Vincent Timmerman

Publications (102)907.91 Total impact

• Article: Reduced penetrance in hereditary motor neuropathy caused by TRPV4 Arg269Cys mutation.

  José Berciano, Jonathan Baets, Elena Gallardo, Magdalena Zimoń, Antonio García, Eduardo López-Laso, Onofre Combarros, Jon Infante, Vincent Timmerman, Albena Jordanova, Peter De Jonghe
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  ABSTRACT: Incomplete penetrance has rarely been reported in Charcot-Marie-Tooth disease. Our aim is to describe reduced penetrance in a hereditary motor neuropathy pedigree due to mutation in the transient receptor potential vallinoid 4 (TRPV4) gene. The pedigree comprised two affected members, the proband aged 44 years and her affected daughter aged 7 years, and seven additional related subjects, three of whom were subclinical gene mutation carriers aged 9, 40 and 70 years. Clinico-electrophysiological studies, MRI of lower-limb musculature and genetic testing of the TRPV4 were performed. The proband presented with a moderate facio-scapulo-peroneal syndrome, whereas her symptomatic daughter suffered from severe congenital spinal muscular atrophy with arthrogryposis, laryngomalacia, and vocal cord paresis. Electrophysiological evaluation revealed a pure motor axonal neuropathy. In the proband, MRI showed extensive and widespread fatty atrophy of lower-leg musculature, whereas in thigh musculature there was just mild distal fatty infiltration of vastus lateralis. Genetic testing revealed a heterozygous Arg269Cys mutation in the TPRV4 gene. In all three mutation carriers results from clinical and electrophysiological examination, and MRI of foot and lower-leg musculature were normal. We conclude that non-penetrance may be an integral feature of neuropathic syndromes associated with TRPV4 gene mutation.
  Journal of Neurology 02/2011; 258(8):1413-21. · 3.47 Impact Factor
• Source

  Available from: Philip Van Damme

  Article: HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease.

  Constantin d'Ydewalle, Jyothsna Krishnan, Driss M Chiheb, Philip Van Damme, Joy Irobi, Alan P Kozikowski, Pieter Vanden Berghe, Vincent Timmerman, Wim Robberecht, Ludo Van Den Bosch
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  ABSTRACT: Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. Mutations in the 27-kDa small heat-shock protein gene (HSPB1) cause axonal CMT or distal hereditary motor neuropathy (distal HMN). We developed and characterized transgenic mice expressing two different HSPB1 mutations (S135F and P182L) in neurons only. These mice showed all features of CMT or distal HMN dependent on the mutation. Expression of mutant HSPB1 decreased acetylated α-tubulin abundance and induced severe axonal transport deficits. An increase of α-tubulin acetylation induced by pharmacological inhibition of histone deacetylase 6 (HDAC6) corrected the axonal transport defects caused by HSPB1 mutations and rescued the CMT phenotype of symptomatic mutant HSPB1 mice. Our findings demonstrate the pathogenic role of α-tubulin deacetylation in mutant HSPB1-induced neuropathies and offer perspectives for using HDAC6 inhibitors as a therapeutic strategy for hereditary axonopathies.
  Nature medicine 01/2011; 17(8):968-74. · 27.14 Impact Factor
• Article: Toll-like receptor expression in the peripheral nerve.

  Sofie Goethals, Elke Ydens, Vincent Timmerman, Sophie Janssens
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  ABSTRACT: Toll-like receptors comprise a family of evolutionary conserved pattern recognition receptors that act as a first defense line in the innate immune system. Upon stimulation with microbial ligands, they orchestrate the induction of a host defense response by activating different signaling cascades. Interestingly, they appear to detect the presence of endogenous signals of danger as well and as such, neurodegeneration is thought to trigger an immune response through ligation of TLRs. Though recent data report the expression of various TLRs in the central nervous system, TLR expression patterns in the peripheral nervous system have not been determined yet. We observed that Schwann cells express relatively high levels of TLRs, with especially TLR3 and TLR4 being prominent. Sensory and motor neurons hardly express TLRs at all. Through the use of NF-κB signaling as read-out, we could show that all TLRs are functional in Schwann cells and that bacterial lipoprotein, a ligand for TLR1/TLR2 receptors yields the strongest response. In sciatic nerve, basal levels of TLRs closely reflect the expression patterns as determined in Schwann cells. TLR3, TLR4, and TLR7 are majorly expressed, pointing to their possible role in immune surveillance. Upon axotomy, TLR1 becomes strongly induced, while most other TLR expression levels remain unaffected. Altogether, our data suggest that similar to microglia in the brain, Schwann cells might act as sentinel cells in the PNS. Furthermore, acute neurodegeneration induces a shift in TLR expression pattern, most likely illustrating specialized functions of TLRs in basal versus activated conditions of the peripheral nerve.
  Glia 11/2010; 58(14):1701-9. · 4.82 Impact Factor
• Article: Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I.

