Vincent Cantagrel

Publications (12) View all

• Source

  Available from: Joseph Gleeson

  Article: Mutations in LAMB1 Cause Cobblestone Brain Malformation without Muscular or Ocular Abnormalities.

  Farid Radmanesh, Ahmet Okay Caglayan, Jennifer L Silhavy, Cahide Yilmaz, Vincent Cantagrel, Tarek Omar, Başak Rosti, Hande Kaymakcalan, Stacey Gabriel, Mingfeng Li, Nenad Sestan, Kaya Bilguvar, William B Dobyns, Maha S Zaki, Murat Gunel, Joseph G Gleeson
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  ABSTRACT: Cobblestone brain malformation (COB) is a neuronal migration disorder characterized by protrusions of neurons beyond the first cortical layer at the pial surface of the brain. It is usually seen in association with dystroglycanopathy types of congenital muscular dystrophies (CMDs) and ocular abnormalities termed muscle-eye-brain disease. Here we report homozygous deleterious mutations in LAMB1, encoding laminin subunit beta-1, in two families with autosomal-recessive COB. Affected individuals displayed a constellation of brain malformations including cortical gyral and white-matter signal abnormalities, severe cerebellar dysplasia, brainstem hypoplasia, and occipital encephalocele, but they had less apparent ocular or muscular abnormalities than are typically observed in COB. LAMB1 is localized to the pial basement membrane, suggesting that defective connection between radial glial cells and the pial surface mediated by LAMB1 leads to this malformation.
  The American Journal of Human Genetics 03/2013; 92(3):468-74. · 10.60 Impact Factor
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  Available from: Joseph Gleeson

  Article: Faulty initiation of proteoglycan synthesis causes cardiac and joint defects.

  Sevjidmaa Baasanjav, Lihadh Al-Gazali, Taishi Hashiguchi, Shuji Mizumoto, Bjoern Fischer, Denise Horn, Dominik Seelow, Bassam R Ali, Samir A A Aziz, Ruth Langer, [......], Vincent Cantagrel, Joseph G Gleeson, Delphine Gomez, Jean-Baptiste Michel, Sigmar Stricker, Tom H Lindner, Peter Nürnberg, Kazuyuki Sugahara, Stefan Mundlos, Katrin Hoffmann
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  ABSTRACT: Proteoglycans are a major component of extracellular matrix and contribute to normal embryonic and postnatal development by ensuring tissue stability and signaling functions. We studied five patients with recessive joint dislocations and congenital heart defects, including bicuspid aortic valve (BAV) and aortic root dilatation. We identified linkage to chromosome 11 and detected a mutation (c.830G>A, p.Arg277Gln) in B3GAT3, the gene coding for glucuronosyltransferase-I (GlcAT-I). The enzyme catalyzes an initial step in the synthesis of glycosaminoglycan side chains of proteoglycans. Patients' cells as well as recombinant mutant protein showed reduced glucuronyltransferase activity. Patient fibroblasts demonstrated decreased levels of dermatan sulfate, chondroitin sulfate, and heparan sulfate proteoglycans, indicating that the defect in linker synthesis affected all three lines of O-glycanated proteoglycans. Further studies demonstrated that GlcAT-I resides in the cis and cis-medial Golgi apparatus and is expressed in the affected tissues, i.e., heart, aorta, and bone. The study shows that reduced GlcAT-I activity impairs skeletal as well as heart development and results in variable combinations of heart malformations, including mitral valve prolapse, ventricular septal defect, and bicuspid aortic valve. The described family constitutes a syndrome characterized by heart defects and joint dislocations resulting from altered initiation of proteoglycan synthesis (Larsen-like syndrome, B3GAT3 type).
  The American Journal of Human Genetics 07/2011; 89(1):15-27. · 10.60 Impact Factor
• Source

  Available from: Éva Morava

  Article: Normal glycosylation screening does not rule out SRD5A3-CDG.

