Human Mutation

Cover image for Vol. 34 Issue 2

February 2013

Volume 34, Issue 2

Pages 275–410, E2382–E2392

  1. Special Articles

    1. Top of page
    2. Special Articles
    3. Brief Reports
    4. Research Articles
    5. Letters to the Editor
    6. Errata
    7. Databases in Brief
    1. You have free access to this content
  2. Brief Reports

    1. Top of page
    2. Special Articles
    3. Brief Reports
    4. Research Articles
    5. Letters to the Editor
    6. Errata
    7. Databases in Brief
    1. Unilateral Cryptorchidism in Mice Mutant for Ptgds (pages 278–282)

      Pascal Philibert, Brigitte Boizet-Bonhoure, Anu Bashamboo, Françoise Paris, Kosuke Aritake, Yoshihiro Urade, Juliane Leger, Charles Sultan and Francis Poulat

      Article first published online: 17 OCT 2012 | DOI: 10.1002/humu.22231

    2. A Novel RAB33B Mutation in Smith–McCort Dysplasia (pages 283–286)

      Nina Dupuis, Sophie Lebon, Manoj Kumar, Séverine Drunat, Luitgard M. Graul-Neumann, Pierre Gressens and Vincent El Ghouzzi

      Article first published online: 8 NOV 2012 | DOI: 10.1002/humu.22235

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      Smith-McCort dysplasia is a disorder with skeletal features identical to those of Dyggve-Melchior-Clausen syndrome but with normal intelligence and no microcephaly. Although both are associated with mutations in the Golgi protein DYMECLIN, genetic heterogeneity has been suspected for SMC. The study describes an SMC patient with a loss-of-function mutation in the GTP-binding domain of RAB33B, which is involved in Golgi trafficking. These data confirm the genetic heterogeneity of SMC and highlight the role of Golgi transport in the pathogenesis of SMC/DMC.

    3. Alternative Splicing of In-Frame Exon Associated with Premature Termination Codons: Implications for Readthrough Therapies (pages 287–291)

      Alexandre Hinzpeter, Abdel Aissat, Alix de Becdelièvre, Eric Bieth, Elvira Sondo, Natacha Martin, Bruno Costes, Catherine Costa, Michel Goossens, Luis J.V. Galietta, Emmanuelle Girodon and Pascale Fanen

      Article first published online: 8 NOV 2012 | DOI: 10.1002/humu.22236

    4. MT-ND5 Mutation Causing Exercise Intolerance Displays Intercellular Heteroplasmy and Rapid Shifts Between Generations (pages 292–295)

      Petter Schandl Sanaker and Laurence A. Bindoff

      Article first published online: 4 JAN 2013 | DOI: 10.1002/humu.22238

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      A maternally inherited, heteroplasmic MT-ND5 mutation, m.13271T>C, causes mitochondrial myopathy in a young female patient. Single myoblast clones harbored only mutated or only wild type mtDNA, indicating possible intercellular heteroplasmy for this mutation. This, in turn, may underlie the extreme shifts in mutation load seen, as the mutation appeared not to be transmitted from the patient to her child. Intercellular heteroplasmy, if present, accentuates the effect of the genetic bottleneck and further complicates genetic counseling for mtDNA diseases.

    5. Kohlschütter–Tönz Syndrome: Mutations in ROGDI and Evidence of Genetic Heterogeneity (pages 296–300)

      Arianna Tucci, Eleanna Kara, Anna Schossig, Nicole I. Wolf, Vincent Plagnol, Katherine Fawcett, Coro Paisán-Ruiz, Matthew Moore, Dena Hernandez, Sebastiano Musumeci, Michael Tennison, Raoul Hennekam, Silvia Palmeri, Alessandro Malandrini, Salmo Raskin, Dian Donnai, Corina Hennig, Andreas Tzschach, Roel Hordijk, Thomas Bast, Katharina Wimmer, Chien-Ning Lo, Simon Shorvon, Heather Mefford, Evan E. Eichler, Roger Hall, Ian Hayes, John Hardy, Andrew Singleton, Johannes Zschocke and Henry Houlden

      Article first published online: 27 NOV 2012 | DOI: 10.1002/humu.22241

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      Kohlschütter-Tönz syndrome (KTS) is a rare autosomal recessive disorder of childhood characterised by amelogenesis imperfecta, developmental delay, and seizures caused by mutations in ROGDI. We undertook genetic studies in 10 families with KTS and identified ROGDI mutations in 5 families presenting with typical KTS; all remaining negative families had atypical features, a finding which supports the notion that mutations in ROGDI are associated to a tight pattern of clinical features.

