In vitro mutations in dihydrofolate reductase that confer resistance to methotrexate: potential for clinical application.


:Mammalian cells cultured in the presence of the chemotherapeutic agent, methotrexate, develop resistance to this drug. Sometimes this is due to mutations in the gene for dihydrofolate reductase, the primary target of methotrexate. However, it has not been possible to link such polymorphism to resistance of neoplastic disease to therapy with methotrexate. Nevertheless, interest in this possibility lead to the introduction of many mutations into the cDNA for human DHFR by mutagenesis. Most of the corresponding enzyme variants have been expressed in Escherichia coli and characterized. Many mutations in codons for hydrophobic residues at the active site greatly decrease inhibition by methotrexate, and by the related substrate analogue, trimetrexate, while allowing the retention of considerable catalytic efficiency. Introduction of some of these mutants into mammalian cells by retroviral transfer provides substantial protection from toxic effects of the inhibitors, and has promise for the myeloprotection of patients receiving therapy with methotrexate or trimetrexate. Another potential use is in therapy for inherited disorders of hematopoiesis, where genetic modification of enough cells is a perennial problem. After transplantation of bone marrow that has been transduced with a bicistronic vector encoding both the mutant DHFR and a therapeutic gene, subsequent administration of methotrexate or trimetrexate should permit selection and enrichment of genetically modified hematopoietic cells.


Hum Mutat


Human mutation


Blakley RL,Sorrentino BP




Has Abstract


1998-01-01 00:00:00














  • A two-tier approach to mutation detection in the COL4A5 gene for Alport syndrome.

    abstract::About 85% of Alport syndrome is an X-linked semi-dominant condition caused by mutations in the collagen gene, COL4A5. The large size and high GC content of this gene have presented diagnostic laboratories with problems in identifying mutations with greater than about a 50% success rate since the gene was first cloned ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: King K,Flinter FA,Green PM

    更新日期:2006-10-01 00:00:00

  • A case of methemoglobinemia type II due to NADH-cytochrome b5 reductase deficiency: determination of the molecular basis.

    abstract::Clinical, biochemical and molecular findings in a patient with methemoglobinemia type II are described. Furthermore, a comparison between methemoglobinemia type I and type II, both caused by a deficiency of NADH-cytochrome b5 reductase (b5R), is made. Although the clinical pictures of type I and II are strikingly diff...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Aalfs CM,Salieb-Beugelaar GB,Wanders RJ,Mannens MM,Wijburg FA

    更新日期:2000-01-01 00:00:00

  • Rapid classification of phenylketonuria genotypes by analysis of heteroduplexes generated by PCR-amplifiable synthetic DNA.

    abstract::We describe a rapid and simple method for phenylketonuria genotyping which identifies five point mutations within exon 12 of the human phenylalanine hydroxylase gene. The method involves PCR amplification of the target exon and hybridization with a PCR-amplifiable synthetic DNA (universal heteroduplex generator, UHG)....

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Wood N,Tyfield L,Bidwell J

    更新日期:1993-01-01 00:00:00

  • Impaired calmodulin binding of myosin-7A causes autosomal dominant hearing loss (DFNA11).

    abstract::Both myosin 7A (MYO7A) and calmodulin (CaM) are required for transduction and adaptation processes in inner ear hair cells. We identified a novel heterozygous missense mutation (c.2557C>T; p.R853C) in a family with autosomal dominant non-syndromic hearing loss that changes an evolutionarily invariant residue of the fi...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Bolz H,Bolz SS,Schade G,Kothe C,Mohrmann G,Hess M,Gal A

    更新日期:2004-09-01 00:00:00

  • An activated 5' cryptic splice site in the human ALG3 gene generates a premature termination codon insensitive to nonsense-mediated mRNA decay in a new case of congenital disorder of glycosylation type Id (CDG-Id).

    abstract::A defect of the dolichyl-P-Man:Man5GlcNAc2-PP-dolichyl mannosyltransferase encoded by the ALG3 gene (alias NOT56L) causes congenital disorder of glycosylation type Id (CDG-Id). In this work, a new mutation in the ALG3 gene causing atypical splicing is described with characterization of expression levels and transcript...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Denecke J,Kranz C,Kemming D,Koch HG,Marquardt T

    更新日期:2004-05-01 00:00:00

  • Predicting functional variants in enhancer and promoter elements using RegulomeDB.