  Annelies Rotthier, Michaela Auer-Grumbach, Katrien Janssens, Jonathan Baets, Anke Penno, Leonardo Almeida-Souza, Kim Van Hoof, An Jacobs, Els De Vriendt, Beate Schlotter-Weigel, Wolfgang Löscher, Petr Vondráček, Pavel Seeman, Peter De Jonghe, Patrick Van Dijck, Albena Jordanova, Thorsten Hornemann, Vincent Timmerman
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  ABSTRACT: Hereditary sensory and autonomic neuropathy type I (HSAN-I) is an axonal peripheral neuropathy associated with progressive distal sensory loss and severe ulcerations. Mutations in the first subunit of the enzyme serine palmitoyltransferase (SPT) have been associated with HSAN-I. The SPT enzyme catalyzes the first and rate-limiting step in the de novo sphingolipid synthesis pathway. However, different studies suggest the implication of other genes in the pathology of HSAN-I. Therefore, we screened the two other known subunits of SPT, SPTLC2 and SPTLC3, in a cohort of 78 HSAN patients. No mutations were found in SPTLC3, but we identified three heterozygous missense mutations in the SPTLC2 subunit of SPT in four families presenting with a typical HSAN-I phenotype. We demonstrate that these mutations result in a partial to complete loss of SPT activity in vitro and in vivo. Moreover, they cause the accumulation of the atypical and neurotoxic sphingoid metabolite 1-deoxy-sphinganine. Our findings extend the genetic heterogeneity in HSAN-I and enlarge the group of HSAN neuropathies associated with SPT defects. We further show that HSAN-I is consistently associated with an increased formation of the neurotoxic 1-deoxysphinganine, suggesting a common pathomechanism for HSAN-I.
  The American Journal of Human Genetics 10/2010; 87(4):513-22. · 10.60 Impact Factor
• Source

  Available from: PubMed Central

  Article: Mutant HSPB8 causes motor neuron-specific neurite degeneration.

  Joy Irobi, Leonardo Almeida-Souza, Bob Asselbergh, Vicky De Winter, Sofie Goethals, Ines Dierick, Jyothsna Krishnan, Jean-Pierre Timmermans, Wim Robberecht, Peter De Jonghe, Ludo Van Den Bosch, Sophie Janssens, Vincent Timmerman
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  ABSTRACT: Missense mutations (K141N and K141E) in the alpha-crystallin domain of the small heat shock protein HSPB8 (HSP22) cause distal hereditary motor neuropathy (distal HMN) or Charcot-Marie-Tooth neuropathy type 2L (CMT2L). The mechanism through which mutant HSPB8 leads to a specific motor neuron disease phenotype is currently unknown. To address this question, we compared the effect of mutant HSPB8 in primary neuronal and glial cell cultures. In motor neurons, expression of both HSPB8 K141N and K141E mutations clearly resulted in neurite degeneration, as manifested by a reduction in number of neurites per cell, as well as in a reduction in average length of the neurites. Furthermore, expression of the K141E (and to a lesser extent, K141N) mutation also induced spheroids in the neurites. We did not detect any signs of apoptosis in motor neurons, showing that mutant HSPB8 resulted in neurite degeneration without inducing neuronal death. While overt in motor neurons, these phenotypes were only very mildly present in sensory neurons and completely absent in cortical neurons. Also glial cells did not show an altered phenotype upon expression of mutant HSPB8. These findings show that despite the ubiquitous presence of HSPB8, only motor neurons appear to be affected by the K141N and K141E mutations which explain the predominant motor neuron phenotype in distal HMN and CMT2L.
  Human Molecular Genetics 08/2010; 19(16):3254-65. · 7.64 Impact Factor
• Article: Mechanisms for nonrecurrent genomic rearrangements associated with CMT1A or HNPP: rare CNVs as a cause for missing heritability.

