Kris Van Den Bogaert

University of Antwerp, Antwerpen, Flanders, Belgium

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Publications (13)58.86 Total impact

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    ABSTRACT: Otosclerosis is caused by an abnormal bone homeostasis of the otic capsule and represents a frequent cause of hearing impairment among white adults. The conductive component of this hearing impairment is due to bony fixation of the stapedial footplate in the oval window, disturbing the conduction of sound vibrations from the middle to the inner ear. In some cases, a sensorineural component develops when the disease extends to the cochlea, leading to a mixed hearing impairment. Although the etiology of otosclerosis is controversial, and both a viral cause and autosomal dominant inheritance with reduced penetrance have been proposed, current evidence favours the latter hypothesis. Three large families segregating autosomal dominant otosclerosis have been used to identify three otosclerosis loci - OTSC1 on chromosome 15q25-26, OTSC2 on chromosome 7q34-36 and OTSC3 on chromosome 6p21-22. Further investigation of genetic heterogeneity within otosclerosis also shows that at least one additional locus must exist. These findings suggest that otosclerosis is, in parallel with non-syndromic sensorineural deafness, a genetically heterogeneous condition.
    Audiological Medicine 07/2009; 1(1).
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    ABSTRACT: Otosclerosis is a progressive hearing loss characterized by an abnormal bone homeostasis of the otic capsule that leads to stapes fixation. Although its etiology remains unknown, otosclerosis can be considered a complex disease. Transforming growth factor-beta 1 (TGF-beta1) was chosen for a case-control association study, because of several non-genetic indications of involvement in otosclerosis. Single nucleotide polymorphism (SNP) analysis in a large Belgian-Dutch sample set gave significant results (P = 0.0044) for an amino acid changing SNP, T263I. Analysis of an independent French population replicated this association with SNP T263I (P = 0.00019). The results remained significant after multiple testing correction in both populations. Haplotype analysis and the results of an independent effect test using the weighted haplotype (WHAP) computer program in both populations were both compatible with SNP T263I being the only causal variant. The variant I263 is under-represented in otosclerosis patients and hence protective against the disease. Combining the data of both case-control groups for SNP T263I with a Mantel-Haenszel estimate of common odds ratios gave a very significant result (P = 9.2 x 10(-6)). Functional analysis of SNP T263I with a luciferase reporter assay showed that the protective variant I263 of TGF-beta1 is more active than the WT variant T263 (P = 1.6 x 10(-6)). On the basis of very low P-values, replication in an independent population and a functional effect of the protective variant, we conclude that TGF-beta1 influences the susceptibility for otosclerosis, and that the I263 variant is protective against the disease.
    Human Molecular Genetics 10/2007; 16(17):2021-30. · 7.69 Impact Factor
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    ABSTRACT: Otosclerosis is a common form of hearing impairment among white adults with a prevalence of 0.3-0.4%. It is caused by abnormal bone homeostasis of the otic capsule that compromises free motion of the stapes in the oval window. Otosclerosis is in most patients a multifactorial disease, caused by both genetic and environmental factors. In some cases, the disease is inherited as a monogenic autosomal dominant trait, sometimes with reduced penetrance. However, families large enough for genetic linkage studies are extremely rare. To date, five loci (OTSC1-5) have been reported, but none of the responsible genes have been cloned yet. An additional locus, OTSC6, has been reported to the HUGO nomenclature committee but the relevant linkage study has not been published. In this study, a genome-wide linkage study was performed in a large Greek pedigree segregating autosomal dominant otosclerosis. A seventh locus, OTSC7, was localized on chromosome 6q13-16.1 with a multipoint LOD score of 7.5 in the 13.47 cM region defined by markers D6S1036 (centromeric) and D6S300 (telomeric). Linkage analysis of this new locus in 13 smaller Belgian and Dutch families has identified one family from The Netherlands in which allele segregation suggests linkage to this region. The overlap between the critical regions of these two families is a 1.06 Mb interval between the genetic markers D6S1036 (centromeric) and D6S406 (telomeric) on chromosome 6q13.
    European Journal of HumanGenetics 04/2007; 15(3):362-8. · 4.32 Impact Factor
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    ABSTRACT: As part of the GENDEAF consortium, a European multi-centre otosclerotic database is under construction to collect the clinical data of as many otosclerotic patients as possible. Otosclerosis represents a heterogeneous group of heritable diseases in which different genes may be involved regulating the bone homeostasis of the otic capsule. The purpose of the GENDEAF otosclerosis database is to explore the otosclerotic phenotype more in depth. Subtle phenotypic differences otherwise not visible, may become statistically relevant in a large number of patients. Their identification can lead towards the discovery of new genes involved in the pathway of abnormal bone metabolism in the human labyrinth. As soon as one of the otosclerotic genes is identified, it would allow us to identify genotype-phenotype correlations. From other deafness genes, it is know that different mutations in the same gene may cause similar phenotypes of varying severity. Also the variability in treatment outcomes after surgery or fluoride therapy may result not only from differences in practice or surgical skill among physicians, but also on the nature of the underlying disorder. Screening large numbers of patients would make it possible to undertake clinical trials comparing different treatments. Identifying a genetic susceptibility would allow us to dissect out possible environmental factors that prevent the expression of clinical otosclerosis in those that carry the mutated gene and yet retain normal hearing.
