A locus-specific database for mutations in GDAP1 allows analysis of genotype-phenotype correlations in Charcot-Marie-Tooth diseases type 4A and 2K

Orphanet Journal of Rare Diseases

Marc Ferré¹  Pascal Reynier¹  Vincent Procaccio¹  Christophe Verny²  Dominique Bonneau¹  Arnaud Chevrollier¹  Julien Cassereau² 

[1] CHU Angers, Département de Biochimie et Génétique, Angers, F-49000, France;CHU Angers, Département de Neurologie, Angers, F-49000, France

关键词: locus-specific database (LSDB);    ganglioside-induced differentiation-associated protein 1 (GDAP1);    Charcot-Marie-Tooth disease (CMT);    inherited peripheral neuropathy;   

Others  :  864477
DOI  :  10.1186/1750-1172-6-87

 received in 2011-08-31, accepted in 2011-12-26,  发布年份 2011

【 摘 要 】

Background

The ganglioside-induced differentiation-associated protein 1 gene (GDAP1), which is involved in the Charcot-Marie-Tooth disease (CMT), the most commonly inherited peripheral neuropathy, encodes a protein anchored to the mitochondrial outer membrane. The phenotypic presentations of patients carrying GDAP1 mutations are heterogeneous, making it difficult to determine genotype-phenotype correlations, since the majority of the mutations have been found in only a few unrelated patients. Locus-specific databases (LSDB) established in the framework of the Human Variome Project provide powerful tools for the investigation of such rare diseases.

Methods and Results

We report the development of a publicly accessible LSDB for the GDAP1 gene. The GDAP1 LSDB has adopted the Leiden Open-source Variation Database (LOVD) software platform. This database, which now contains 57 unique variants reported in 179 cases of CMT, offers a detailed description of the molecular, clinical and electrophysiological data of the patients. The usefulness of the GDAP1 database is illustrated by the finding that GDAP1 mutations lead to primary axonal damage in CMT, with secondary demyelination in the more severe cases of the disease.

Conclusion

Findings of this nature should lead to a better understanding of the pathophysiology of CMT. Finally, the GDAP1 LSDB, which is part of the mitodyn.org portal of databases of genes incriminated in disorders involving mitochondrial dynamics and bioenergetics, should yield new insights into mitochondrial diseases.

