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Dive into the research topics where Joke Vandewalle is active.

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Featured researches published by Joke Vandewalle.


American Journal of Human Genetics | 2008

Submicroscopic Duplications of the Hydroxysteroid Dehydrogenase HSD17B10 and the E3 Ubiquitin Ligase HUWE1 Are Associated with Mental Retardation

Guy Froyen; Mark Corbett; Joke Vandewalle; Irma Järvelä; O Lawrence; Cliff Meldrum; Marijke Bauters; Karen Govaerts; Lucianne Vandeleur; Hilde Van Esch; Jamel Chelly; Damien Sanlaville; Hans van Bokhoven; Hans-Hilger Ropers; Frédéric Laumonnier; Enzo Ranieri; Charles E. Schwartz; Fatima Abidi; Patrick Tarpey; P. Andrew Futreal; Annabel Whibley; F. Lucy Raymond; Michael R. Stratton; Jean Pierre Fryns; Rodney J. Scott; Maarit Peippo; Marjatta Sipponen; Michael Partington; David Mowat; Michael Field

Submicroscopic copy-number imbalances contribute significantly to the genetic etiology of human disease. Here, we report a novel microduplication hot spot at Xp11.22 identified in six unrelated families with predominantly nonsyndromic XLMR. All duplications segregate with the disease, including the large families MRX17 and MRX31. The minimal, commonly duplicated region contains three genes: RIBC1, HSD17B10, and HUWE1. RIBC1 could be excluded on the basis of its absence of expression in the brain and because it escapes X inactivation in females. For the other genes, expression array and quantitative PCR analysis in patient cell lines compared to controls showed a significant upregulation of HSD17B10 and HUWE1 as well as several important genes in their molecular pathways. Loss-of-function mutations of HSD17B10 have previously been associated with progressive neurological disease and XLMR. The E3 ubiquitin ligase HUWE1 has been implicated in TP53-associated regulation of the neuronal cell cycle. Here, we also report segregating sequence changes of highly conserved residues in HUWE1 in three XLMR families; these changes are possibly associated with the phenotype. Our findings demonstrate that an increased gene dosage of HSD17B10, HUWE1, or both contribute to the etiology of XLMR and suggest that point mutations in HUWE1 are associated with this disease too.


American Journal of Human Genetics | 2009

Dosage-Dependent Severity of the Phenotype in Patients with Mental Retardation Due to a Recurrent Copy-Number Gain at Xq28 Mediated by an Unusual Recombination

Joke Vandewalle; Hilde Van Esch; Karen Govaerts; Jelle Verbeeck; Christiane Zweier; Irene Madrigal; Montserrat Milà; E Pijkels; Isabel Fernandez; Jürgen Kohlhase; Christiane Spaich; Anita Rauch; Jean-Pierre Fryns; Peter Marynen; Guido Froyen

We report on the identification of a 0.3 Mb inherited recurrent but variable copy-number gain at Xq28 in affected males of four unrelated families with X-linked mental retardation (MR). All aberrations segregate with the disease in the families, and the carrier mothers show nonrandom X chromosome inactivation. Tiling Xq28-region-specific oligo array revealed that all aberrations start at the beginning of the low copy repeat LCR-K1, at position 153.20 Mb, and end just distal to LCR-L2, at 153.54 Mb. The copy-number gain always includes 18 annotated genes, of which RPL10, ATP6AP1 and GDI1 are highly expressed in brain. From these, GDI1 is the most likely candidate gene. Its copy number correlates with the severity of clinical features, because it is duplicated in one family with nonsyndromic moderate MR, is triplicated in males from two families with mild MR and additional features, and is present in five copies in a fourth family with a severe syndromic form of MR. Moreover, expression analysis revealed copy-number-dependent increased mRNA levels in affected patients compared to control individuals. Interestingly, analysis of the breakpoint regions suggests a recombination mechanism that involves two adjacent but different sets of low copy repeats. Taken together, our data strongly suggest that an increased expression of GDI1 results in impaired cognition in a dosage-dependent manner. Moreover, these data also imply that a copy-number gain of an individual gene present in the larger genomic aberration that leads to the severe MECP2 duplication syndrome can of itself result in a clinical phenotype as well.