    Advances in oto-rhino-laryngology 02/2007; 65:114-8.
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    ABSTRACT: To report the audiometric and radiologic findings in the first otosclerosis family linked to OTSC5. A clinical investigation of a family linked to OTSC5, including analyses of audiometric data and of high-resolution computed tomography (CT) images of the temporal bones from genetically affected family members. Tertiary referral center. Family members from a four-generation pedigree with otosclerosis segregating as an autosomal dominant trait. Pre-surgery pure tone audiometric data. Classification of otosclerotic foci on high-resolution spiral CT images of the temporal bones of genetically affected individuals. Audiometric data showed a considerable degree of phenotypic variability. Cross-sectional regression analysis did not disclose any clear age dependence of threshold-related data. Systematic differences between mean parameter values relating to the thresholds in the best or the worst ear were found. High-resolution CT images revealed a fenestral otosclerotic focus in seven of nine (78%) clinically affected individuals and cochlear foci in one of these seven patients. The phenotype of OTSC5 seems to be variable. Additional long-term audiometric data are needed to construct age-related typical audiograms, which may also facilitate the comparison between phenotypes of the different otosclerosis loci. The detection rate of otospongiotic foci in our study group is similar or lower compared with previous reports on CT data in consecutive otosclerosis patients who had stapes replacing surgery.
    Ontology & Neurotology 05/2006; 27(3):308-15. · 2.01 Impact Factor
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    ABSTRACT: The aim of our study was to characterize the hearing impairment in a large multigenerational Greek family with autosomal dominant nonsyndromic otosclerosis and to perform genetic linkage analysis to known otosclerosis loci and collagen genes. In addition, we looked for mutations in the NOG gene to rule out congenital stapes ankylosis syndrome. Audiological analysis of the affected persons was based on multiple linear regression (MLR) analysis and construction of age-related typical audiograms (ARTA). Genotyping of microsatellite DNA polymorphisms for known otosclerosis (OTSC) loci or collagen genes and linkage analysis using the MLINK computer program were performed. The coding region of the NOG gene was screened for mutations by direct DNA sequencing. The hearing loss in this family appears in childhood as conductive, but soon becomes mixed. Because the additional sensorineural component is progressive, this finally has lead to a pure sensorineural hearing loss in some family members, as the conductive component is masked. Audiological analysis showed an age-independent conductive component and a progressive frequency-specific sensorineural component. Linkage analysis excluded linkage to the four known otosclerosis loci (OTSC1, OTSC2, OTSC3, and OTSC5), as well as to the COL1A1 and COL1A2 genes. Mutation analysis of the coding region of the NOG gene did not reveal any disease causing mutation. This study represents the first description of a detailed audiological analysis in a large pedigree segregating otosclerosis as a monogenic autosomal dominant trait. Exclusion of the four known otosclerosis loci in this family shows that monogenic otosclerosis is a genetically heterogeneous disease involving at least five different genes. A mutation in the NOG gene is not the underlying molecular mechanism of the early onset otosclerosis segregating in this family.
    International Journal of Pediatric Otorhinolaryngology 05/2006; 70(4):631-7. · 1.35 Impact Factor
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    ABSTRACT: Dowling-Degos disease (DDD) is an autosomal dominant genodermatosis characterized by progressive and disfiguring reticulate hyperpigmentation of the flexures. We performed a genomewide linkage analysis of two German families and mapped DDD to chromosome 12q, with a total LOD score of 4.42 ( theta =0.0) for marker D12S368. This region includes the keratin gene cluster, which we screened for mutations. We identified loss-of-function mutations in the keratin 5 gene (KRT5) in all affected family members and in six unrelated patients with DDD. These represent the first identified mutations that lead to haploinsufficiency in a keratin gene. The identification of loss-of-function mutations, along with the results from additional functional studies, suggest a crucial role for keratins in the organization of cell adhesion, melanosome uptake, organelle transport, and nuclear anchorage.