  Feng Zhang, Pavel Seeman, Pengfei Liu, Marian A J Weterman, Claudia Gonzaga-Jauregui, Charles F Towne, Sat Dev Batish, Els De Vriendt, Peter De Jonghe, Bernd Rautenstrauss, Klaus-Henning Krause, Mehrdad Khajavi, Jan Posadka, Antoon Vandenberghe, Francesc Palau, Lionel Van Maldergem, Frank Baas, Vincent Timmerman, James R Lupski
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  ABSTRACT: Genomic rearrangements involving the peripheral myelin protein gene (PMP22) in human chromosome 17p12 are associated with neuropathy: duplications cause Charcot-Marie-Tooth disease type 1A (CMT1A), whereas deletions lead to hereditary neuropathy with liability to pressure palsies (HNPP). Our previous studies showed that >99% of these rearrangements are recurrent and mediated by nonallelic homologous recombination (NAHR). Rare copy number variations (CNVs) generated by nonrecurrent rearrangements also exist in 17p12, but their underlying mechanisms are not well understood. We investigated 21 subjects with rare CNVs associated with CMT1A or HNPP by oligonucleotide-based comparative genomic hybridization microarrays and breakpoint sequence analyses, and we identified 17 unique CNVs, including two genomic deletions, ten genomic duplications, two complex rearrangements, and three small exonic deletions. Each of these CNVs includes either the entire PMP22 gene, or exon(s) only, or ultraconserved potential regulatory sequences upstream of PMP22, further supporting the contention that PMP22 is the critical gene mediating the neuropathy phenotypes associated with 17p12 rearrangements. Breakpoint sequence analysis reveals that, different from the predominant NAHR mechanism in recurrent rearrangement, various molecular mechanisms, including nonhomologous end joining, Alu-Alu-mediated recombination, and replication-based mechanisms (e.g., FoSTeS and/or MMBIR), can generate nonrecurrent 17p12 rearrangements associated with neuropathy. We document a multitude of ways in which gene function can be altered by CNVs. Given the characteristics, including small size, structural complexity, and location outside of coding regions, of selected rare CNVs, their identification remains a challenge for genome analysis. Rare CNVs may potentially represent an important portion of "missing heritability" for human diseases.
  The American Journal of Human Genetics 06/2010; 86(6):892-903. · 10.60 Impact Factor
• Article: Dominant mutations in the cation channel gene transient receptor potential vanilloid 4 cause an unusual spectrum of neuropathies.

  Magdalena Zimoń, Jonathan Baets, Michaela Auer-Grumbach, José Berciano, Antonio Garcia, Eduardo Lopez-Laso, Luciano Merlini, David Hilton-Jones, Meriel McEntagart, Andrew H Crosby, [......], Guida Landouré, Christy L Ludlow, Rachelle Gaudet, Henry Houlden, Mary M Reilly, Kenneth H Fischbeck, Charlotte J Sumner, Vincent Timmerman, Albena Jordanova, Peter De Jonghe
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  ABSTRACT: Hereditary neuropathies form a heterogeneous group of disorders for which over 40 causal genes have been identified to date. Recently, dominant mutations in the transient receptor potential vanilloid 4 gene were found to be associated with three distinct neuromuscular phenotypes: hereditary motor and sensory neuropathy 2C, scapuloperoneal spinal muscular atrophy and congenital distal spinal muscular atrophy. Transient receptor potential vanilloid 4 encodes a cation channel previously implicated in several types of dominantly inherited bone dysplasia syndromes. We performed DNA sequencing of the coding regions of transient receptor potential vanilloid 4 in a cohort of 145 patients with various types of hereditary neuropathy and identified five different heterozygous missense mutations in eight unrelated families. One mutation arose de novo in an isolated patient, and the remainder segregated in families. Two of the mutations were recurrent in unrelated families. Four mutations in transient receptor potential vanilloid 4 targeted conserved arginine residues in the ankyrin repeat domain, which is believed to be important in protein-protein interactions. Striking phenotypic variability between and within families was observed. The majority of patients displayed a predominantly, or pure, motor neuropathy with axonal characteristics observed on electrophysiological testing. The age of onset varied widely, ranging from congenital to late adulthood onset. Various combinations of additional features were present in most patients including vocal fold paralysis, scapular weakness, contractures and hearing loss. We identified six asymptomatic mutation carriers, indicating reduced penetrance of the transient receptor potential vanilloid 4 defects. This finding is relatively unusual in the context of hereditary neuropathies and has important implications for diagnostic testing and genetic counselling.
  Brain 06/2010; 133(Pt 6):1798-809. · 9.46 Impact Factor
• Article: L239F founder mutation in GDAP1 is associated with a mild Charcot-Marie-Tooth type 4C4 (CMT4C4) phenotype.

