Martin de Boer

Publications (89) View all

• Source

  Available from: Martin de Boer

  Conference Proceeding: Chronic granulomatous disease caused by a partly exonised retroposed TMF1 gene copy inserted into the CYBB gene

  m. de boer
  [show abstract] [hide abstract]
  ABSTRACT: Background: The NADPH-oxidase complex catalyzes the for- mation of superoxide, which enables the destruction of patho- gens engulfed in phagocytes. An X-linked gene ( CYBB ) and four autosomal genes encode the proteins of this complex. Dis- abling mutations in CYBB lead to gp91 -phox- deficient X-linked CGD. Materials and methods: We studied an immunocompromised male individual who suffered from recurrent infections. None of the patient’s relatives studied had a health record suggest- ing an immunodeficiency. The patient was diagnosed with X- CGD. Results: In the first intron of CYBB we detected a novel inser- tion, which originated either in the maternal germline or dur- ing the fetal development of the patient. The insertion arose via retroposition of a partially processed transcript of the TMF1 gene located on chromosome 3. In the patient we stud- ied, the inserted retrocopy is partly exonised into a defective CYBB splice variant carrying a premature stop codon. Conclusions: We describe the first retroposed gene copy lead- ing to a human disease, which illustrates that although gene retroposition has contributed numerous beneficial novelties during mammalian evolution, it may also produce genetic alterations with immediate and adverse consequences. This is also the first example of a polymorphic retrocopy in man.
  ESCI, 137; 03/2011
• Source

  Available from: Martin de Boer

  Article: Four different NCF2 mutations in six families from Turkey and an overview of NCF2 gene mutations.

  M Y Köker, O Sanal, K van Leeuwen, M de Boer, A Metin, T Patiroğlu, T T Ozgür, I Tezcan, D Roos
  [show abstract] [hide abstract]
  ABSTRACT: One of the rarest forms of autosomal recessive chronic granulomatous disease (AR-CGD) is attributable to mutations in the NCF2 gene, which encodes the polypeptide p67(phox), a key cytoplasmic protein in the phagocyte NADPH oxidase system. NCF2 is localized on chromosome 1q25, encompasses 40 kb and contains 16 exons. We report here the clinical and molecular characterization of six patients with CGD from six consanguineous Turkish families. The ages of the five female patients were between 3 and 22 years and a male patient was 2 years old; all patients showed clear clinical symptoms of CGD. The mothers of the patients did not show a bimodal histogram pattern specific for X-CGD in the dihydrorhodamine-1,2,3 (DHR) assay. Moreover, p67(phox) protein expression was not detectable using flow cytometric analysis of the patients' neutrophils except in those from patient 6, which had a diminished expression. Mutation analysis of NCF2 revealed four different homozygous mutations: a novel nonsense mutation in exon 3 c.229C>T, p.Arg77X; a novel missense mutation in exon 4 c.279C>G, p.Asp93Glu; a nonsense mutation in exon 4 c.304C>T, p.Arg102X; and a novel missense mutation in exon 6 c.605C>T, p.Ala202Val. The parents were found to be heterozygotes for these mutations. The prevalence of NCF2 mutant families is approximately 15% in our series of 40 CGD families. This high incidence of A67 CGD in Turkey is undoubtedly caused by the high incidence of consanguineous marriages. We found three new mutations in NCF2 and one previously described. These are presented together with an overview of all NCF2 mutations now known.
  European Journal of Clinical Investigation 08/2009; 39(10):942-51. · 3.02 Impact Factor
• Source

  Available from: Martin de Boer

  Article: Six different CYBA mutations including three novel mutations in ten families from Turkey, resulting in autosomal recessive chronic granulomatous disease.

  M Y Köker, K van Leeuwen, M de Boer, F Celmeli, A Metin, T T Ozgür, I Tezcan, O Sanal, D Roos
  [show abstract] [hide abstract]
  ABSTRACT: One of the rarest forms of autosomal recessive chronic granulomatous disease (AR-CGD) is attributable to mutations in the CYBA gene, which encodes the alpha polypeptide of cytochrome b(558), (also known as p22-phox), a key transmembrane protein in the phagocyte NADPH oxidase system. This gene is localized on chromosome 16q24, encompasses 8.5 kb and contains six exons. We report here the clinical and molecular characterization of 12 AR-CGD patients from 10 consanguineous, unrelated Turkish families with clinical CGD and positive family history. The ages of the six male and six female patients were between 1and 18 years. Before mutation analysis, subgroup analysis of patients was made by flow cytometry with antibodies against NADPH-oxidase components and with the DHR assay (flow cytometric assay of NADPH oxidase activity in leucocytes). Mutation analysis of CYBA showed six different mutations: a frameshift insertion in exon 3 (C after C166); a missense mutation in exon 2 (p.Gly24Arg), a splice-site deletion in intron 1 (4-bp deletion +4_+7 AGTG), a novel nonsense mutation in exon 6 (p.Cys113X), a novel large deletion of exons 3-6 and a novel 1-bp deletion in exon 6 (c.408delC). All mutations were present in homozygous form and all parents investigated were found to be heterozygotes for these mutations. In our series of 40 CGD families, approximately 25% of the families have p22-phox defects, with six different mutations, including three novel mutations. The high rate of consanguineous marriages seems to be the underlying aetiology.
  European Journal of Clinical Investigation 05/2009; 39(4):311-9. · 3.02 Impact Factor
• Source

