Expanding the Mutation Spectrum Affecting αIIbβ3 Integrin in Glanzmann Thrombasthenia: Screening of the ITGA2B and ITGB3 Genes in a Large International Cohort.


:We report the largest international study on Glanzmann thrombasthenia (GT), an inherited bleeding disorder where defects of the ITGA2B and ITGB3 genes cause quantitative or qualitative defects of the αIIbβ3 integrin, a key mediator of platelet aggregation. Sequencing of the coding regions and splice sites of both genes in members of 76 affected families identified 78 genetic variants (55 novel) suspected to cause GT. Four large deletions or duplications were found by quantitative real-time PCR. Families with mutations in either gene were indistinguishable in terms of bleeding severity that varied even among siblings. Families were grouped into type I and the rarer type II or variant forms with residual αIIbβ3 expression. Variant forms helped identify genes encoding proteins mediating integrin activation. Splicing defects and stop codons were common for both ITGA2B and ITGB3 and essentially led to a reduced or absent αIIbβ3 expression; included was a heterozygous c.1440-13_c.1440-1del in intron 14 of ITGA2B causing exon skipping in seven unrelated families. Molecular modeling revealed how many missense mutations induced subtle changes in αIIb and β3 domain structure across both subunits, thereby interfering with integrin maturation and/or function. Our study extends knowledge of GT and the pathophysiology of an integrin.


Hum Mutat


Human mutation


Nurden AT,Pillois X,Fiore M,Alessi MC,Bonduel M,Dreyfus M,Goudemand J,Gruel Y,Benabdallah-Guerida S,Latger-Cannard V,Négrier C,Nugent D,Oiron RD,Rand ML,Sié P,Trossaert M,Alberio L,Martins N,Sirvain-Trukniewicz P,Co




Has Abstract


2015-05-01 00:00:00












  • Duarte allele impairs biostability of galactose-1-phosphate uridyltransferase in human lymphoblasts.

    abstract::The Duarte allele (D) is a missense mutation (N314D) that produces a characteristic isoform and partial impairment of galactose-1-phosphate uridyltransferase (GALT) in human erythrocytes, fibroblasts, and transformed lymphoblasts. The position of this amino acid is distant, however, from presumptive catalytic site(s) ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Lai K,Langley SD,Dembure PP,Hjelm LN,Elsas LJ 2nd

    更新日期:1998-01-01 00:00:00

  • Exome and genome analysis as a tool for disease identification and treatment: the 2011 Human Genome Variation Society scientific meeting.

    abstract::The 2011 annual scientific meeting of the Human Genome Variation Society (HGVS) was held on the 11th of October, in Montreal, Canada. The theme of this meeting was "Exome and Genome Analysis as a Tool for Disease Identification and Treatment." In the last few years, there has been a substantial increase in the use of ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Oetting WS

    更新日期:2012-03-01 00:00:00

  • Mutation nomenclature in practice: findings and recommendations from the cystic fibrosis external quality assessment scheme.

    abstract::Currently, two nomenclature systems are in use to describe sequence variants for cystic fibrosis: the established traditional nomenclature system and the more recent Human Genome Variation Society (HGVS) nomenclature system. We have evaluated the use of both systems in the laboratory reports of 217 participants in the...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Berwouts S,Morris MA,Girodon E,Schwarz M,Stuhrmann M,Dequeker E

    更新日期:2011-11-01 00:00:00

  • Comprehensive profiling of BRCA1 and BRCA2 variants in breast and ovarian cancer in Chinese patients.

    abstract::The identification and interpretation of germline BRCA1/2 variants become increasingly important in breast and ovarian cancer (OC) treatment. However, there is no comprehensive analysis of the germline BRCA1/2 variants in a Chinese population. Here we performed a systematic review and meta-analysis on such variants fr...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Gao X,Nan X,Liu Y,Liu R,Zang W,Shan G,Gai F,Zhang J,Li L,Cheng G,Song L

    更新日期:2020-03-01 00:00:00

  • Higher-than-expected population prevalence of potentially pathogenic germline TP53 variants in individuals unselected for cancer history.

    abstract::Li-Fraumeni syndrome (LFS) is an autosomal-dominant cancer predisposition disorder associated with pathogenic germline variants in TP53, with a high penetrance over an individual's lifetime. The actual population prevalence of pathogenic germline TP53 mutations is still unclear, most likely due to biased selection of ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: de Andrade KC,Mirabello L,Stewart DR,Karlins E,Koster R,Wang M,Gapstur SM,Gaudet MM,Freedman ND,Landi MT,Lemonnier N,Hainaut P,Savage SA,Achatz MI

