Publications (73) View all
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Article: The Classification and Diagnostic Algorithm for Primary Lymphatic Dysplasia: an update from 2010 to include molecular findings.
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ABSTRACT: Historically, primary lymphoedema was classified into just three categories depending on the age of onset of swelling; congenital, praecox and tarda. Developments in clinical phenotyping and identification of the genetic cause of some of these conditions have demonstrated that primary lymphoedema is highly heterogenous. In 2010 we introduced a new classification and diagnostic pathway as a clinical and research tool. This algorithm has been used to delineate specific primary lymphoedema phenotypes, facilitating the discovery of new causative genes. This paper reviews the latest molecular findings and provides an updated version of the classification and diagnostic pathway based on this new knowledge.Clinical Genetics 04/2013; · 3.13 Impact Factor -
Article: A Mutation in VEGFC, a Ligand for VEGFR3, is Associated with Autosomal Dominant Milroy-like Primary Lymphedema.
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ABSTRACT: Rationale: Mutations in VEGFR3 (FLT4) cause Milroy Disease (MD), an autosomal dominant condition that presents with congenital lymphedema. Mutations in VEGFR3 are identified in only 70% of patients with classic MD, suggesting genetic heterogeneity. Objective: To investigate the underlying cause in patients with clinical signs resembling MD in whom sequencing of the coding region of VEGFR3 did not reveal any pathogenic variation. Methods and Results: Exome sequencing of five such patients was performed and a novel frameshift variant, c.571_572insTT in VEGFC, a ligand for VEGFR3, was identified in one proband. The variant co-segregated with the affected status in the family. An assay to assess the biological function of VEGFC activity in vivo, by expressing human VEGFC in the zebrafish floorplate was established. Forced expression of wildtype human VEGFC in the floorplate of zebrafish embryos leads to excessive sprouting in neighbouring vessels. However, when overexpressing the human c.571_572insTT variant in the floorplate, no sprouting of vessels was observed, indicating that the base changes have a marked effect on the activity of VEGFC. Conclusions: We propose that the mutation in VEGFC is causative for the MD-like phenotype seen in this family. This is the first time a mutation in one of the ligands of VEGFR3 has been reported to cause primary lymphedema.Circulation Research 02/2013; · 9.49 Impact Factor -
Article: FLT4/VEGFR3 and Milroy Disease: Novel Mutations, a Review of Published Variants and Database Update.
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ABSTRACT: Milroy disease (MD) is an autosomal dominantly inherited primary lymphedema. In 1998, the gene locus for MD was mapped to 5q35.3 and variants in the VEGFR3 (FLT4) gene, encoding vascular endothelial growth factor receptor 3 (VEGFR3), were identified as being responsible for the majority of MD cases. Several reports have since been published detailing pathogenic FLT4 mutations. To date, a total of 58 different variants in FLT4, 20 of which are unpublished, have been observed in 95 families with MD. A review of published mutations is presented in this update. Furthermore, the unpublished variants are presented including clinical data. Comparison of clinical features in patients and their families with the same mutations reveals incomplete penetrance and variable expression, making genotype-phenotype correlations difficult. Most mutations are missense, but a few deletions and one splicing variant have also been reported. Several animal models have confirmed the role of VEGFR3 in lymphangiogenesis and studies show mutant VEGFR3 receptors are not phosphorylated. Here, an MD patient with the same p.Ile1053Phe change as seen in the Chy mouse is presented for the first time. This finding confirms that this mouse lineage is an excellent model for MD. All the data reviewed here has been submitted to a database based on the Leiden Open (source) Variation Database (LOVD) and is accessible online at www.lovd.nl/flt4.Human Mutation 10/2012; · 5.69 Impact Factor -
Article: Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling.
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ABSTRACT: 3-M syndrome is a primordial growth disorder caused by mutations in CUL7, OBSL1 or CCDC8. 3-M patients typically have a modest response to GH treatment, but the mechanism is unknown. Our aim was to screen 13 clinically identified 3-M families for mutations, define the status of the GH-IGF axis in 3-M children, and using fibroblast cell lines assess signalling responses to GH or IGF-I. 11 CUL7, 3 OBSL1 and 1 CCDC8 mutations in 9, 3 and 1 families respectively were identified, those with CUL7 mutations being significantly shorter than those with OBSL1 or CCDC8 mutations. The majority of 3-M patients tested had normal peak serum GH and normal/low IGF-I. While the generation of IGFBPs by 3-M cells was dysregulated. Activation of STAT5b and MAPK in response to GH was normal in CUL7-/- cells, but reduced in OBSL1-/- and CCDC8-/- cells compared to controls. Activation of AKT to IGF-I was reduced in CUL7-/- and OBSL1-/- cells at 5 minutes post-stimulation but normal in CCDC8-/- cells. The prevalence of 3-M mutations was: 69% CUL7, 23% OBSL1 and 8% CCDC8. The GH-IGF axis evaluation could reflect a degree of GH resistance and/or IGF-I resistance. This is consistent with the signalling data in which the CUL7-/- cells showed impaired IGF-I signalling, CCDC8-/- cells impaired GH signalling and the OBSL1-/- cells impairment in both pathways. Dysregulation of the GH-IGF-IGFBP axis is a feature of the 3-M syndrome.Journal of Molecular Endocrinology 09/2012; · 3.48 Impact Factor -
Article: Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa.
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ABSTRACT: Autosomal recessive cutis laxa type I (ARCL type I) is characterized by generalized cutis laxa with pulmonary emphysema and/or vascular complications. Rarely, mutations can be identified in FBLN4 or FBLN5. Recently, LTBP4 mutations have been implicated in a similar phenotype. Studying FBLN4, FBLN5, and LTBP4 in 12 families with ARCL type I, we found bi-allelic FBLN5 mutations in two probands, whereas nine probands harbored biallelic mutations in LTBP4. FBLN5 and LTBP4 mutations cause a very similar phenotype associated with severe pulmonary emphysema, in the absence of vascular tortuosity or aneurysms. Gastrointestinal and genitourinary tract involvement seems to be more severe in patients with LTBP4 mutations. Functional studies showed that most premature termination mutations in LTBP4 result in severely reduced mRNA and protein levels. This correlated with increased transforming growth factor-beta (TGFβ) activity. However, one mutation, c.4127dupC, escaped nonsense-mediated decay. The corresponding mutant protein (p.Arg1377Alafs(*) 27) showed reduced colocalization with fibronectin, leading to an abnormal morphology of microfibrils in fibroblast cultures, while retaining normal TGFβ activity. We conclude that LTBP4 mutations cause disease through both loss of function and gain of function mechanisms.Human Mutation 07/2012; · 5.69 Impact Factor