  Dagmara Kabzińska, Halina Strugalska-Cynowska, Anna Kostera-Pruszczyk, Barbara Ryniewicz, Renata Posmyk, Alina Midro, Pavel Seeman, Lucia Báranková, Magdalena Zimoń, Jonathan Baets, Vincent Timmerman, Velina Guergueltcheva, Ivailo Tournev, Stayko Sarafov, Peter De Jonghe, Albena Jordanova, Irena Hausmanowa-Petrusewicz, Andrzej Kochański
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  ABSTRACT: Over 40 mutations in the GDAP1 gene have been shown to segregate with Charcot-Marie-Tooth disease (CMT). Among these, only two mutations, i.e., S194X and Q163X have been reported in a sufficient number of CMT families to allow for the construction of reliable phenotype-genotype correlations. Both the S194X and Q163X mutations have been shown to segregate with an early-onset and severe neuropathy resulting in loss of ambulance at the beginning of the second decade of life. In this study, we identified the L239F mutation in the GDAP1 gene in one Bulgarian and five Polish families. We hypothesized that the L239F mutation may result from a founder effect in the European population since this mutation has previously been reported in Belgian, Czech, and Polish patients. In fact, we detected a common disease-associated haplotype within the 8q13-q21 region in the Polish, German, Italian, Czech, and Bulgarian CMT families. Like the previously detected "regional" S194X and Q163X mutations, respectively present in Maghreb countries and in patients of Spanish descent, the L239F mutation seems to be the most common GDAP1 pathogenic variant in the Central and Eastern European population. Given the likely presence of a common ancestor harboring the L239F mutation, we decided to compare the phenotypes of the CMT (L239F) patients collected in this study with those of previously reported cases. In contrast to CMT4A caused by the S194X and Q163X mutations, the CMT phenotype resulting from the L239F substitution represents a milder clinical entity with a long-preserved period of ambulance at least until the end of the second decade of life.
  Neurogenetics 03/2010; 11(3):357-66. · 3.35 Impact Factor
• Article: Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy.

  Marina L Kennerson, Garth A Nicholson, Stephen G Kaler, Bartosz Kowalski, Julian F B Mercer, Jingrong Tang, Roxana M Llanos, Shannon Chu, Reinaldo I Takata, Carlos E Speck-Martins, [......], Dirk Fischer, Vincent Timmerman, Philip E Taylor, Steven S Scherer, Toby A Ferguson, Thomas D Bird, Peter De Jonghe, Shawna M E Feely, Michael E Shy, James Y Garbern
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  ABSTRACT: Distal hereditary motor neuropathies comprise a clinically and genetically heterogeneous group of disorders. We recently mapped an X-linked form of this condition to chromosome Xq13.1-q21 in two large unrelated families. The region of genetic linkage included ATP7A, which encodes a copper-transporting P-type ATPase mutated in patients with Menkes disease, a severe infantile-onset neurodegenerative condition. We identified two unique ATP7A missense mutations (p.P1386S and p.T994I) in males with distal motor neuropathy in two families. These molecular alterations impact highly conserved amino acids in the carboxyl half of ATP7A and do not directly involve the copper transporter's known critical functional domains. Studies of p.P1386S revealed normal ATP7A mRNA and protein levels, a defect in ATP7A trafficking, and partial rescue of a S. cerevisiae copper transport knockout. Although ATP7A mutations are typically associated with severe Menkes disease or its milder allelic variant, occipital horn syndrome, we demonstrate here that certain missense mutations at this locus can cause a syndrome restricted to progressive distal motor neuropathy without overt signs of systemic copper deficiency. This previously unrecognized genotype-phenotype correlation suggests an important role of the ATP7A copper transporter in motor-neuron maintenance and function.
  The American Journal of Human Genetics 02/2010; 86(3):343-52. · 10.60 Impact Factor
• Article: Increased monomerization of mutant HSPB1 leads to protein hyperactivity in Charcot-Marie-Tooth neuropathy.

  Leonardo Almeida-Souza, Sofie Goethals, Vicky de Winter, Ines Dierick, Rodrigo Gallardo, Joost Van Durme, Joy Irobi, Jan Gettemans, Frederic Rousseau, Joost Schymkowitz, Vincent Timmerman, Sophie Janssens
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  ABSTRACT: Small heat shock proteins are molecular chaperones capable of maintaining denatured proteins in a folding-competent state. We have previously shown that missense mutations in the small heat shock protein HSPB1 (HSP27) cause distal hereditary motor neuropathy and axonal Charcot-Marie-Tooth disease. Here we investigated the biochemical consequences of HSPB1 mutations that are known to cause peripheral neuropathy. In contrast to other chaperonopathies, our results revealed that particular HSPB1 mutations presented higher chaperone activity compared with wild type. Hyperactivation of HSPB1 was accompanied by a change from its wild-type dimeric state to a monomer without dissociation of the 24-meric state. Purification of protein complexes from wild-type and HSPB1 mutants showed that the hyperactive isoforms also presented enhanced binding to client proteins. Furthermore, we show that the wild-type HSPB1 protein undergoes monomerization during heat-shock activation, strongly suggesting that the monomer is the active form of the HSPB1 protein.
  Journal of Biological Chemistry 02/2010; 285(17):12778-86. · 4.77 Impact Factor
• Article: Autosomal-dominant striatal degeneration is caused by a mutation in the phosphodiesterase 8B gene.