    The American Journal of Human Genetics 04/2006; 78(3):510-9. · 11.20 Impact Factor
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    ABSTRACT: Fifty to eighty percent of autosomal recessive deafness is due to mutations in the GJB2 gene encoding connexin 26. Among Caucasians, the c.35delG mutation in this gene accounts for up to 30 to 70% of all cases with early childhood deafness. In this study, we present the analysis of the GJB2 gene in 159 Egyptians from 111 families with non-syndromic mild to profound hearing impairment. An additional family with Vohwinkel syndrome, a combination of hearing impairment and palmoplantar keratoderma with constriction of the digits, was also included. We used direct sequencing analysis to detect all possible coding GJB2 variants in this population. The presence of the g.1777179_2085947del mutation (hereafter called del(GJB6-D13S1830)) was also investigated as it was shown to be the second most common mutation causing non-syndromic prelingual hearing impairment in Spain. Sequencing analysis of one randomly chosen individual per family revealed that the c.35delG mutation was present in 24 out of 222 chromosomes (10.8%), making it the most frequent mutation in the GJB2 gene in Egypt. Five other mutations were already described previously [p.Thr8Met, p.Val37Ile, p.Val153Ile, c.333_334delAA, c.1-3172G>A (commonly designated as IVS1+1G>A)]. This study also revealed three other novel gene variants resulting in amino acid substitutions (p.Phe142del, p.Asp117His, p.Ala148Pro). In contrast with most populations, the del(GJB6-D13S1830) mutation upstream of the GJB2 gene was not present in this Egyptian population. A dominant mutation at a highly conserved residue, p.Gly130Val, was found in the family with Vohwinkel syndrome.
    Human Mutation 07/2005; 26(1):60-1. · 5.21 Impact Factor
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    Journal of Medical Genetics 07/2004; 41(6):450-3. · 5.70 Impact Factor
  • Journal of Medical Genetics - J MED GENET. 01/2004; 41(6):450-453.
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    ABSTRACT: Clinical otosclerosis (OMIM 166800/605727) has a prevalence of 0.2-1% among white adults, making it the single most common cause of hearing impairment in this group. It is caused by abnormal bone homeostasis of the otic capsule with the consequent development of sclerotic foci that invade the stapedio-vestibular joint (oval window) interfering with free motion of the stapes. Impaired ossicular chain mobility results in a conductive hearing loss. We identified the first locus for otosclerosis (OTSC1) on chromosome 15 in 1998 and reported a second locus (OTSC2) on chromosome 7 last year. Here we present results of a genome wide linkage study on a large Cypriot family segregating otosclerosis. Results of this study exclude linkage to OTSC1 and OTSC2 and identify a third locus, OTSC3, on chromosome 6p. The defined OTSC3 interval covers the HLA region, consistent with reported associations between HLA-A/HLA-B antigens and otosclerosis.
    Journal of Medical Genetics 08/2002; 39(7):473-7. · 5.70 Impact Factor
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    ABSTRACT: Otosclerosis is caused by abnormal bone homeostasis of the otic capsule, resulting in hearing impairment in 0.3%-0.4% of the white population. The etiology of the disease remains unclear and environmental as well as genetic factors have been implicated. We localized the first autosomal-dominant locus to chromosome 15 in 1998 (OTSC1) in an Indian family and, recently, we reported the localization of a second gene for otosclerosis to a 16 cM interval on chromosome 7q (OTSC2). In this study, we recruited and analyzed nine additional families (seven Belgian and two Dutch families with 53 affected and 20 unaffected subjects) to investigate the importance of these loci in autosomal-dominant otosclerosis. We completed linkage analysis with three microsatellite markers of chromosome 15 (D15S652, D15S1004, D15S657) and five microsatellite markers of chromosome 7 (D7S495, D7S2560, D7S684, D7S2513, D7S2426). In two families, results compatible with linkage to OTSC2 were found, but in the seven remaining families OTSC1 and OTSC2 were excluded. Heterogeneity testing provided significant evidence for genetic heterogeneity, with an estimated 25% of families linked to OTSC2. These results indicate that, besides OTSC1 and OTSC2, there must be at least one additional otosclerosis locus.
    Bone 05/2002; 30(4):624-30. · 4.46 Impact Factor
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    ABSTRACT: Otosclerosis due to abnormal bone homeostasis of the otic capsule is a frequent cause of hearing loss in adults. Usually, the hearing loss is conductive, resulting from fixation of the stapedial footplate, which prevents normal ossicular vibration in response to sound. An additional type of sensorineural hearing loss may be caused by otosclerotic damage to the cochlea. The etiology of the disease is unknown, and both environmental and genetic factors have been implicated. Autosomal dominant inheritance with reduced penetrance has been proposed, but large families are extremely rare. To elucidate the pathogenesis of the disease, identification of the responsible genes is essential. In this study, we completed linkage analysis in a Belgian family in which otosclerosis segregates as an autosomal dominant disease. After excluding linkage to a known locus on chromosome 15 (OTSC1), we found linkage on chromosome 7q, with a multipoint LOD score of 3.54. Analysis of key recombinant individuals maps this otosclerosis locus (OTSC2) to a 16-cM interval on chromosome 7q34-36 between markers D7S495 and D7S2426.
    The American Journal of Human Genetics 03/2001; 68(2):495-500. · 11.20 Impact Factor