Isaäc J Nijman

Publications (85) View all

• Article: A systematic genome-wide analysis of zebrafish protein-coding gene function.

  Ross N W Kettleborough, Elisabeth M Busch-Nentwich, Steven A Harvey, Christopher M Dooley, Ewart de Bruijn, Freek van Eeden, Ian Sealy, Richard J White, Colin Herd, Isaac J Nijman, Fruzsina Fényes, Selina Mehroke, Catherine Scahill, Richard Gibbons, Neha Wali, Samantha Carruthers, Amanda Hall, Jennifer Yen, Edwin Cuppen, Derek L Stemple
  [show abstract] [hide abstract]
  ABSTRACT: Since the publication of the human reference genome, the identities of specific genes associated with human diseases are being discovered at a rapid rate. A central problem is that the biological activity of these genes is often unclear. Detailed investigations in model vertebrate organisms, typically mice, have been essential for understanding the activities of many orthologues of these disease-associated genes. Although gene-targeting approaches and phenotype analysis have led to a detailed understanding of nearly 6,000 protein-coding genes, this number falls considerably short of the more than 22,000 mouse protein-coding genes. Similarly, in zebrafish genetics, one-by-one gene studies using positional cloning, insertional mutagenesis, antisense morpholino oligonucleotides, targeted re-sequencing, and zinc finger and TAL endonucleases have made substantial contributions to our understanding of the biological activity of vertebrate genes, but again the number of genes studied falls well short of the more than 26,000 zebrafish protein-coding genes. Importantly, for both mice and zebrafish, none of these strategies are particularly suited to the rapid generation of knockouts in thousands of genes and the assessment of their biological activity. Here we describe an active project that aims to identify and phenotype the disruptive mutations in every zebrafish protein-coding gene, using a well-annotated zebrafish reference genome sequence, high-throughput sequencing and efficient chemical mutagenesis. So far we have identified potentially disruptive mutations in more than 38% of all known zebrafish protein-coding genes. We have developed a multi-allelic phenotyping scheme to efficiently assess the effects of each allele during embryogenesis and have analysed the phenotypic consequences of over 1,000 alleles. All mutant alleles and data are available to the community and our phenotyping scheme is adaptable to phenotypic analysis beyond embryogenesis.
  Nature 04/2013; · 36.28 Impact Factor
• Source

  Available from: Martin Poot

  Dataset: EJHG (2012, proofs) MYH11 paper Harakalova Baas

  Lisa Golmard, Jaap Deckers, Jolien W Roos-Hesselink, Xavier Jeunemaitre, Marja W Wessels, Hubert F Baars, Magdalena Harakalova, Marjan M Weiss, Martin Poot, Jasper van der Smagt, Isaac J Nijman, Dick Lindhout, Carolien G F de Kovel, Gerard Pals, Jelena Medic, Ruben Van't Slot, Annette F Baas, Edwin Cuppen, Irene Joziasse
• Article: Incomplete segregation of MYH11 variants with thoracic aortic aneurysms and dissections and patent ductus arteriosus.

  Magdalena Harakalova, Jasper van der Smagt, Carolien G F de Kovel, Ruben Van't Slot, Martin Poot, Isaac J Nijman, Jelena Medic, Irene Joziasse, Jaap Deckers, Jolien W Roos-Hesselink, Marja W Wessels, Hubert F Baars, Marjan M Weiss, Gerard Pals, Lisa Golmard, Xavier Jeunemaitre, Dick Lindhout, Edwin Cuppen, Annette F Baas
  [show abstract] [hide abstract]
  ABSTRACT: Thoracic aortic aneurysms and dissections (TAAD) is a serious condition with high morbidity and mortality. It is estimated that 20% of non-syndromic TAAD cases are inherited in an autosomal-dominant pattern with variable expression and reduced penetrance. Mutations in myosin heavy chain 11 (MYH11), one of several identified TAAD genes, were shown to simultaneously cause TAAD and patent ductus arteriosus (PDA). We identified two large Dutch families with TAAD/PDA and detected two different novel heterozygote MYH11 variants in the probands. These variants, a heterozygote missense variant and a heterozygote in-frame deletion, were predicted to have damaging effects on protein structure and function. However, these novel alterations did not segregate with the TAAD/PDA in 3 out of 11 cases in family TAAD01 and in 2 out of 6 cases of family TAAD02. No mutation was detected in other known TAAD genes. Thus, it is expected that within these families other genetic factors contribute to the disease either by themselves or by interacting with the MYH11 variants. Such an oligogenic model for TAAD would explain the variable onset and progression of the disorder and its reduced penetrance in general. We conclude that in familial TAAD/PDA with an MYH11 variant in the index case caution should be exercised upon counseling family members. Specialized surveillance should still be offered to the non-carriers to prevent catastrophic aortic dissections or ruptures. Furthermore, our study underscores that segregation analysis remains very important in clinical genetics. Prediction programs and mutation evaluation algorithms need to be interpreted with caution.European Journal of Human Genetics advance online publication, 12 September 2012; doi:10.1038/ejhg.2012.206.
  European journal of human genetics: EJHG 09/2012; · 3.56 Impact Factor
• Source

  Available from: Martin Poot

  Article: Discovery of variants unmasked by hemizygous deletions.