    更新日期:2017-12-01 00:00:00

  • Mucolipidosis II-related mutations inhibit the exit from the endoplasmic reticulum and proteolytic cleavage of GlcNAc-1-phosphotransferase precursor protein (GNPTAB).

    abstract::Mucolipidosis (ML) II and MLIII alpha/beta are two pediatric lysosomal storage disorders caused by mutations in the GNPTAB gene, which encodes an α/β-subunit precursor protein of GlcNAc-1-phosphotransferase. Considerable variations in the onset and severity of the clinical phenotype in these diseases are observed. We ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: De Pace R,Coutinho MF,Koch-Nolte F,Haag F,Prata MJ,Alves S,Braulke T,Pohl S

    更新日期:2014-03-01 00:00:00

  • Central mutation databases--a review.

    abstract::The Internet has been a key component in the coordination of the diverse group of scientists involved in the Human Genome Project. Nowhere has this contribution been more critical than in the maintenance and exchange of information about genetic variation and mutation. Whereas the majority of DNA sequence is generated...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Porter CJ,Talbot CC,Cuticchia AJ

    更新日期:2000-01-01 00:00:00

  • Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene.

    abstract::N-acetylglutamate synthase (NAGS) deficiency, an autosomal recessive disorder, is the last urea cycle disorder for which molecular testing became available. This is the first comprehensive report of 21 mutations that cause NAGS deficiency and of commonly found polymorphisms in the NAGS gene. Five mutations are reporte...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Caldovic L,Morizono H,Tuchman M

    更新日期:2007-08-01 00:00:00

  • High incidence of 550delA mutation of CAPN3 in LGMD2 patients from Russia.

    abstract::Autosomal recessive limb gird muscular dystrophy (LGMD2) is a clinically and genetically heterogeneous group of diseases that are characterized by progressive atrophy and weakness of the proximal limb muscles. At least eight genetic loci leading to LGMD2 are recognized. The proportion of particular gene involved in pr...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Pogoda TV,Krakhmaleva IN,Lipatova NA,Shakhovskaya NI,Shishkin SS,Limborska SA

    更新日期:2000-03-01 00:00:00

  • Maternal MTHFR variant forms increase the risk in offspring of isolated nonsyndromic cleft lip with or without cleft palate.

    abstract::The pathogenesis of cleft lip with or without cleft palate (CL/P) is complex; its onset could be due to the interaction of various genetic and environmental factors. Recently MTHFR functional polymorphisms were found to increase the risk of this common malformation; however, this finding is still debated. We investiga...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Pezzetti F,Martinelli M,Scapoli L,Carinci F,Palmieri A,Marchesini J,Carinci P,Caramelli E,Rullo R,Gombos F,Tognon M

    更新日期:2004-07-01 00:00:00

  • STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility.

    abstract::SH3 and cysteine-rich domain-containing protein 3 (STAC3) is an essential component of the skeletal muscle excitation-contraction coupling (ECC) machinery, though its role and function are not yet completely understood. Here, we report 18 patients carrying a homozygous p.(Trp284Ser) STAC3 variant in addition to a pati...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Zaharieva IT,Sarkozy A,Munot P,Manzur A,O'Grady G,Rendu J,Malfatti E,Amthor H,Servais L,Urtizberea JA,Neto OA,Zanoteli E,Donkervoort S,Taylor J,Dixon J,Poke G,Foley AR,Holmes C,Williams G,Holder M,Yum S,Medne L

    更新日期:2018-12-01 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

  • Fanconi anemia A due to a novel frameshift mutation in hotspot motifs: lack of FANCA protein.

    abstract::Homozygosity for a frameshift mutation at codon 1213 of FANCA gene was identified in a Turkish patient. Immunoprecipitation-western blot analysis showed the complete absence of the FANCA protein band. This novel mutation, a deletion of T at position 3639 in exon 37 (3639delT), is responsible for the disease and causes...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Balta G,de Winter JP,Kayserili H,Pronk JC,Joenje H

    更新日期:2000-06-01 00:00:00

  • Two novel types of contiguous gene deletion of the AVPR2 and ARHGAP4 genes in unrelated Japanese kindreds with nephrogenic diabetes insipidus.

    abstract::Study of two families containing individuals with nephrogenic diabetes insipidus (NDI) indicated different types of 21.3 kb and 26.3 kb deletions involving the AVPR2 and ARHGAP4 (RhoGAP C1) genes. In the case of the 21.3 kb deletion, the deletion consensus motif (5'-TGAAGG-3') and polypurine runs, known as the arrest ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Demura M,Takeda Y,Yoneda T,Furukawa K,Usukura M,Itoh Y,Mabuchi H