  Miski Mohamed, Vincent Cantagrel, Lihadh Al-Gazali, Ron A Wevers, Dirk J Lefeber, Eva Morava
  European journal of human genetics: EJHG 07/2011; 19(10):1019. · 3.56 Impact Factor
• Source

  Available from: Vincent Cantagrel

  Article: From glycosylation disorders to dolichol biosynthesis defects: a new class of metabolic diseases.

  Vincent Cantagrel, Dirk J Lefeber
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  ABSTRACT: Polyisoprenoid alcohols are membrane lipids that are present in every cell, conserved from archaea to higher eukaryotes. The most common form, alpha-saturated polyprenol or dolichol is present in all tissues and most organelle membranes of eukaryotic cells. Dolichol has a well defined role as a lipid carrier for the glycan precursor in the early stages of N-linked protein glycosylation, which is assembled in the endoplasmic reticulum of all eukaryotic cells. Other glycosylation processes including C- and O-mannosylation, GPI-anchor biosynthesis and O-glucosylation also depend on dolichol biosynthesis via the availability of dolichol-P-mannose and dolichol-P-glucose in the ER. The ubiquity of dolichol in cellular compartments that are not involved in glycosylation raises the possibility of additional functions independent of these protein post-translational modifications. The molecular basis of several steps involved in the synthesis and the recycling of dolichol and its derivatives is still unknown, which hampers further research into this direction. In this review, we summarize the current knowledge on structural and functional aspects of dolichol metabolites. We will describe the metabolic disorders with a defect in known steps of dolichol biosynthesis and recycling in human and discuss their pathogenic mechanisms. Exploration of the developmental, cellular and biochemical defects associated with these disorders will provide a better understanding of the functions of this lipid class in human.
  Journal of Inherited Metabolic Disease 03/2011; 34(4):859-67. · 3.58 Impact Factor
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  Available from: Conny van Ravenswaaij-Arts

  Article: A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism.

  Eva Morava, Ron A Wevers, Vincent Cantagrel, Lies H Hoefsloot, Lihadh Al-Gazali, Jeroen Schoots, Arno van Rooij, Karin Huijben, Connie M A van Ravenswaaij-Arts, Marjolein C J Jongmans, [......], Bobby G Ng, Jorieke E H Bergman, Hans van Bokhoven, Christian Körner, Dusica Babovic-Vuksanovic, Michel A Willemsen, Joseph G Gleeson, Ludwig Lehle, Arjan P M de Brouwer, Dirk J Lefeber
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  ABSTRACT: Cerebellar hypoplasia and slowly progressive ophthalmological symptoms are common features in patients with congenital disorders of glycosylation type I. In a group of patients with congenital disorders of glycosylation type I with unknown aetiology, we have previously described a distinct phenotype with severe, early visual impairment and variable eye malformations, including optic nerve hypoplasia, retinal coloboma, congenital cataract and glaucoma. Some of the symptoms overlapped with the phenotype in other congenital disorders of glycosylation type I subtypes, such as vermis hypoplasia, anaemia, ichtyosiform dermatitis, liver dysfunction and coagulation abnormalities. We recently identified pathogenic mutations in the SRD5A3 gene, encoding steroid 5α-reductase type 3, in a group of patients who presented with this particular phenotype and a common metabolic pattern. Here, we report on the clinical, genetic and metabolic features of 12 patients from nine families with cerebellar ataxia and congenital eye malformations diagnosed with SRD5A3-congenital disorders of glycosylation due to steroid 5α-reductase type 3 defect. This enzyme is necessary for the reduction of polyprenol to dolichol, the lipid anchor for N-glycosylation in the endoplasmic reticulum. Dolichol synthesis is an essential metabolic step in protein glycosylation. The current defect leads to a severely abnormal glycosylation state already in the early phase of the N-glycan biosynthesis pathway in the endoplasmic reticulum. We detected high expression of SRD5A3 in foetal brain tissue, especially in the cerebellum, consistent with the finding of the congenital cerebellar malformations. Based on the overlapping clinical, biochemical and genetic data in this large group of patients with congenital disorders of glycosylation, we define a novel syndrome of cerebellar ataxia associated with congenital eye malformations due to a defect in dolichol metabolism.
  Brain 11/2010; 133(11):3210-20. · 9.46 Impact Factor