  Ron Hochstenbach, Martin Poot, Isaac J Nijman, Ivo Renkens, Karen J Duran, Ruben Van't Slot, Ellen van Binsbergen, Bert van der Zwaag, Maartje J Vogel, Paulien A Terhal, Hans Kristian Ploos van Amstel, Wigard P Kloosterman, Edwin Cuppen
  [show abstract] [hide abstract]
  ABSTRACT: Array-based genome-wide segmental aneuploidy screening detects both de novo and inherited copy number variations (CNVs). In sporadic patients de novo CNVs are interpreted as potentially pathogenic. However, a deletion, transmitted from a healthy parent, may be pathogenic if it overlaps with a mutated second allele inherited from the other healthy parent. To detect such events, we performed multiplex enrichment and next-generation sequencing of the entire coding sequence of all genes within unique hemizygous deletion regions in 20 patients (1.53 Mb capture footprint). Out of the detected 703 non-synonymous single-nucleotide variants (SNVs), 8 represented variants being unmasked by a hemizygous deletion. Although evaluation of inheritance patterns, Grantham matrix scores, evolutionary conservation and bioinformatic predictions did not consistently indicate pathogenicity of these variants, no definitive conclusions can be drawn without functional validation. However, in one patient with severe mental retardation, lack of speech, microcephaly, cheilognathopalatoschisis and bilateral hearing loss, we discovered a second smaller deletion, inherited from the other healthy parent, resulting in loss of both alleles of the highly conserved heat shock factor binding protein 1 (HSBP1) gene. Conceivably, inherited deletions may unmask rare pathogenic variants that may exert a phenotypic impact through a recessive mode of gene action.
  European journal of human genetics: EJHG 01/2012; 20(7):748-53. · 3.56 Impact Factor
• Article: Primary colorectal cancers and their subsequent hepatic metastases are genetically different: implications for selection of patients for targeted treatment.

  Joost S Vermaat, Isaac J Nijman, Marco J Koudijs, Frank L Gerritse, Stefan J Scherer, Michal Mokry, Wijnand M Roessingh, Nico Lansu, Ewart de Bruijn, Richard van Hillegersberg, Paul J van Diest, Edwin Cuppen, Emile E Voest
  [show abstract] [hide abstract]
  ABSTRACT: In the era of DNA-guided personalized cancer treatment, it is essential to conduct predictive analysis on the tissue that matters. Here, we analyzed genetic differences between primary colorectal adenocarcinomas (CRC) and their respective hepatic metastasis. The primary CRC and the subsequent hepatic metastasis of 21 patients with CRC were analyzed using targeted deep-sequencing of DNA isolated from formalin-fixed, paraffin-embedded archived material. We have interrogated the genetic constitution of a designed "Cancer Mini-Genome" consisting of all exons of 1,264 genes associated with pathways relevant to cancer. In total, 6,696 known and 1,305 novel variations were identified in 1,174 and 667 genes, respectively, including 817 variants that potentially altered protein function. On average, 83 (SD = 69) potentially function-impairing variations were gained in the metastasis and 70 (SD = 48) variations were lost, showing that the primary tumor and hepatic metastasis are genetically significantly different. Besides novel and known variations in genes such as KRAS, BRAF, KDR, FLT1, PTEN, and PI3KCA, aberrations in the up/downstream genes of EGFR/PI3K/VEGF-pathways and other pathways (mTOR, TGFβ, etc.) were also detected, potentially influencing therapeutic responsiveness. Chemotherapy between removal of the primary tumor and the metastasis (N = 11) did not further increase the amount of genetic variation. Our study indicates that the genetic characteristics of the hepatic metastases are different from those of the primary CRC tumor. As a consequence, the choice of treatment in studies investigating targeted therapies should ideally be based on the genetic properties of the metastasis rather than on those of the primary tumor.
  Clinical Cancer Research 12/2011; 18(3):688-99. · 7.74 Impact Factor