    abstract::Here we present a computational model, Score of Unified Regulatory Features (SURF), that predicts functional variants in enhancer and promoter elements. SURF is trained on data from massively parallel reporter assays and predicts the effect of variants on reporter expression levels. It achieved the top performance in ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Dong S,Boyle AP

    更新日期:2019-09-01 00:00:00

  • Network-Informed Gene Ranking Tackles Genetic Heterogeneity in Exome-Sequencing Studies of Monogenic Disease.

    abstract::Genetic heterogeneity presents a significant challenge for the identification of monogenic disease genes. Whole-exome sequencing generates a large number of candidate disease-causing variants and typical analyses rely on deleterious variants being observed in the same gene across several unrelated affected individuals...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Dand N,Schulz R,Weale ME,Southgate L,Oakey RJ,Simpson MA,Schlitt T

    更新日期:2015-12-01 00:00:00

  • EEC- and ADULT-associated TP63 mutations exhibit functional heterogeneity toward P63 responsive sequences.

    abstract::TP63 germ-line mutations are responsible for a group of human ectodermal dysplasia syndromes, underlining the key role of P63 in the development of ectoderm-derived tissues. Here, we report the identification of two TP63 alleles, G134V (p.Gly173Val) and insR155 (p.Thr193_Tyr194insArg), associated to ADULT and EEC synd...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Monti P,Russo D,Bocciardi R,Foggetti G,Menichini P,Divizia MT,Lerone M,Graziano C,Wischmeijer A,Viadiu H,Ravazzolo R,Inga A,Fronza G

    更新日期:2013-06-01 00:00:00

  • Clinically relevant variants - identifying, collecting, interpreting, and disseminating: the 2013 annual scientific meeting of the Human Genome Variation Society.

    abstract::The dramatic advances in genetic sequencing technologies used in research laboratories are now entering the clinic, and applications of whole-genome and whole-exome sequencing to disease diagnosis, predisposition, and treatment will soon be commonplace. However, the standards and methods for identifying clinically rel...

    journal_title:Human mutation



    authors: Stanley CM,Sunyaev SR,Greenblatt MS,Oetting WS

    更新日期:2014-04-01 00:00:00

  • Thermal instability of compound variants of carnitine palmitoyltransferase II and impaired mitochondrial fuel utilization in influenza-associated encephalopathy.

    abstract::Influenza-associated encephalopathy (IAE) is characterized by persistent high fever, febrile convulsions, severe brain edema, and high mortality in otherwise apparently healthy individuals. We have reported that a large proportion of patients suffering from disabling or fatal IAE, with transiently elevated serum acylc...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Yao D,Mizuguchi H,Yamaguchi M,Yamada H,Chida J,Shikata K,Kido H

    更新日期:2008-05-01 00:00:00

  • The human TBX5 gene mutation database.

    abstract::Germline mutations of the TBX5 gene were identified as the primary cause in up to 70% of patients with Holt-Oram syndrome (HOS), an autosomal dominant disorder characterized by malformations of the upper limbs and cardiac defects. Furthermore, somatic mutations of the TBX5 gene have been described in diseased heart ti...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Heinritz W,Shou L,Moschik A,Froster UG

    更新日期:2005-10-01 00:00:00

  • Discovery of genetic profiles impacting response to chemotherapy: application to gemcitabine.

    abstract::Chemotherapy is a major treatment modality for individuals affected by cancer. Currently, a number of genome-based technologies are being adopted to identify genes associated with drug response; however, large-scale genetic association applications are still limited. Here we describe a novel strategy based on the gene...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Jarjanazi H,Kiefer J,Savas S,Briollais L,Tuzmen S,Pabalan N,Ibrahim-Zada I,Mousses S,Ozcelik H

    更新日期:2008-04-01 00:00:00

  • The novel p.Ser263Phe mutation in the human high-affinity choline transporter 1 (CHT1/SLC5A7) causes a lethal form of fetal akinesia syndrome.

    abstract::A subset of a larger and heterogeneous class of disorders, the congenital myasthenic syndromes (CMS) are caused by pathogenic variants in genes encoding proteins that support the integrity and function of the neuromuscular junction (NMJ). A central component of the NMJ is the sodium-dependent high-affinity choline tra...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Banerjee M,Arutyunov D,Brandwein D,Janetzki-Flatt C,Kolski H,Hume S,Leonard NJ,Watt J,Lacson A,Baradi M,Leslie EM,Cordat E,Caluseriu O