  3. Research Articles

    1. Top of page
    2. Special Articles
    3. Brief Reports
    4. Research Articles
    5. Letters to the Editor
    6. Errata
    7. Databases in Brief
    1. Mutations in NLRP7 and KHDC3L Confer a Complete Hydatidiform Mole Phenotype on Digynic Triploid Conceptions (pages 301–308)

      Masoumeh Fallahian, Neil J. Sebire, Philip M. Savage, Michael J. Seckl and Rosemary A. Fisher

      Article first published online: 2 NOV 2012 | DOI: 10.1002/humu.22228

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      This article describes two digynic triploid conceptions presenting with histopathological features of complete hydatidiform mole (CHM). Both were associated with familial recurrent hydatidiform mole (FRHM), a condition usually characterised by recurrent CHM of diploid biparental origin. Both cases carried mutations in genes associated with FRHM, the first in NLRP7 and the second in KHDC3L. This study demonstrates that the presence of mutations in either gene confers a molar phenotype on successive pregnancies irrespective of the genetic constitution of the conception.

    2. Destabilization and Mislocalization of POU3F4 by C-Terminal Frameshift Truncation and Extension Mutation (pages 309–316)

      Byung Yoon Choi, Do-Hwan Kim, Taesu Chung, Mi Chang, Eun-Hye Kim, Ah Reum Kim, Jungirl Seok, Sun O Chang, Jinwoong Bok, Dongsup Kim, Seung-Ha Oh and Woong-Yang Park

      Article first published online: 17 OCT 2012 | DOI: 10.1002/humu.22232

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      A majority of X-linked non-syndromic hearing loss is caused by various types of mutations of the POU3F4 gene, as seen in DFNX2. We identified unique C-terminal frameshift truncation and extension mutations in Korean DFNX2 patients, which caused functional deterioration by reducing protein stability and mislocalization within the cell. In this study, we propose a molecular mechanism of frameshift extension mutations, which could be used to develop therapeutics for various Mendelian disorders.

    3. The UBIAD1 Prenyltransferase Links Menaquione-4 Synthesis to Cholesterol Metabolic Enzymes (pages 317–329)

      Michael L. Nickerson, Allen D. Bosley, Jayne S. Weiss, Brittany N. Kostiha, Yoshihisa Hirota, Wolfgang Brandt, Dominic Esposito, Shigeru Kinoshita, Ludger Wessjohann, Scott G. Morham, Thorkell Andresson, Howard S. Kruth, Toshio Okano and Michael Dean

      Article first published online: 27 NOV 2012 | DOI: 10.1002/humu.22230

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      Schnyder corneal dystrophy (SCD), an autosomal dominant disease characterized by corneal cholesterol deposition and loss of visual acuity, results from germline mutations in UBIAD1 causing missense protein alterations. We report a novel UBIAD1 founder mutation, p.G177E, in four SCD families from Finland and show significantly decreased MK-4 synthesis by SCD-altered UBIAD1. UBIAD1 interacts with HMGCR and SOAT1, enzymes catalyzing cholesterol synthesis and storage, respectively, indicating vitamin K and cholesterol synthesis are linked by UBIAD1 to maintain cornea health and visual acuity.