Human Reproduction | 2010

Array comparative genomic hybridization for the detection of submicroscopic copy number variations of the X chromosome in women with premature ovarian failure

Tracy Dudding; O Lawrence; Ingrid Winship; Guido Froyen; Joke Vandewalle; Rodney J. Scott; Andrew N. Shelling

(Shelling, 2000). Of interest is the lower copy number detection rate in our study (4%) compared with the detection rate of 48% in the recent publication by Quilter et al. (2010). Quilter et al. report that one of the 15 women with a CNV had primary amenorrhea. Possibilities to explain the differences in detection rate compared with this study may be differences in the age of onset of POF, or the presence of a positive family history of POF. Quilter et al. (2010) does not provide these demographic details. Further studies in larger numbers of POF patients clinically characterized by age of onset and the presence of a positive family history would help clarify the association between X chromosome CNV and POF.


Human Genetics | 2013

The mitochondrial solute carrier SLC25A5 at Xq24 is a novel candidate gene for non-syndromic intellectual disability

Joke Vandewalle; Marijke Bauters; Hilde Van Esch; Stefanie Belet; Jelle Verbeeck; Nathalie Fieremans; Maureen Holvoet; Jodie M. Vento; Ana Spreiz; Dieter Kotzot; Edda Haberlandt; Jill A. Rosenfeld; Joris Andrieux; Bruno Delobel; Marie-Bertille Dehouck; Koenraad Devriendt; Jean-Pierre Fryns; Peter Marynen; Amy Goldstein; Guy Froyen

Loss-of-function mutations in several different neuronal pathways have been related to intellectual disability (ID). Such mutations often are found on the X chromosome in males since they result in functional null alleles. So far, microdeletions at Xq24 reported in males always have been associated with a syndromic form of ID due to the loss of UBE2A. Here, we report on overlapping microdeletions at Xq24 that do not include UBE2A or affect its expression, in patients with non-syndromic ID plus some additional features from three unrelated families. The smallest region of overlap, confirmed by junction sequencing, harbors two members of the mitochondrial solute carrier family 25, SLC25A5 and SLC25A43. However, identification of an intragenic microdeletion including SLC25A43 but not SLC25A5 in a healthy boy excluded a role for SLC25A43 in cognition. Therefore, our findings point to SLC25A5 as a novel gene for non-syndromic ID. This highly conserved gene is expressed ubiquitously with high levels in cortex and hippocampus, and a presumed role in mitochondrial exchange of ADP/ATP. Our data indicate that SLC25A5 is involved in memory formation or establishment, which could add mitochondrial processes to the wide array of pathways that regulate normal cognitive functions.


PLOS ONE | 2013

Ubiquitin Ligase HUWE1 Regulates Axon Branching through the Wnt/β-Catenin Pathway in a Drosophila Model for Intellectual Disability

Joke Vandewalle; Marion Langen; Marlen Zschaetzsch; Bonnie Nijhof; Jamie M. Kramer; Hilde Brems; Marijke Bauters; Elsa Lauwers; Mohammed Srahna; Peter Marynen; Patrik Verstreken; Annette Schenck; Bassem A. Hassan; Guy Froyen

We recently reported that duplication of the E3 ubiquitin ligase HUWE1 results in intellectual disability (ID) in male patients. However, the underlying molecular mechanism remains unknown. We used Drosophila melanogaster as a model to investigate the effect of increased HUWE1 levels on the developing nervous system. Similar to the observed levels in patients we overexpressed the HUWE1 mRNA about 2-fold in the fly. The development of the mushroom body and neuromuscular junctions were not altered, and basal neurotransmission was unaffected. These data are in agreement with normal learning and memory in the courtship conditioning paradigm. However, a disturbed branching phenotype at the axon terminals of the dorsal cluster neurons (DCN) was detected. Interestingly, overexpression of HUWE1 was found to decrease the protein levels of dishevelled (dsh) by 50%. As dsh as well as Fz2 mutant flies showed the same disturbed DCN branching phenotype, and the constitutive active homolog of β-catenin, armadillo, could partially rescue this phenotype, our data strongly suggest that increased dosage of HUWE1 compromises the Wnt/β-catenin pathway possibly by enhancing the degradation of dsh.


