Nicole de Leeuw

Publications (87) View all

• Article: CEP89 is required for mitochondrial metabolism and neuronal function in man and fly.

  Bregje W M van Bon, Merel A W Oortveld, Leo G Nijtmans, Michaela Fenckova, Bonnie Nijhof, Judith Besseling, Melissa Vos, Jamie M Kramer, Nicole de Leeuw, Anna Castells-Nobau, [......], Falko Hofmann, Lillian Eshuis, Licio Collavin, Martijn A Huynen, Zoltan Asztalos, Patrik Verstreken, Richard J Rodenburg, Jan A Smeitink, Bert B A de Vries, Annette Schenck
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  ABSTRACT: It is estimated that the human mitochondrial proteome consists of 1,000-1,500 distinct proteins. The majority of these support the various biochemical pathways that are active in these organelles. Individuals with an oxidative phosphorylation disorder of unknown cause provide a unique opportunity to identify novel genes implicated in mitochondrial biology. We identified a homozygous deletion of CEP89 in a patient with isolated complex IV deficiency, intellectual disability and multisystemic problems. CEP89 is an ubiquitously expressed and highly conserved gene of unknown function. Immunocytochemistry and cellular fractionation experiments showed that CEP89 is present both in the cytosol and in the mitochondrial intermembrane space. Furthermore, we ascertained in vitro that downregulation of CEP89 resulted in a severe decrease in complex IV in-gel activity and altered mobility, suggesting that the complex is aberrantly formed. Two-dimensional BN-SDS gel analysis revealed that CEP89 associates with a high molecular weight complex. Together, these data confirm a role for CEP89 in mitochondrial metabolism. In addition, we modeled CEP89 loss of function in Drosophila. Ubiquitous knockdown of fly Cep89 decreased complex IV activity and resulted in complete lethality. Furthermore, Cep89 is required for mitochondrial integrity, membrane depolarization and synaptic transmission of photoreceptor neurons, and for (sub)synaptic organization of the larval neuromuscular junction. Finally, we tested neuronal Cep89 knockdown flies in the light-off jump reflex habituation assay, which revealed its role in learning. We conclude that CEP89 proteins play an important role in mitochondrial metabolism, especially complex IV activity, and are required for neuronal and cognitive function across evolution.
  Human Molecular Genetics 04/2013; · 7.64 Impact Factor
• Article: Severe Myopia with Unusual Retinal Anomalies and Dandy-Walker Sequence in Two Sibs. A Distinct New Neuro-ocular Disorder.

  Giuseppe de Crecchio, Gilda Cennamo, Nicole de Leeuw, Maria Luisa Ventruto, Maria Concetta Lonardo, Patrizia Friso, Valerio Ventruto
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  ABSTRACT: Abstract We have observed a male and a female, sibs of non-consanguineous parents, affected by severe myopia with characteristic retinal defects and Dandy-Walker variant. The peculiarity of the retinopathy consists of pathological myopia with anomalous vitreal fenestrated membranes in the retinal periphery. We suppose that these associations may configure a new genetic syndrome.
  Ophthalmic Genetics 01/2013; · 0.93 Impact Factor
• Article: Two patients with intellectual disability, overlapping facial features, and overlapping deletions in 6p25.1p24.3.

  Bart C W Kuipers, Anneke T Vulto-van Silfhout, Carlo Marcelis, Rolph Pfundt, Nicole de Leeuw, Bert B A de Vries
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  ABSTRACT: The clinical and molecular characterizations of two patients with a 1.4 Mb overlapping deletion in the 6p25.1p24.3 region are reported. In addition to the mild intellectual disability, they shared feeding problems in infancy and several dysmorphic facial features including a prominent forehead, almond-shaped eyes, a short philtrum, and low-set ears with square helices. The overlapping deleted region harbors six genes (RREB1, NRN1, CAGE1, LY86, SSR1, and F13A1), of which NRN1 and RREB1 are considered as candidate genes for the intellectual disability and the overlapping dysmorphism, respectively.
  Clinical dysmorphology 11/2012; · 0.47 Impact Factor
• Article: Phelan-McDermid syndrome: Clinical report of a 70-year-old woman.

  Willem M A Verhoeven, Jos I M Egger, Ruthy Cohen-Snuijf, Sarina G Kant, Nicole de Leeuw
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  ABSTRACT: Phelan-McDermid or 22q13.3 deletion syndrome is characterized by global intellectual disability, childhood hypotonia, severely delayed or absent speech, features of autism spectrum disorder, without any major dysmorphisms or somatic anomalies. It is typically diagnosed before adolescence and data about adult patients are virtually absent. The expression of its phenotypical characteristics appears to be linearly related to the deletion size. Here, an intellectually disabled geriatric female patient is described with a long history of challenging behaviors in whom Phelan-McDermid syndrome was demonstrated. Detailed analysis of the patient's history and functioning resulted in a psychiatric diagnosis of atypical bipolar disorder and her behavior significantly improved upon maintenance treatment with a mood stabilizing agent. The present article confirms recent findings that atypical bipolar disorder may be part of the psychopathological phenotype of Phelan-McDermid syndrome, reason why careful etiological search is warranted, also in the geriatric population. © 2012 Wiley Periodicals, Inc.
  American Journal of Medical Genetics Part A 11/2012; · 2.39 Impact Factor
• Article: Monosomy 9pter and trisomy 9q34.11qter in two sisters due to a maternal pericentric inversion.

  Farmaditya E P Mundhofir, Dominique Smeets, Willy Nillesen, Tri Indah Winarni, Helger G Yntema, Nicole de Leeuw, Ben C J Hamel, Sultana M H Faradz, Bregje W M van Bon
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  ABSTRACT: Pericentric inversions of chromosome 9 leading to unbalanced live-born offspring are relatively rare and so far only four cases have been reported. Here we present two sisters with an unbalanced recombinant chromosome 9 which resulted from a large maternal pericentric inversion inv(9)(p24.3q34.1). Further molecular characterisation of the aberrant chromosome 9 by 250k SNP array analysis showed a terminal 460kb loss of 9p24.3 and a terminal 8.9Mb gain of 9q34.11. We compared the clinical features of these two patients with the previous reported four cases as well as with patients with similar sized 9pter deletions or 9qter duplications. Based upon this study, we suggest that the recombinant chromosome 9 phenotype is mainly the result of duplication of a 3.4Mb region of chromosome 9q34.11q34.13.
  Gene 09/2012; · 2.34 Impact Factor