    更新日期:2002-01-01 00:00:00

  • The most common mutation in FKRP causing limb girdle muscular dystrophy type 2I (LGMD2I) may have occurred only once and is present in Hutterites and other populations.

    abstract::Limb girdle muscular dystrophy (LGMD) is common in the Hutterite population of North America. We previously identified a mutation in the TRIM32 gene in chromosome region 9q32, causing LGMD2H in approximately two-thirds of the 60 Hutterite LGMD patients studied to date. A genomewide scan was undertaken in five families...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Frosk P,Greenberg CR,Tennese AA,Lamont R,Nylen E,Hirst C,Frappier D,Roslin NM,Zaik M,Bushby K,Straub V,Zatz M,de Paula F,Morgan K,Fujiwara TM,Wrogemann K

    更新日期:2005-01-01 00:00:00

  • Evidence of a four-hit mechanism involving SMARCB1 and NF2 in schwannomatosis-associated schwannomas.

    abstract::Schwannomatosis is characterized by the onset of multiple intracranial, spinal, or peripheral schwannomas, without involvement of the vestibular nerve, which is instead pathognomonic of neurofibromatosis type 2 (NF2). Recently, a schwannomatosis family with a germline mutation of the SMARCB1 gene on chromosome 22 has ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Sestini R,Bacci C,Provenzano A,Genuardi M,Papi L

    更新日期:2008-02-01 00:00:00

  • Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy.

    abstract::Approximately two-thirds of Duchenne muscular dystrophy (DMD) patients show intragenic deletions ranging from one to several exons of the DMD gene and leading to a premature stop codon. Other deletions that maintain the translational reading frame of the gene result in the milder Becker muscular dystrophy (BMD) form o...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Béroud C,Tuffery-Giraud S,Matsuo M,Hamroun D,Humbertclaude V,Monnier N,Moizard MP,Voelckel MA,Calemard LM,Boisseau P,Blayau M,Philippe C,Cossée M,Pagès M,Rivier F,Danos O,Garcia L,Claustres M

    更新日期:2007-02-01 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

  • High-resolution breakpoint analysis provides evidence for the sequence-directed nature of genome rearrangements in hereditary disorders.

    abstract::Although most of the pertinent data on the sequence-directed processes leading to genome rearrangements (GRs) have come from studies on somatic tissues, little is known about GRs in the germ line of patients with hereditary disorders. This study aims at identifying DNA motifs and higher order structures of genome arch...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Kovac MB,Kovacova M,Bachraty H,Bachrata K,Piscuoglio S,Hutter P,Ilencikova D,Bartosova Z,Tomlinson I,Roethlisberger B,Heinimann K

    更新日期:2015-02-01 00:00:00

  • Functional characterization of splicing and ligand-binding domain variants in the LDL receptor.

    abstract::Familial hypercholesterolemia (FH) is an autosomal dominant disorder mostly caused by mutations in the LDLR gene. Although the detection of functional mutations in the LDLR gene provides an unequivocal diagnosis of the FH condition, there are many variants whose pathogenicity is still unknown. The aims of this study w...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Etxebarria A,Palacios L,Stef M,Tejedor D,Uribe KB,Oleaga A,Irigoyen L,Torres B,Ostolaza H,Martin C

    更新日期:2012-01-01 00:00:00

  • Sequence variation in the ATP-binding domain of the Wilson disease transporter, ATP7B, affects copper transport in a yeast model system.

    abstract::ATP7B is a copper transporting P-type ATPase defective in the autosomal recessive copper storage disorder, Wilson disease (WND). Functional assessment of variants helps to distinguish normal from disease-causing variants and provides information on important amino acid residues. A total of 11 missense variants of ATP7...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Hsi G,Cullen LM,Macintyre G,Chen MM,Glerum DM,Cox DW

    更新日期:2008-04-01 00:00:00

  • In silico and in vivo models for Qatari-specific classical homocystinuria as basis for development of novel therapies.

    abstract::Homocystinuria is a rare inborn error of methionine metabolism caused by cystathionine β-synthase (CBS) deficiency. The prevalence of homocystinuria in Qatar is 1:1,800 births, mainly due to a founder Qatari missense mutation, c.1006C>T; p.R336C (p.Arg336Cys). We characterized the structure-function relationship of th...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Ismail HM,Krishnamoorthy N,Al-Dewik N,Zayed H,Mohamed NA,Giacomo VD,Gupta S,Häberle J,Thöny B,Blom HJ,Kruger WD,Ben-Omran T,Nasrallah GK

    更新日期:2019-02-01 00:00:00

  • Molecular subtyping of gastric cancer combining genetic and epigenetic anomalies provides distinct clinicopathological features and prognostic impacts.