      Corrected by:

      Erratum: The UBIAD1 Prenyltransferase Links Menaquinone-4 Synthesis to Cholesterol Metabolic Enzymes

      Vol. 34, Issue 7, 1046, Article first published online: 30 APR 2013

    4. Modeling Tumor Progression by the Sequential Introduction of Genetic Alterations into the Genome of Human Normal Cells (pages 330–337)

      Davide Zecchin, Sabrina Arena, Miriam Martini, Francesco Sassi, Alberto Pisacane, Federica Di Nicolantonio and Alberto Bardelli

      Article first published online: 4 JAN 2013 | DOI: 10.1002/humu.22234

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      We developed cellular models recapitulating the occurrence of multiple cancer mutations to investigate their role in tumor progression. Knock in of EGFR, KRAS, BRAF or PIK3CA oncogenic variants was combined with knock-down of PTEN or RB1 in human non-transformed epithelial cells. Different combinations of alterations resulted in distinct biochemical properties and anchorage-independent growth abilities. Nevertheless, those genetic events were insufficient to fully transform target cells. Our results raise questions on the requirements for transformation of epithelial cells.

    5. Genome-Wide Analysis of Human SNPs at Long Intergenic Noncoding RNAs (pages 338–344)

      Geng Chen, Chengxiang Qiu, Qipeng Zhang, Bing Liu and Qinghua Cui

      Article first published online: 27 NOV 2012 | DOI: 10.1002/humu.22239

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      A genome-wide analysis of human SNPs at long intergenic noncoding RNAs (lincRNAs) revealed a significantly lower SNP density in lincRNA regions than flanking regions. However, the lincRNAs under recent positive selection have higher SNP density than flanking regions. Functional regions show lower SNP density than other regions in lincRNAs. We revealed that SNP density of lincRNAs is correlated with expression level and tissue specificity. We provided evidence that lincRNA SNP can affect phenotype and be associated with disease.

    6. Mechanisms of Formation of Structural Variation in a Fully Sequenced Human Genome (pages 345–354)

      Andy Wing Chun Pang, Ohsuke Migita, Jeffrey R. MacDonald, Lars Feuk and Stephen W. Scherer

      Article first published online: 19 NOV 2012 | DOI: 10.1002/humu.22240

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      We examined breakpoint junction sequences to infer the formation processes of 408,532 gains, 383,804 losses and 166 inversions identified in the Venter (HuRef) genome. We noticed a differential proportion of mechanisms according to size. Ligation and replication slippage were prevalent for small variants, whereas larger variants were associated with retrotransposition and nonalleleic homologous recombination. By characterizing the full spectrum of variants and comparing with earlier studies, this work should represent the closest estimate of the true proportion of mutational processes in the genome.

    7. A Novel Regulatory Defect in the Branched-Chain α-Keto Acid Dehydrogenase Complex Due to a Mutation in the PPM1K Gene Causes a Mild Variant Phenotype of Maple Syrup Urine Disease (pages 355–362)

      Alfonso Oyarzabal, Mercedes Martínez-Pardo, Begoña Merinero, Rosa Navarrete, Lourdes R Desviat, Magdalena Ugarte and Pilar Rodríguez-Pombo

      Article first published online: 12 DEC 2012 | DOI: 10.1002/humu.22242

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      We describe the unreported involvement of the cell-survival and stress-signaling essential mitochondrial phosphatase (PP2CM), a member of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, in maple syrup urine disease (MSUD). The disease-causing mutation was identified in a patient with a mild variant phenotype. SNP array-based genotyping showed a copy-neutral homozygous pattern for chromosome 4. Mutation analysis of the candidate gene, PPM1K, revealed a homozygous c.417_418delTA change. The rescue of BCKDH activity upon transfection with wild-type PPM1K verified the variant's involvement in clinical disease.