  Silke Appenzeller, Anja Schirmacher, Hartmut Halfter, Sebastian Bäumer, Manuela Pendziwiat, Vincent Timmerman, Peter De Jonghe, Klára Fekete, Florian Stögbauer, Peter Lüdemann, Margret Hund, Elgar Susanne Quabius, E Bernd Ringelstein, Gregor Kuhlenbäumer
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  ABSTRACT: Autosomal-dominant striatal degeneration (ADSD) is an autosomal-dominant movement disorder affecting the striatal part of the basal ganglia. ADSD is characterized by bradykinesia, dysarthria, and muscle rigidity. These symptoms resemble idiopathic Parkinson disease, but tremor is not present. Using genetic linkage analysis, we have mapped the causative genetic defect to a 3.25 megabase candidate region on chromosome 5q13.3-q14.1. A maximum LOD score of 4.1 (Theta = 0) was obtained at marker D5S1962. Here we show that ADSD is caused by a complex frameshift mutation (c.94G>C+c.95delT) in the phosphodiesterase 8B (PDE8B) gene, which results in a loss of enzymatic phosphodiesterase activity. We found that PDE8B is highly expressed in the brain, especially in the putamen, which is affected by ADSD. PDE8B degrades cyclic AMP, a second messenger implied in dopamine signaling. Dopamine is one of the main neurotransmitters involved in movement control and is deficient in Parkinson disease. We believe that the functional analysis of PDE8B will help to further elucidate the pathomechanism of ADSD as well as contribute to a better understanding of movement disorders.
  The American Journal of Human Genetics 01/2010; 86(1):83-7. · 10.60 Impact Factor
• Article: Mutations in FAM134B, encoding a newly identified Golgi protein, cause severe sensory and autonomic neuropathy.

  Ingo Kurth, Torsten Pamminger, J Christopher Hennings, Désirée Soehendra, Antje K Huebner, Annelies Rotthier, Jonathan Baets, Jan Senderek, Haluk Topaloglu, Sandra A Farrell, Gudrun Nürnberg, Peter Nürnberg, Peter De Jonghe, Andreas Gal, Christoph Kaether, Vincent Timmerman, Christian A Hübner
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  ABSTRACT: Hereditary sensory and autonomic neuropathy type II (HSAN II) leads to severe mutilations because of impaired nociception and autonomic dysfunction. Here we show that loss-of-function mutations in FAM134B, encoding a newly identified cis-Golgi protein, cause HSAN II. Fam134b knockdown results in structural alterations of the cis-Golgi compartment and induces apoptosis in some primary dorsal root ganglion neurons. This implicates FAM134B as critical in long-term survival of nociceptive and autonomic ganglion neurons.
  Nature Genetics 11/2009; 41(11):1179-81. · 35.53 Impact Factor
• Source

  Available from: Jonathan Baets

  Article: Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype correlation.

  Annelies Rotthier, Jonathan Baets, Els De Vriendt, An Jacobs, Michaela Auer-Grumbach, Nicolas Lévy, Nathalie Bonello-Palot, Sara Sebnem Kilic, Joachim Weis, Andrés Nascimento, Marielle Swinkels, Moyo C Kruyt, Albena Jordanova, Peter De Jonghe, Vincent Timmerman
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  ABSTRACT: Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders characterized by axonal atrophy and degeneration, exclusively or predominantly affecting the sensory and autonomic neurons. So far, disease-associated mutations have been identified in seven genes: two genes for autosomal dominant (SPTLC1 and RAB7) and five genes for autosomal recessive forms of HSAN (WNK1/HSN2, NTRK1, NGFB, CCT5 and IKBKAP). We performed a systematic mutation screening of the coding sequences of six of these genes on a cohort of 100 familial and isolated patients diagnosed with HSAN. In addition, we screened the functional candidate gene NGFR (p75/NTR) encoding the nerve growth factor receptor. We identified disease-causing mutations in SPTLC1, RAB7, WNK1/HSN2 and NTRK1 in 19 patients, of which three mutations have not previously been reported. The phenotypes associated with mutations in NTRK1 and WNK1/HSN2 typically consisted of congenital insensitivity to pain and anhidrosis, and early-onset ulcero-mutilating sensory neuropathy, respectively. RAB7 mutations were only found in patients with a Charcot-Marie-Tooth type 2B (CMT2B) phenotype, an axonal sensory-motor neuropathy with pronounced ulcero-mutilations. In SPTLC1, we detected a novel mutation (S331F) corresponding to a previously unknown severe and early-onset HSAN phenotype. No mutations were found in NGFB, CCT5 and NGFR. Overall disease-associated mutations were found in 19% of the studied patient group, suggesting that additional genes are associated with HSAN. Our genotype-phenotype correlation study broadens the spectrum of HSAN and provides additional insights for molecular and clinical diagnosis.
  Brain 09/2009; 132(Pt 10):2699-711. · 9.46 Impact Factor
• Article: Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy.