Cytogenetic and Genome Research | 2008

Detection and validation of copy number variation in X-linked mental retardation

Marijke Bauters; A. Weuts; Joke Vandewalle; Joke Nevelsteen; Peter Marynen; H. Van Esch; Guy Froyen

Studies to identify the genetic defects associated with X-linked mental retardation (XLMR) in males have revealed tens of genes important for normal brain development and cognitive functioning in men. Despite extensive efforts in breakpoint cloning of chromosomal rearrangements and mutation screening of candidate genes on the X chromosome, still many XLMR families and sporadic cases remain unsolved. It is now clear that submicroscopic copy number changes on the X chromosome can explain about 5% of these idiopathic cases. Interestingly, beside gene deletions, an increase in gene dosage due to genomic duplications seems to contribute to causality more often than expected. Since larger duplications on the X chromosome are tolerated compared to deletions, they often harbour more than one gene hampering the identification of the causal gene. In contrast to copy number variations (CNVs) on autosomes, most disease-associated CNVs on the X chromosome in males are inherited from their mothers who normally do not present with any clinical symptoms due to non-random X inactivation. Here, we review the different methods applied to study copy number alterations on the X chromosome in patients with cognitive impairment, discuss those CNVs that are associated with disease and elaborate on the genes and mechanisms involved. At the end, we will resume in vivo assays to study the relation of CNVs on the X chromosome and mental disability.


Human Genetics | 2014

X-linked congenital ptosis and associated intellectual disability, short stature, microcephaly, cleft palate, digital and genital abnormalities define novel Xq25q26 duplication syndrome

Rikke S. Møller; Lars R. Jensen; S. M. Maas; J. Filmus; M. Capurro; C. Hansen; Carlo Marcelis; Kirstine Ravn; Joris Andrieux; M. Mathieu; Maria Kirchhoff; Olaug K. Rødningen; N. de Leeuw; Helger G. Yntema; Guy Froyen; Joke Vandewalle; K. Ballon; E. Klopocki; S. Joss; J. Tolmie; A. C. Knegt; A. M. Lund; Helle Hjalgrim; Andreas W. Kuss; Niels Tommerup; Reinhard Ullmann; A.P.M. de Brouwer; Petter Strømme; Susanne Kjaergaard; Zeynep Tümer


Archive | 2010

A recurrent copy number gain at Xq28 mediated by an unusual recombination results in a dosagedependent severity of the phenotype in patients with mental retardation

Joke Vandewalle; Hilde Van Esch; Karen Govaerts; J Verbeek; Christiane Zweier; Irene Madrigal; Montserrat Milà; E Pijkels; Isabel Fernandez; Jürgen Kohlhase; Christiane Spaich; Anita Rauch; Jean-Pierre Fryns; Peter Marynen; Guy Froyen


Archive | 2010

Breakpoint cloning of aberrations on the X chromosome: identification of an unusual type of recombination that results in a dosage-dependent severity of the phenotype

Guido Froyen; Marijke Bauters; Joke Vandewalle; Peter Marynen


Archive | 2009

A novel recurrent copy number gain at Xq28 in four MR families

Hilde Van Esch; Joke Vandewalle; Karen Govaerts; J Verbeek; Christiane Zweier; Irene Madrigal; M Montserrat; E Pijkels; Isabel Fernandez; D Böhm; Christiane Spaich; Jürgen Kohlhase; Anita Rauch

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Guy Froyen

Katholieke Universiteit Leuven

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Peter Marynen

Katholieke Universiteit Leuven

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Marijke Bauters

Katholieke Universiteit Leuven

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Hilde Van Esch

Katholieke Universiteit Leuven

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Karen Govaerts

Katholieke Universiteit Leuven

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Damien Sanlaville

Necker-Enfants Malades Hospital

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