole-exome sequencing (WES), and the genotypes of family members were identified using Sanger sequencing...
March 7, 2018: European Journal of Medical Genetics
Gajendrahar Dwivedi, James E Haber
DNA double-strand break (DSB) is a cytotoxic lesion and needs to be repaired immediately. There are several metabolic pathways evolved to repair a DSB. Gene conversion is one of the least error-prone pathway for repair of a DNA DSB. Despite this there is nearly 1000-fold increase in mutation rate associated with gene conversion. Not only higher mutation rate is associated with gene conversion but also there is a very distinct mutation profile compared to spontaneous mutation events. Gene conversion is characterized by the presence of very high frameshift mutation events and other complex mutations that are not present during regular DNA replication...
2018: Methods in Enzymology
Julie Gauthier, Inge A Meijer, Davor Lessel, Niccolò E Mencacci, Dimitri Krainc, Maja Hempel, Konstantinos Tsiakas, Holger Prokisch, Elsa Rossignol, Margaret H Helm, Lance H Rodan, Jason Karamchandani, Miryam Carecchio, Steven J Lubbe, Aida Telegrafi, Lindsay B Henderson, Kerry Lorenzo, Stephanie E Wallace, Ian A Glass, Fadi F Hamdan, Jacques L Michaud, Guy A Rouleau, Philippe M Campeau
VPS13 protein family members, VPS13A through VPS13C, have been associated with various recessive movement disorders. We describe the first disease association of rare recessive VPS13D variants including a frameshift, missense and a partial duplication with a novel complex, hyperkinetic neurological disorder. The clinical features include developmental delay, a childhood onset movement disorder (chorea, dystonia or tremor) and progressive spastic ataxia or paraparesis. Characteristic brain MRI shows basal ganglia or diffuse white matter T2 hyperintensities as seen in Leigh syndrome and chorea-acanthocytosis...
March 8, 2018: Annals of Neurology
Yun Sol Jo, Min Sung Kim, Nam Jin Yoo, Sug Hyung Lee
MYH11 functions as a contractile protein, converting chemical energy into mechanical energy through adenosine triphosphate hydrolysis. In cancers, an oncogenic fusion CBFB/MYH11 and frameshift mutations have been reported. Truncating mutants of MYH11 exhibited increased ATPase and motor activity, suggesting their roles in energy balance and movement of cancer cells. MYH11 gene has a mononucleotide repeat (C8) in the coding sequences that could be a mutational target in the cancers exhibiting microsatellite instability (MSI)...
March 6, 2018: Applied Immunohistochemistry & Molecular Morphology: AIMM
Jackline P Ayres-Silva, Martin H Bonamino, Maria E Gouveia, Barbara C R Monte-Mor, Diego F Coutinho, Adelmo H Daumas, Cristiana Solza, Esteban Braggio, Ilana Renault Zalcberg
The genetic events associated with transformation of myeloproliferative neoplasms (MPNs) to secondary acute myeloid leukemia (sAML), particularly in the subgroup of essential thrombocythemia (ET) patients, remain incompletely understood. Deep studies using high-throughput methods might lead to a better understanding of genetic landscape of ET patients who transformed to sAML. We performed array-based comparative genomic hybridization (aCGH) and whole exome sequencing (WES) to analyze paired samples from ET and sAML phases...
2018: Frontiers in Oncology
Angel Fernandez I Marti, Christopher A Saski, George A Manganaris, Ksenija Gasic, Carlos H Crisosto
It has recently been described that the Japanese plum "Santa Rosa" bud sport series contains variations in ripening pattern: climacteric, suppressed-climacteric and non-climacteric types. This provides an interesting model to study the role of ethylene and other key mechanisms governing fruit ripening, softening and senescence. The aim of the current study was to investigate such differences at the genomic level, using this series of plum bud sports, with special reference to genes involved in ethylene biosynthesis, signal transduction, and sugar metabolism...
2018: Frontiers in Plant Science
Huawen Lin, Zhengyan Zhang, Carlo Iomini, Susan K Dutcher
Intraflagellar transport moves proteins in and out of flagella/cilia and it is essential for the assembly of these organelles. Using whole-genome sequencing, we identified splice site mutations in two IFT genes, IFT81 ( fla9 ) and IFT121 ( ift121-2 ), which lead to flagellar assembly defects in the unicellular green alga Chlamydomonas reinhardtii The splicing defects in these ift mutants are partially corrected by mutations in two conserved spliceosome proteins, DGR14 and FRA10. We identified a dgr14 deletion mutant, which suppresses the 3' splice site mutation in IFT81 , and a frameshift mutant of FRA10 , which suppresses the 5' splice site mutation in IFT121 Surprisingly, we found dgr14-1 and fra10 mutations suppress both splice site mutations...
March 2018: Open Biology
Jakub Zmajkovic, Pontus Lundberg, Ronny Nienhold, Maria L Torgersen, Anders Sundan, Anders Waage, Radek C Skoda
Familial erythrocytosis with elevated erythropoietin levels is frequently caused by mutations in genes that regulate oxygen-dependent transcription of the gene encoding erythropoietin ( EPO). We identified a mutation in EPO that cosegregated with disease with a logarithm of the odds (LOD) score of 3.3 in a family with autosomal dominant erythrocytosis. This mutation, a single-nucleotide deletion (c.32delG), introduces a frameshift in exon 2 that interrupts translation of the main EPO messenger RNA (mRNA) transcript but initiates excess production of erythropoietin from what is normally a noncoding EPO mRNA transcribed from an alternative promoter located in intron 1...
March 8, 2018: New England Journal of Medicine
Vesna Grivčeva-Panovska, Mitja Košnik, Peter Korošec, Slađana Andrejević, Ljerka Karadža-Lapić, Matija Rijavec
OBJECTIVE: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare disease, characterized by swellings. We aimed to characterize on a clinical and molecular basis C1-INH-HAE patients in the Republic of Macedonia. RESULTS: All 15 patients from six unrelated families were diagnosed with C1-INH-HAE type I, with a mean age of symptom onset of 11 years and an average delay of diagnosis of 7 years. Patients reported on average 31 angioedema attacks/year, with a median clinical severity score (CSS) of 7...
March 7, 2018: Annals of Medicine
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