    abstract::Both genetic and epigenetic abnormalities play important roles in gastric cancer (GC) development. We investigated whether the molecular subtypes of gastric cancer by combining genetic and epigenetic anomalies define its clinicopathological features and prognosis. The CpG island methylator phenotype (CIMP), MLH1 methy...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Tahara T,Tahara S,Horiguchi N,Okubo M,Terada T,Yamada H,Yoshida D,Omori T,Osaki H,Maeda K,Kamano T,Funasaka K,Nagasaka M,Nakagawa Y,Shibata T,Ohmiya N

    更新日期:2019-03-01 00:00:00

  • Functional assessment of TSC2 variants identified in individuals with tuberous sclerosis complex.

    abstract::Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in the TSC1 or TSC2 genes. The TSC1 and TSC2 gene products, TSC1 and TSC2, form a complex that inhibits the mammalian target of rapamycin (mTOR) complex 1 (TORC1). Here, we investigate the effects of 78 TSC2 variants identified in i...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Hoogeveen-Westerveld M,Ekong R,Povey S,Mayer K,Lannoy N,Elmslie F,Bebin M,Dies K,Thompson C,Sparagana SP,Davies P,van Eeghen AM,Thiele EA,van den Ouweland A,Halley D,Nellist M

    更新日期:2013-01-01 00:00:00

  • Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and ovarian cancer patients.

    abstract::There is strong evidence that overtly inactivating mutations in RAD51C predispose to hereditary breast and ovarian cancer but the prevalence of such mutations, and whether they are associated with a particular clinical phenotype, remains unclear. Resolving these questions has important implications for the implementat...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Thompson ER,Boyle SE,Johnson J,Ryland GL,Sawyer S,Choong DY,kConFab,Chenevix-Trench G,Trainer AH,Lindeman GJ,Mitchell G,James PA,Campbell IG

    更新日期:2012-01-01 00:00:00

  • Absence of exon 15 BRAF germline mutations in familial melanoma.

    abstract::We have analyzed DNA from peripheral blood of 42 cases of familial melanoma for germline mutations in exon 15 of the BRAF gene. No evidence of mutation was found. We have also analyzed DNA extracted from secondary melanoma from two members of these families. These results were also negative. In addition we have search...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Lang J,Boxer M,MacKie R

    更新日期:2003-03-01 00:00:00

  • Stability related bias in residues replacing glycines within the collagen triple helix (Gly-Xaa-Yaa) in inherited connective tissue disorders.

    abstract::A missense mutation leading to the replacement of one Gly in the (Gly-Xaa-Yaa)n repeat of the collagen triple helix can cause a range of heritable connective tissue disorders that depend on the gene in which the mutation occurs. Osteogenesis imperfecta results from mutations in type I collagen, Ehlers-Danlos syndrome ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Persikov AV,Pillitteri RJ,Amin P,Schwarze U,Byers PH,Brodsky B

    更新日期:2004-10-01 00:00:00

  • Six novel ATM mutations in Italian patients with classical ataxia-telangiectasia.

    abstract::Mutations in the ATM gene are responsible for the autosomal recessive syndrome Ataxia Telangiectasia (AT). In a group of 26 classical AT Italian patients studied by protein truncation test (PTT), we identified six new mutations, never reported so far. Mutations -spread over the entire ATM coding sequence with not clea...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Saviozzi S,Saluto A,Piane M,Prudente S,Migone N,DeMarchi M,Brusco A,Chessa L

    更新日期:2003-04-01 00:00:00

  • A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC).

    abstract::Inherited retinal diseases (IRDs) cause visual loss due to dysfunction or progressive degeneration of photoreceptors. These diseases show marked phenotypic and genetic heterogeneity. The Israeli IRD consortium (IIRDC) was established in 2013 with the goal of performing clinical and genetic mapping of the majority of I...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Sharon D,Ben-Yosef T,Goldenberg-Cohen N,Pras E,Gradstein L,Soudry S,Mezer E,Zur D,Abbasi AH,Zeitz C,Cremers FPM,Khan MI,Levy J,Rotenstreich Y,Birk OS,Ehrenberg M,Leibu R,Newman H,Shomron N,Banin E,Perlman I

    更新日期:2020-01-01 00:00:00

  • Novel tools for extraction and validation of disease-related mutations applied to Fabry disease.

    abstract::Genetic disorders are often caused by nonsynonymous nucleotide changes in one or more genes associated with the disease. Specific amino acid changes, however, can lead to large variability of phenotypic expression. For many genetic disorders this results in an increasing amount of publications describing phenotype-ass...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Kuipers R,van den Bergh T,Joosten HJ,Lekanne dit Deprez RH,Mannens MM,Schaap PJ

    更新日期:2010-09-01 00:00:00