  Kristl G Claeys, Stephan Züchner, Marina Kennerson, José Berciano, Antonio Garcia, Kristien Verhoeven, Elsdon Storey, John R Merory, Henriette M E Bienfait, Martin Lammens, Eva Nelis, Jonathan Baets, Els De Vriendt, Zwi N Berneman, Ilse De Veuster, Jefferey M Vance, Garth Nicholson, Vincent Timmerman, Peter De Jonghe
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  ABSTRACT: Dominant intermediate Charcot-Marie-Tooth neuropathy type B is caused by mutations in dynamin 2. We studied the clinical, haematological, electrophysiological and sural nerve biopsy findings in 34 patients belonging to six unrelated dominant intermediate Charcot-Marie-Tooth neuropathy type B families in whom a dynamin 2 mutation had been identified: Gly358Arg (Spain); Asp551_Glu553del; Lys550fs (North America); Lys558del (Belgium); Lys558Glu (Australia, the Netherlands) and Thr855_Ile856del (Belgium). The Gly358Arg and Thr855_Ile856del mutations were novel, and in contrast to the other Charcot-Marie-Tooth-related mutations in dynamin 2, which are all located in the pleckstrin homology domain, they were situated in the middle domain and proline-rich domain of dynamin 2, respectively. We report the first disease-causing mutation in the proline-rich domain of dynamin 2. Patients with a dynamin 2 mutation presented with a classical Charcot-Marie-Tooth phenotype, which was mild to moderately severe since only 3% of the patients were wheelchair-bound. The mean age at onset was 16 years with a large variability ranging from 2 to 50 years. Interestingly, in the Australian and Belgian families, which carry two different mutations affecting the same amino acid (Lys558), Charcot-Marie-Tooth cosegregated with neutropaenia. In addition, early onset cataracts were observed in one of the Charcot-Marie-Tooth families. Our electrophysiological data indicate intermediate or axonal motor median nerve conduction velocities (NCV) ranging from 26 m/s to normal values in four families, and less pronounced reduction of motor median NCV (41-46 m/s) with normal amplitudes in two families. Sural nerve biopsy in a Dutch patient with Lys558Glu mutation showed diffuse loss of large myelinated fibres, presence of many clusters of regenerating myelinated axons and fibres with focal myelin thickenings--findings very similar to those previously reported in the Australian family. We conclude that dynamin 2 mutations should be screened in the autosomal dominant Charcot-Marie-Tooth neuropathy families with intermediate or axonal NCV, and in patients with a classical mild to moderately severe Charcot-Marie-Tooth phenotype, especially when Charcot-Marie-Tooth is associated with neutropaenia or cataracts.
  Brain 08/2009; 132(Pt 7):1741-52. · 9.46 Impact Factor
• Source

  Available from: Tanja Godenschwege

  Article: Dominant mutations in the tyrosyl-tRNA synthetase gene recapitulate in Drosophila features of human Charcot-Marie-Tooth neuropathy.