    8. You have full text access to this OnlineOpen article
      A Pan-European Study of the C9orf72 Repeat Associated with FTLD: Geographic Prevalence, Genomic Instability, and Intermediate Repeats (pages 363–373)

      Julie van der Zee, Ilse Gijselinck, Lubina Dillen, Tim Van Langenhove, Jessie Theuns, Sebastiaan Engelborghs, Stéphanie Philtjens, Mathieu Vandenbulcke, Kristel Sleegers, Anne Sieben, Veerle Bäumer, Githa Maes, Ellen Corsmit, Barbara Borroni, Alessandro Padovani, Silvana Archetti, Robert Perneczky, Janine Diehl-Schmid, Alexandre de Mendonça, Gabriel Miltenberger-Miltenyi, Sónia Pereira, José Pimentel, Benedetta Nacmias, Silvia Bagnoli, Sandro Sorbi, Caroline Graff, Huei-Hsin Chiang, Marie Westerlund, Raquel Sanchez-Valle, Albert Llado, Ellen Gelpi, Isabel Santana, Maria Rosário Almeida, Beatriz Santiago, Giovanni Frisoni, Orazio Zanetti, Cristian Bonvicini, Matthis Synofzik, Walter Maetzler, Jennifer Müller vom Hagen, Ludger Schöls, Michael T. Heneka, Frank Jessen, Radoslav Matej, Eva Parobkova, Gabor G. Kovacs, Thomas Ströbel, Stayko Sarafov, Ivailo Tournev, Albena Jordanova, Adrian Danek, Thomas Arzberger, Gian Maria Fabrizi, Silvia Testi, Eric Salmon, Patrick Santens, Jean-Jacques Martin, Patrick Cras, Rik Vandenberghe, Peter Paul De Deyn, Marc Cruts, Christine Van Broeckhoven, Julie van der Zee, Ilse Gijselinck, Lubina Dillen, Tim Van Langenhove, Jessie Theuns, Stéphanie Philtjens, Kristel Sleegers, Veerle Bäumer, Githa Maes, Ellen Corsmit, Marc Cruts, Christine Van Broeckhoven, Julie van der Zee, Ilse Gijselinck, Lubina Dillen, Tim Van Langenhove, Stéphanie Philtjens, Jessie Theuns, Kristel Sleegers, Veerle Bäumer, Githa Maes, Marc Cruts, Christine Van Broeckhoven, Sebastiaan Engelborghs, Peter P. De Deyn, Patrick Cras, Sebastiaan Engelborghs, Peter P. De Deyn, Mathieu Vandenbulcke, Mathieu Vandenbulcke, Barbara Borroni, Alessandro Padovani, Silvana Archetti, Robert Perneczky, Janine Diehl-Schmid, Matthis Synofzik, Walter Maetzler, Jennifer Müller vom Hagen, Ludger Schöls, Matthis Synofzik, Walter Maetzler, Jennifer Müller vom Hagen, Ludger Schöls, Michael T. Heneka, Frank Jessen, Alfredo Ramirez, Delia Kurzwelly, Carmen Sachtleben, Wolfgang Mairer, Alexandre de Mendonça, Gabriel Miltenberger-Miltenyi, Sónia Pereira, Clara Firmo, José Pimentel, Raquel Sanchez-Valle, Albert Llado, Anna Antonell, Jose Molinuevo , Ellen Gelpi, Caroline Graff, Huei-Hsin Chiang, Marie Westerlund, Caroline Graff, Anne Kinhult Ståhlbom, Håkan Thonberg, Inger Nennesmo, Anne Börjesson-Hanson, Benedetta Nacmias, Silvia Bagnoli, Sandro Sorbi, Valentina Bessi, Irene Piaceri, Isabel Santana, Beatriz Santiago, Isabel Santana, Maria Helena Ribeiro, Maria Rosário Almeida, Catarina Oliveira, João Massano, Carolina Garret, Paula Pires, Giovanni Frisoni, Orazio Zanetti, Cristian Bonvicini, Stayko Sarafov, Ivailo Tournev, Albena Jordanova, Ivailo Tournev, Gabor G. Kovacs, Thomas Ströbel, Michael T. Heneka, Frank Jessen, Alfredo Ramirez, Delia Kurzwelly, Carmen Sachtleben, Wolfgang Mairer;, Frank Jessen, Radoslav Matej, Eva Parobkova, Adrian Danel, Thomas Arzberger, Gian Maria Fabrizi, Silvia Testi, Sergio Ferrari, Tiziana Cavallaro, Eric Salmon, Patrick Santens, Patrick Cras and on behalf of the European Early-Onset Dementia (EOD) Consortium