    更新日期:2019-10-01 00:00:00

  • Novel TMPRSS6 mutations associated with iron-refractory iron deficiency anemia (IRIDA).

    abstract::Mutations leading to abrogation of matriptase-2 proteolytic activity in humans are associated with an iron-refractory iron deficiency anemia (IRIDA) due to elevated hepcidin levels. In this paper we describe 12 IRIDA patients belonging to 7 unrelated families and identify 10 (9 novel) TMPRSS6 mutations spread along th...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: De Falco L,Totaro F,Nai A,Pagani A,Girelli D,Silvestri L,Piscopo C,Campostrini N,Dufour C,Al Manjomi F,Minkov M,Van Vuurden DG,Feliu A,Kattamis A,Camaschella C,Iolascon A

    更新日期:2010-05-01 00:00:00

  • Guide and links to online genetic and genomic educational resources, valuable for all levels.

    abstract::There is a well-recognized growing need for improved access to online genetic and genomics education for professionals, students, teachers, and the public. Numerous individual online genetic and genomic educational resources have been developed, but many are difficult to identify or locate when required. Consequently,...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Tobias AP,Tobias ES

    更新日期:2020-12-01 00:00:00

  • Capillary electrophoresis analysis of conventional splicing assays: IARC analytical and clinical classification of 31 BRCA2 genetic variants.

    abstract::Rare sequence variants in "high-risk" disease genes, often referred as unclassified variants (UVs), pose a serious challenge to genetic testing. However, UVs resulting in splicing alterations can be readily assessed by in vitro assays. Unfortunately, analytical and clinical interpretation of these assays is often chal...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: de Garibay GR,Acedo A,García-Casado Z,Gutiérrez-Enríquez S,Tosar A,Romero A,Garre P,Llort G,Thomassen M,Díez O,Pérez-Segura P,Díaz-Rubio E,Velasco EA,Caldés T,de la Hoya M

    更新日期:2014-01-01 00:00:00

  • Annotation of functional impact of voltage-gated sodium channel mutations.

    abstract::Voltage-gated sodium channels are pore-forming transmembrane proteins that selectively allow sodium ions to flow across the plasma membrane according to the electro-chemical gradient thus mediating the rising phase of action potentials in excitable cells and playing key roles in physiological processes such as neurotr...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Hinard V,Britan A,Schaeffer M,Zahn-Zabal M,Thomet U,Rougier JS,Bairoch A,Abriel H,Gaudet P

    更新日期:2017-05-01 00:00:00

  • p53 website and analysis of p53 gene mutations in human cancer: forging a link between epidemiology and carcinogenesis.

    abstract::The p53 tumor suppressor gene has proven to be one of the genes most often mutated in human cancers. It involves mainly point mutations leading to amino acid substitutions in the central region of the protein which impairs normal functions. Analysis of the mutational events that target the p53 gene has revealed eviden...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Soussi T,Dehouche K,Béroud C

    更新日期:2000-01-01 00:00:00

  • Screening practices for mutations in the CFTR gene ABCC7.

    abstract::Cystic fibrosis transmembrane conductance regulator (CFTR) gene studies are now one of the most frequent activities in clinical molecular genetics laboratories. The number of requests is growing, owing to the increasingly wide range of recognized CFTR gene diseases (cystic fibrosis, congenital bilateral absence of the...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Girodon-Boulandet E,Cazeneuve C,Goossens M

    更新日期:2000-01-01 00:00:00

  • Cafe Variome: general-purpose software for making genotype-phenotype data discoverable in restricted or open access contexts.

    abstract::Biomedical data sharing is desirable, but problematic. Data "discovery" approaches-which establish the existence rather than the substance of data-precisely connect data owners with data seekers, and thereby promote data sharing. Cafe Variome ( was therefore designed to provide a general-pur...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Lancaster O,Beck T,Atlan D,Swertz M,Thangavelu D,Veal C,Dalgleish R,Brookes AJ

    更新日期:2015-10-01 00:00:00

  • Novel mutations in African American patients with glycogen storage disease Type II. Mutations in brief no. 209. Online.

    abstract::The infantile form of GSD II (an inherited deficiency of the lysosomal enzyme, acid alpha-glucosidase, Pompe disease) is a severe and invariably fatal disease characterized by a rapidly progressive generalized hypotonia, hepatomegaly, and cardiomegaly. We have recently demonstrated that African American patients share...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Raben N,Lee E,Lee L,Hirschhorn R,Plotz PH