  Erik Storkebaum, Ricardo Leitão-Gonçalves, Tanja Godenschwege, Leslie Nangle, Monica Mejia, Inge Bosmans, Tinne Ooms, An Jacobs, Patrick Van Dijck, Xiang-Lei Yang, Paul Schimmel, Koen Norga, Vincent Timmerman, Patrick Callaerts, Albena Jordanova
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  ABSTRACT: Dominant-intermediate Charcot-Marie-Tooth neuropathy (DI-CMT) is characterized by axonal degeneration and demyelination of peripheral motor and sensory neurons. Three dominant mutations in the YARS gene, encoding tyrosyl-tRNA synthetase (TyrRS), have so far been associated with DI-CMT type C. The molecular mechanisms through which mutations in YARS lead to peripheral neuropathy are currently unknown, and animal models for DI-CMTC are not yet available. Here, we report the generation of a Drosophila model of DI-CMTC: expression of the 3 mutant--but not wild type--TyrRS in Drosophila recapitulates several hallmarks of the human disease, including a progressive deficit in motor performance, electrophysiological evidence of neuronal dysfunction and morphological signs of axonal degeneration. Not only ubiquitous, but also neuron-specific expression of mutant TyrRS, induces these phenotypes, indicating that the mutant enzyme has cell-autonomous effects in neurons. Furthermore, biochemical and genetic complementation experiments revealed that loss of enzymatic activity is not a common feature of DI-CMTC-associated mutations. Thus, the DI-CMTC phenotype is not due to haploinsufficiency of aminoacylation activity, but most likely to a gain-of-function alteration of the mutant TyrRS or interference with an unknown function of the WT protein. Our results also suggest that the molecular pathways leading to mutant TyrRS-associated neurodegeneration are conserved from flies to humans.
  Proceedings of the National Academy of Sciences 07/2009; 106(28):11782-7. · 9.68 Impact Factor
• Article: A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated.

  Thorsten Hornemann, Anke Penno, Stephane Richard, Garth Nicholson, Fleur S van Dijk, Annelies Rotthier, Vincent Timmerman, Arnold von Eckardstein
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  ABSTRACT: Hereditary sensory neuropathy type 1 (HSAN I) is an autosomal dominant inherited neurodegenerative disorder of the peripheral nervous system associated with mutations in the SPTLC1 subunit of the serine palmitoyltransferase (SPT). Four missense mutations (C133W, C133Y, V144D and G387A) in SPTLC1 were reported to cause HSAN I. SPT catalyses the condensation of Serine and Palmitoyl-CoA, which is the first and rate-limiting step in the de novo synthesis of ceramides. Earlier studies showed that C133W and C133Y mutants have a reduced activity, whereas the impact of the V144D and G387A mutations on the human enzyme was not tested yet. In this paper, we show that none of the HSAN I mutations interferes with SPT complex formation. We demonstrate that also V144D has a reduced SPT activity, however to a lower extent than C133W and C133Y. In contrast, the G387A mutation showed no influence on SPT activity. Furthermore, the growth phenotype of LY-B cells--a SPTLC1 deficient CHO cell line--could be reversed by expressing either the wild-type SPTLC1 or the G387A mutant, but not the C133W mutant. This indicates that the G387A mutation is most likely not directly associated with HSAN I. These findings were genetically confirmed by the identification of a nuclear HSAN family which showed segregation of the G387A variant as a non-synonymous SNP.
  Neurogenetics 02/2009; 10(2):135-43. · 3.35 Impact Factor
• Article: Peripheral neuropathy and 46XY gonadal dysgenesis: a heterogeneous entity.

  Jonathan Baets, Ines Dierick, Chantal Ceuterick-de Groote, Jenneke van den Ende, Jean-Jacques Martin, Karin Geens, Wim Robberecht, Eva Nelis, Vincent Timmerman, Peter De Jonghe
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  ABSTRACT: Gonadal dysgenesis with normal male karyotype (46XY) is a sexual differentiation disorder. So far three patients have been reported presenting the association of 46XY gonadal dysgenesis with peripheral neuropathy. Examination of sural nerves revealed minifascicle formation in two of them. In one patient, a mutation was found in desert hedgehog homolog (Drosophila), a gene important in gonadal differentiation and peripheral nerve development. We studied neuropathological and molecular genetic aspects of a patient with 46XY gonadal dysgenesis and peripheral neuropathy. Examination of a sural nerve biopsy specimen revealed an axonal neuropathy with pronounced axonal loss, limited signs of axonal regeneration and no minifascicle formation. A normal male karyotype was found (46XY) without micro-deletions in the Y chromosome. No mutations were found in the sex determining region Y gene, peripheral myelin protein 22, Myelin Protein Zero, Gap-Junction protein Beta 1, Mitofusin 2 or desert hedgehog homolog. The absence of minifascicle formation and the absence of a mutation in desert hedgehog homolog in this patient with gonadal dysgenesis and peripheral neuropathy expand the clinical and genetic heterogeneity of this rare entity.
  Neuromuscular Disorders 02/2009; 19(2):172-5. · 2.80 Impact Factor
• Article: Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study.