【 授权许可】

   
2011 Cassereau et al; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Emery AE: Population frequencies of inherited neuromuscular diseases--a world survey. Neuromuscul Disord 1991, 1:19-29.
• [2]Baxter RV, Ben Othmane K, Rochelle JM, Stajich JE, Hulette C, Dew-Knight S, Hentati F, Ben Hamida M, Bel S, Stenger JE, et al.: Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. Nat Genet 2002, 30:21-22.
• [3]Cuesta A, Pedrola L, Sevilla T, Garcia-Planells J, Chumillas MJ, Mayordomo F, LeGuern E, Marin I, Vilchez JJ, Palau F: The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease. Nat Genet 2002, 30:22-25.
• [4]Senderek J, Bergmann C, Ramaekers VT, Nelis E, Bernert G, Makowski A, Zuchner S, De Jonghe P, Rudnik-Schoneborn S, Zerres K, Schroder JM: Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy. Brain 2003, 126:642-649.
• [5]Cassereau J, Chevrollier A, Gueguen N, Malinge MC, Letournel F, Nicolas G, Richard L, Ferre M, Verny C, Dubas F, et al.: Mitochondrial complex I deficiency in GDAP1-related autosomal dominant Charcot-Marie-Tooth disease (CMT2K). Neurogenetics 2009, 10:145-150.
• [6]Chung KW, Kim SM, Sunwoo IN, Cho SY, Hwang SJ, Kim J, Kang SH, Park KD, Choi KG, Choi IS, Choi BO: A novel GDAP1 Q218E mutation in autosomal dominant Charcot-Marie-Tooth disease. J Hum Genet 2008, 53:360-364.
• [7]Claramunt R, Pedrola L, Sevilla T, Lopez de Munain A, Berciano J, Cuesta A, Sanchez-Navarro B, Millan JM, Saifi GM, Lupski JR, et al.: Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. J Med Genet 2005, 42:358-365.
• [8]Ben Othmane K, Hentati F, Lennon F, Ben Hamida C, Blel S, Roses AD, Pericak-Vance MA, Ben Hamida M, Vance JM: Linkage of a locus (CMT4A) for autosomal recessive Charcot-Marie-Tooth disease to chromosome 8q. Hum Mol Genet 1993, 2:1625-1628.
• [9]Liu H, Nakagawa T, Kanematsu T, Uchida T, Tsuji S: Isolation of 10 differentially expressed cDNAs in differentiated Neuro2a cells induced through controlled expression of the GD3 synthase gene. J Neurochem 1999, 72:1781-1790.
• [10]Marco A, Cuesta A, Pedrola L, Palau F, Marin I: Evolutionary and structural analyses of GDAP1, involved in Charcot-Marie-Tooth disease, characterize a novel class of glutathione transferase-related genes. Mol Biol Evol 2004, 21:176-187.
• [11]Shield AJ, Murray TP, Board PG: Functional characterisation of ganglioside-induced differentiation-associated protein 1 as a glutathione transferase. Biochem Biophys Res Commun 2006, 347:859-866.
• [12]Pedrola L, Espert A, Wu X, Claramunt R, Shy ME, Palau F: GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria. Hum Mol Genet 2005, 14:1087-1094.
• [13]Wagner KM, Ruegg M, Niemann A, Suter U: Targeting and function of the mitochondrial fission factor GDAP1 are dependent on its tail-anchor. PLoS One 2009, 4:e5160.
• [14]Niemann A, Ruegg M, La Padula V, Schenone A, Suter U: Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease. J Cell Biol 2005, 170:1067-1078.
• [15]Pedrola L, Espert A, Valdes-Sanchez T, Sanchez-Piris M, Sirkowski EE, Scherer SS, Farinas I, Palau F: Cell expression of GDAP1 in the nervous system and pathogenesis of Charcot-Marie-Tooth type 4A disease. J Cell Mol Med 2008, 12:679-689.
• [16]Cassereau J, Chevrollier A, Gueguen N, Desquiret V, Verny C, Nicolas G, Dubas F, Amati-Bonneau P, Reynier P, Bonneau D, Procaccio V: Mitochondrial dysfunction and pathophysiology of Charcot-Marie-Tooth disease involving GDAP1 mutations. Experimental neurology 2011, 227:31-41.
• [17]Moroni I, Morbin M, Milani M, Ciano C, Bugiani M, Pagliano E, Cavallaro T, Pareyson D, Taroni F: Novel mutations in the GDAP1 gene in patients affected with early-onset axonal Charcot-Marie-Tooth type 4A. Neuromuscul Disord 2009, 19:476-480.
• [18]Azzedine H, Ruberg M, Ente D, Gilardeau C, Perie S, Wechsler B, Brice A, LeGuern E, Dubourg O: Variability of disease progression in a family with autosomal recessive CMT associated with a S194X and new R310Q mutation in the GDAP1 gene. Neuromuscul Disord 2003, 13:341-346.
• [19]The Inherited Peripheral Neuropathies Mutation Database [http://www.molgen.ua.ac.be/CMTMutations/] webcite
• [20]Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT: LOVD v.2.0: the next generation in gene variant databases. Human mutation 2011, 32:557-563.
• [21]Wildeman M, van Ophuizen E, den Dunnen JT, Taschner PE: Improving sequence variant descriptions in mutation databases and literature using the Mutalyzer sequence variation nomenclature checker. Human mutation 2008, 29:6-13.
• [22]den Dunnen JT, Antonarakis SE: Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat 2000, 15:7-12.
• [23]den Dunnen JT, Paalman MH: Standardizing mutation nomenclature: why bother? Hum Mutat 2003, 22:181-182.
• [24]Crimella C, Tonelli A, Airoldi G, Baschirotto C, D'Angelo MG, Bonato S, Losito L, Trabacca A, Bresolin N, Bassi MT: The GST domain of GDAP1 is a frequent target of mutations in the dominant form of axonal Charcot Marie Tooth type 2K. J Med Genet 2010, 47:712-716.
• [25]AAN: Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Neurology 1991, 41:617-618.
• [26]Dubourg O: Charcot-Marie-Tooth disease: from phenotype to genotype. Revue neurologique 2004, 160:1221-1229.
• [27]Birouk N, Gouider R, Le Guern E, Gugenheim M, Tardieu S, Maisonobe T, Le Forestier N, Agid Y, Brice A, Bouche P: Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases. Brain 1997, 120(Pt 5):813-823.
• [28]Hattori N, Yamamoto M, Yoshihara T, Koike H, Nakagawa M, Yoshikawa H, Ohnishi A, Hayasaka K, Onodera O, Baba M, et al.: Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients. Brain 2003, 126:134-151.
• [29]Lewis RA, Sumner AJ, Shy ME: Electrophysiological features of inherited demyelinating neuropathies: A reappraisal in the era of molecular diagnosis. Muscle Nerve 2000, 23:1472-1487.
• [30]Dubourg O, Azzedine H, Verny C, Durosier G, Birouk N, Gouider R, Salih M, Bouhouche A, Thiam A, Grid D, et al.: Autosomal-recessive forms of demyelinating Charcot-Marie-Tooth disease. Neuromolecular Med 2006, 8:75-86.
• [31]Cassereau J, Casasnovas C, Gueguen N, Malinge MC, Guillet V, Reynier P, Bonneau D, Amati-Bonneau P, Banchs I, Volpini V, et al.: Simultaneous MFN2 and GDAP1 mutations cause major mitochondrial defects in a patient with CMT. Neurology 2011, 76:1524-1526.
• [32]The MITOchondrial DYNamics variation pages [http://mitodyn.org] webcite
• [33]Ferre M, Amati-Bonneau P, Tourmen Y, Malthiery Y, Reynier P: eOPA1: an online database for OPA1 mutations. Human mutation 2005, 25:423-428.
• [34]Zuchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, Zappia M, Nelis E, Patitucci A, Senderek J, et al.: Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 2004, 36:449-451.
• [35]Waterham HR, Koster J, van Roermund CW, Mooyer PA, Wanders RJ, Leonard JV: A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med 2007, 356:1736-1741.