      Article first published online: 4 JAN 2013 | DOI: 10.1002/humu.22244

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      We assessed the geographical distribution of C9orf72 G4C2 expansions in a pan-European FTLD cohort. The overall FTLD frequency was 9.98% with frequencies of 18.52% in familial 6.26% in sporadic patients. We demonstrated that C9orf72 transcriptional activity significantly decreased with increasing number of repeats of intermediate length (7 to 24 units), suggesting that they might act as predisposing alleles. Notably, we observed in expansion carriers increased frequencies of short indels in a GC-rich, low complexity sequence adjacent to the G4C2 repeat.

    9. Primary Microcephaly, Impaired DNA Replication, and Genomic Instability Caused by Compound Heterozygous ATR Mutations (pages 374–384)

      Houda Mokrani-Benhelli, Laetitia Gaillard, Patricia Biasutto, Tangui Le Guen, Fabien Touzot, Nadia Vasquez, Jun Komatsu, Emmanuel Conseiller, Capucine Pïcard, Eliane Gluckman, Christine Francannet, Alain Fischer, Anne Durandy, Jean Soulier, Jean-Pierre de Villartay, Marina Cavazzana-Calvo and Patrick Revy

      Article first published online: 20 DEC 2012 | DOI: 10.1002/humu.22245

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      We here report the first patient with compound heterozygous ATR mutations. By using DNA combing technology we demonstrate that ATR-deficient cells exhibit a profound spontaneous alteration of DNA replication parameters. Moreover, we show that the genomic instability caused by ATR deficiency is exacerbated by ATM inhibition. Collectively, our results emphasize the crucial role for ATR in the control of DNA replication, and reinforce the complementary and non redundant contributions of ATM and ATR in human cells to warrant genome integrity.

    10. Mutations in SYNGAP1 Cause Intellectual Disability, Autism, and a Specific Form of Epilepsy by Inducing Haploinsufficiency (pages 385–394)

      Martin H. Berryer, Fadi F. Hamdan, Laura L. Klitten, Rikke S. Møller, Lionel Carmant, Jeremy Schwartzentruber, Lysanne Patry, Sylvia Dobrzeniecka, Daniel Rochefort, Mathilde Neugnot-Cerioli, Jean-Claude Lacaille, Zhiyv Niu, Christine M. Eng, Yaping Yang, Sylvain Palardy, Céline Belhumeur, Guy A. Rouleau, Niels Tommerup, LaDonna Immken, Miriam H. Beauchamp, Gayle Simpson Patel, Jacek Majewski, Mark A. Tarnopolsky, Klaus Scheffzek, Helle Hjalgrim, Jacques L. Michaud and Graziella Di Cristo

      Article first published online: 12 DEC 2012 | DOI: 10.1002/humu.22248

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      We identified the first pathogenic de novo missense mutations (p.W362R, p.P562L) and three novel truncating mutations in SYNGAP1 in patients with non-syndromic intellectual disability (NSID) with or without autism or epilepsy. Both missense mutations and the previously described p.R579X impaired SYNGAP1 ability to reduce pERK levels in transfected cortical organotypic cultures, suggesting a possible loss of SYNGAP1 function. Moreover, our study confirms the involvement of SYNGAP1 in autism while providing novel insight into the epileptic manifestations associated with its disruption.

    11. Functional Characterization of Novel Mutations Affecting Survivin (BIRC5)-Mediated Therapy Resistance in Head and Neck Cancer Patients (pages 395–404)

      Shirley K. Knauer, Britta Unruhe, Sarah Karczewski, Rouven Hecht, Verena Fetz, Carolin Bier, Sandra Friedl, Barbara Wollenberg, Ralph Pries, Negusse Habtemichael, Ulf-Rüdiger Heinrich and Roland H. Stauber

      Article first published online: 20 DEC 2012 | DOI: 10.1002/humu.22249

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      Survivin is an acknowledged cancer therapy-resistance factor and overexpressed in head and neck squamous cell carcinomas (HNSCC). Driven by its nuclear export signal, Survivin shuttles between the nucleus and the cytoplasm, and is detectable in both cellular compartments in tumor biopsies. As predominantly nuclear Survivin is considered a favorable prognostic disease marker for HNSCC patients, we performed laser capture microdissection on corresponding biopsies. Thereby we detected somatic mutations affecting Survivin's nuclear export and thus its cytoprotective activity against chemo-radiation-induced apoptosis.