    更新日期:1999-01-01 00:00:00

  • Mutations in the genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) in diabetes mellitus and hyperinsulinism.

    abstract::The beta-cell ATP-sensitive potassium channel is a key component of stimulus-secretion coupling in the pancreatic beta-cell. The channel couples metabolism to membrane electrical events, bringing about insulin secretion. Given the critical role of this channel in glucose homeostasis, it is not surprising that mutation...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Gloyn AL,Siddiqui J,Ellard S

    更新日期:2006-03-01 00:00:00

  • Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations.

    abstract::BRCA1 and BRCA2 testing for hereditary breast and ovarian cancer (HBOC) does not identify all pathogenic variants. Sequencing of 20 complete genes in HBOC patients with uninformative test results (N = 287), including noncoding and flanking sequences of ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, EPCAM, MLH1, MRE11A, MSH2, ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Caminsky NG,Mucaki EJ,Perri AM,Lu R,Knoll JH,Rogan PK

    更新日期:2016-07-01 00:00:00

  • Transport, enzymatic activity, and stability of mutant sulfamidase (SGSH) identified in patients with mucopolysaccharidosis type III A.

    abstract::Mucopolysaccharidosis type IIIA (MPSIIIA) is an autosomal recessive lysosomal storage disease caused by mutations in the N-sulfoglucosamine sulfohydrolase gene (SGSH; encoding sulfamidase, also sulphamidase) leading to the lysosomal accumulation and urinary excretion of heparan sulfate. Considerable variation in the o...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Muschol N,Storch S,Ballhausen D,Beesley C,Westermann JC,Gal A,Ullrich K,Hopwood JJ,Winchester B,Braulke T

    更新日期:2004-06-01 00:00:00

  • An automated procedure to identify biomedical articles that contain cancer-associated gene variants.

    abstract::The proliferation of biomedical literature makes it increasingly difficult for researchers to find and manage relevant information. However, identifying research articles containing mutation data, a requisite first step in integrating large and complex mutation data sets, is currently tedious, time-consuming and impre...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: McDonald R,Scott Winters R,Ankuda CK,Murphy JA,Rogers AE,Pereira F,Greenblatt MS,White PS

    更新日期:2006-09-01 00:00:00

  • Conservation of the RB1 gene in human and primates.

    abstract::Mutations in the RB1 gene are associated with retinoblastoma, which has served as an important model for understanding hereditary predisposition to cancer. Despite the great scrutiny that RB1 has enjoyed as the prototypical tumor suppressor gene, it has never been the object of a comprehensive survey of sequence varia...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Sivakumaran TA,Shen P,Wall DP,Do BH,Kucheria K,Oefner PJ

    更新日期:2005-04-01 00:00:00

  • Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome.

    abstract::Several different genetic alterations in the etiology of Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]) are known, mostly point mutations and genomic rearrangements in 1 of at least 3 mismatch-repair (MMR) genes. However, no susceptibility factor has yet been identified in a significant part (30-50...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Kovacs ME,Papp J,Szentirmay Z,Otto S,Olah E

    更新日期:2009-02-01 00:00:00

  • Mechanistic insights into the link between a polymorphism of the 3'UTR of the SLC7A1 gene and hypertension.

    abstract::We previously identified the polymorphism ss52051869 in the 3'UTR of human SLC7A1, and demonstrated that it might participate in the apparent link between altered endothelial function, decreased L-arginine and nitric oxide (NO) metabolism, and a genetic predisposition to essential hypertension. Here, we demonstrate th...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Yang Z,Kaye DM

    更新日期:2009-03-01 00:00:00

  • Seven novel and four recurrent point mutations in the factor VIII (F8C) gene.

    abstract::Haemophilia A is a X-linked bleeding disorder, caused by deficiency in the activity of coagulation factor VIII due to mutations in the corresponding gene. The most common defect in patients is an inversion of the factor VIII gene that accounts for nearly 45% of individuals with severe hemophilia A. Point mutations and...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Bogdanova N,Lemcke B,Markoff A,Pollmann H,Dworniczak B,Eigel A,Horst J

    更新日期:2001-12-01 00:00:00

  • Kindler syndrome: extension of FERMT1 mutational spectrum and natural history.

    abstract::Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and pr...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Has C,Castiglia D,del Rio M,Diez MG,Piccinni E,Kiritsi D,Kohlhase J,Itin P,Martin L,Fischer J,Zambruno G,Bruckner-Tuderman L

    更新日期:2011-11-01 00:00:00