  Ines Dierick, Jonathan Baets, Joy Irobi, An Jacobs, Els De Vriendt, Tine Deconinck, Luciano Merlini, Peter Van den Bergh, Vedrana Milic Rasic, Wim Robberecht, [......], Pavel Seeman, Radim Mazanec, Andrzej Kochanski, Albena Jordanova, Michaela Auer-Grumbach, A T J M Helderman-van den Enden, John H J Wokke, Eva Nelis, Peter De Jonghe, Vincent Timmerman
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  ABSTRACT: Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; glycyl-tRNA synthetase (GARS), dynactin 1 (DCTN1), small heat shock 27 kDa protein 1 (HSPB1), small heat shock 22 kDa protein 8 (HSPB8), Berardinelli-Seip congenital lipodystrophy (BSCL2) and senataxin (SETX). In addition a mutation in the (VAMP)-associated protein B and C (VAPB) was found in several Brazilian families with complex and atypical forms of autosomal dominantly inherited motor neuron disease. We have investigated the distribution of mutations in these seven genes in a cohort of 112 familial and isolated patients with a diagnosis of distal motor neuropathy and found nine different disease-causing mutations in HSPB8, HSPB1, BSCL2 and SETX in 17 patients of whom 10 have been previously reported. No mutations were found in GARS, DCTN1 and VAPB. The phenotypic features of patients with mutations in HSPB8, HSPB1, BSCL2 and SETX fit within the distal HMN classification, with only one exception; a C-terminal HSPB1-mutation was associated with upper motor neuron signs. Furthermore, we provide evidence for a genetic mosaicism in transmitting an HSPB1 mutation. This study, performed in a large cohort of familial and isolated distal HMN patients, clearly confirms the genetic and phenotypic heterogeneity of distal HMN and provides a basis for the development of algorithms for diagnostic mutation screening in this group of disorders.
  Brain 06/2008; 131(Pt 5):1217-27. · 9.46 Impact Factor
• Article: Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity.

  Philip Van Damme, Elke Bogaert, Maarten Dewil, Nicole Hersmus, Dora Kiraly, Wendy Scheveneels, Ilse Bockx, Dries Braeken, Nathalie Verpoorten, Kristien Verhoeven, Vincent Timmerman, Paul Herijgers, Geert Callewaert, Peter Carmeliet, Ludo Van Den Bosch, Wim Robberecht
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  ABSTRACT: Influx of Ca(2+) ions through alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors contributes to neuronal damage in stroke, epilepsy, and neurodegenerative disorders such as ALS. The Ca(2+) permeability of AMPA receptors is largely determined by the glutamate receptor 2 (GluR2) subunit, receptors lacking GluR2 being permeable to Ca(2+) ions. We identified a difference in GluR2 expression in motor neurons from two rat strains, resulting in a difference in vulnerability to AMPA receptor-mediated excitotoxicity both in vitro and in vivo. Astrocytes from the ventral spinal cord were found to mediate this difference in GluR2 expression in motor neurons. The presence of ALS-causing mutant superoxide dismutase 1 in astrocytes abolished their GluR2-regulating capacity and thus affected motor neuron vulnerability to AMPA receptor-mediated excitotoxicity. These results reveal a mechanism through which astrocytes influence neuronal functioning in health and disease.
  Proceedings of the National Academy of Sciences 10/2007; 104(37):14825-30. · 9.68 Impact Factor
• Article: Genotype-phenotype analysis in patients with giant axonal neuropathy (GAN).

  Olga Koop, Anja Schirmacher, Eva Nelis, Vincent Timmerman, Peter De Jonghe, Bernd Ringelstein, Vedrana Milic Rasic, Philippe Evrard, Jutta Gärtner, Kristl G Claeys, Silke Appenzeller, Bernd Rautenstrauss, Kathrin Hühne, Maria A Ramos-Arroyo, Helmut Wörle, Jukka S Moilanen, Simon Hammans, Gregor Kuhlenbäumer
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  ABSTRACT: Giant axonal neuropathy (GAN, MIM: 256850) is a devastating autosomal recessive disorder characterized by an early onset severe peripheral neuropathy, varying central nervous system involvement and strikingly frizzly hair. Giant axonal neuropathy is usually caused by mutations in the gigaxonin gene (GAN) but genetic heterogeneity has been demonstrated for a milder variant of this disease. Here, we report ten patients referred to us for molecular genetic diagnosis. All patients had typical clinical signs suggestive of giant axonal neuropathy. In seven affected individuals, we found disease causing mutations in the gigaxonin gene affecting both alleles: two splice-site and four missense mutations, not reported previously. Gigaxonin binds N-terminally to ubiquitin activating enzyme E1 and C-terminally to various microtubule associated proteins causing their ubiquitin mediated degradation. It was shown for a number of gigaxonin mutations that they impede this process leading to accumulation of microtubule associated proteins and there by impairing cellular functions.
  Neuromuscular Disorders 09/2007; 17(8):624-30. · 2.80 Impact Factor