  4. Letters to the Editor

    1. Top of page
    2. Special Articles
    3. Brief Reports
    4. Research Articles
    5. Letters to the Editor
    6. Errata
    7. Databases in Brief
    1. You have free access to this content
      Statistical Analysis of Missense Mutation Classifiers (pages 405–406)

      Stephanie Hicks, Sharon E. Plon and Marek Kimmel

      Article first published online: 31 DEC 2012 | DOI: 10.1002/humu.22243

    2. You have free access to this content
      Response to: Statistical Analysis of Missense Mutation Classifiers (page 407)

      Vishal Acharya and Hampapathalu A. Nagarajaram

      Article first published online: 29 JAN 2013 | DOI: 10.1002/humu.22250

  5. Errata

    1. Top of page
    2. Special Articles
    3. Brief Reports
    4. Research Articles
    5. Letters to the Editor
    6. Errata
    7. Databases in Brief
    1. You have free access to this content
      Jagged1 (JAG1) Mutations in Alagille Syndrome: Increasing the Mutation Detection Rate (page 408)

      D. M. Warthen, E. C. Moore, B. M. Kamath, J. J. D. Morrissette, P. A. Sanchez-Lara, D. A. Piccoli, I. D. Krantz and N. B. Spinner

      Article first published online: 20 DEC 2012 | DOI: 10.1002/humu.22255

      This article corrects:

      Jagged1 (JAG1) mutations in Alagille syndrome: increasing the mutation detection rate12

      Vol. 27, Issue 5, 436–443, Article first published online: 30 MAR 2006

    2. You have free access to this content
      Functional Assessment of TSC2 Variants Identified in Individuals with Tuberous Sclerosis Complex (pages 409–410)

      Marianne Hoogeveen-Westerveld, Rosemary Ekong, Sue Povey, Karin Mayer, Nathalie Lannoy, Frances Elmslie, Martina Bebin, Kira Dies, Catherine Thompson, Steven P. Sparagana, Peter Davies, Agnies M. van Eeghen, Elizabeth A. Thiele, Ans van den Ouweland, Dicky Halley and Mark Nellist

      Article first published online: 7 JAN 2013 | DOI: 10.1002/humu.22256

      This article corrects:

      Functional Assessment of TSC2 Variants Identified in Individuals with Tuberous Sclerosis Complex

      Vol. 34, Issue 1, 167–175, Article first published online: 11 OCT 2012

  6. Databases in Brief

    1. Top of page
    2. Special Articles
    3. Brief Reports
    4. Research Articles
    5. Letters to the Editor
    6. Errata
    7. Databases in Brief
    1. You have free access to this content
      The CDC Hemophilia A Mutation Project (CHAMP) Mutation List: A New Online Resource (pages E2382–E2392)

      Amanda B. Payne, Connie H. Miller, Fiona M. Kelly, J. Michael Soucie and W. Craig Hooper

      Article first published online: 26 DEC 2012 | DOI: 10.1002/humu.22247

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      To assist hemophilia A (HA) researchers conducting genotyping analyses, we have developed a listing of Factor VIII gene (F8) mutations. Mutations were reviewed and uniquely identified using Human Genome Variation Society (HGVS) nomenclature standards. Listings also include the associated HA severity, associations of the mutations with inhibitors, and reference information. The mutation list currently contains 2,537 unique mutations. HA severity caused by the mutation is available for 2,002 mutations (80%) and information on inhibitors is available for 1,795 mutations (71%).

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