  Available from: Martin de Boer

  Article: Mutations of chronic granulomatous disease in Turkish families.

  M Y Köker, O Sanal, M De Boer, I Tezcan, A Metin, F Ersoy, D Roos
  [show abstract] [hide abstract]
  ABSTRACT: Chronic granulomatous disease (CGD) is an inherited disorder of the innate immune system characterized by impairment of intracellular microbicidal activity of phagocytes. Mutations in one of four known NADPH-oxidase components preclude generation of superoxide and related antimicrobial oxidants, leading to the phenotype of CGD. Defects in gp91-phox, encoded by CYBB, lead to X-linked CGD and have been reported to be responsible for approximately 70% of all CGD cases. The aim of this study was to identify the CGD mutations in a group of Turkish CGD patients and to evaluate the predominance of CGD mutations as X-linked or autosomal recessive (AR) within the Turkish CGD families with known mutations. Two Turkish CGD families were included in the study, and mutations were identified by sequence analysis of DNA and RNA from peripheral blood in the patients. Before mutation analysis, subgroup analysis of patients was made by flow cytometry with antibodies against NADPH oxidase components and with DHR-123 oxidase activity assay. For comparison, we included previously reported results from four other Turkish CGD families. Two different mutations were identified, one of them a novel mutation g.700G>T located in exon 7 of CYBB, and the other a hot-spot mutation located in exon 2 of the NCF1 gene. These mutations were detected in three patients from two Turkish families. Until now, we have altogether identified mutations in six Turkish CGD families. In this limited number of families our results show AR-CGD in two-thirds of the Turkish families investigated, in contrast to previous reports in the literature. This is probably due to the high rate of consanguineous marriages in Turkey. Consanguineous parents were found in 75% of the families with AR-CGD patients, which favours homozygous deficiencies.
  European Journal of Clinical Investigation 08/2007; 37(7):589-95. · 3.02 Impact Factor
• Source

  Available from: Martin de Boer

  Article: Skewing of X-chromosome inactivation in three generations of carriers with X-linked chronic granulomatous disease within one family.

  M Y Köker, O Sanal, M de Boer, I Tezcan, A Metin, C Tan, F Ersoy, D Roos
  [show abstract] [hide abstract]
  ABSTRACT: Chronic granulomatous disease (CGD) is an inherited disorder of the innate immune system characterized by impairment of intracellular microbicidal activity of phagocytes. Mutations in one of the four known NADPH-oxidase components preclude generation of superoxide and related antimicrobial oxidants, leading to the phenotype of CGD. Defects in gp91-phox, encoded by CYBB, lead to X-linked CGD, responsible for approximately 70% of all CGD cases. The aim of the study was to evaluate the hypothesis that age-related skewing of X-chromosome inactivation, as described in several CGD families, is caused by preferential survival of bone marrow clones with an inactive NADPH oxidase. We studied the neutrophils from three patients and four carriers in three generations of a Turkish family with X-linked CGD. Carrier detection was carried out by the dihydrorhodamine (DHR)-1,2,3 assay, which measures on a per-cell basis the NADPH oxidase-dependent oxidation of DHR by phagocytes. The X-chromosome inactivation pattern was determined with the HUMARA assay in DNA from leucocytes as well as in DNA from a buccal smear of the four carriers. The three patients were identified by a negative DHR test, and the mutation in their CYBB gene was characterized by DNA sequencing. Moreover, we found an age-related degree of skewing of X-chromosome inactivation in the leucocytes of the four X-CGD carriers, both at the protein level (NADPH oxidase activity) and at the DNA level (HUMARA assay). However, similar skewing of X-chromosome inactivation was found in the buccal DNA from these women. These novel findings indicate that the age-related degree of skewing was probably a chance finding, not related to preferential survival of NADPH oxidase-deficient precursor cells, because this enzyme is not expressed in (buccal) epithelial cells.
  European Journal of Clinical Investigation 05/2006; 36(4):257-64. · 3.02 Impact Factor