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Genes involved in leukodystrophies: A glance at glial functions

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Abstract

Leukodystrophies are a group of orphan genetic diseases that primarily affect the white matter (WM) of the brain. The diagnosis and classification of these pathologies have been improved in the past decade thanks to the development of brain MRI, which allows the diagnosis of WM abnormalities in vivo and the continuous follow-up of patients. This article reviews recent advances made in leukodystrophy research by identifying causative genes. It focuses particularly on the genes involved in the hypomyelinated and vacuolating leukodystrophies, which provide new insights into the understanding of myelin formation and WM homeostasis.

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References and Recommended Reading

  1. Baumann N, Pham-Dinh D: Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev 2001, 81:871–927.

    PubMed  CAS  Google Scholar 

  2. van der Knaap MS, Valk J: Classification of myelin disorders. In Magnetic Resonance of Myelination and Myelin Disorders. Edited by van der Knaap MS, Valk J. Berlin: Spinger-Verlag; 2005:20–24.

    Google Scholar 

  3. Ellison D, Love S: Disorders that primarily affect white matter. In Neuropathology. Edited by Ellison D, Love S: Orlando, FL: Harcourt; 2000: Page #s.

    Google Scholar 

  4. Barkovich AJ: Concepts of myelin and myelination in neuroradiology. Am J Neuroradiol 2000, 21:1099–1109.

    PubMed  CAS  Google Scholar 

  5. Mimault C, Giraud G, Courtois V, et al.: Proteolipoprotein gene analysis in 82 patients with sporadic Pelizaeus-Merzbacher Disease: duplications, the major cause of the disease, originate more frequently in male germ cells, but point mutations do not. The Clinical European Network on Brain Dysmyelinating Disease. Am J Hum Genet 1999, 65:360–369.

    Article  PubMed  CAS  Google Scholar 

  6. Saugier-Veber P, Munnich A, Bonneau D, et al.: X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus. Nat Genet 1994, 6:257–262.

    Article  PubMed  CAS  Google Scholar 

  7. Cailloux F, Gauthier-Barichard F, Mimault C, et al.: Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Clinical European Network on Brain Dysmyelinating Disease. Eur J Hum Genet 2000, 8:837–845.

    Article  PubMed  CAS  Google Scholar 

  8. Garbern JY, Cambi F, Lewis R, et al.: Peripheral neuropathy caused by proteolipid protein gene mutations. Ann N Y Acad Sci 1999, 883:351–365.

    Article  PubMed  CAS  Google Scholar 

  9. Inoue K, Tanaka H, Scaglia F, et al.: Compensating for central nervous system dysmyelination: females with a proteolipid protein gene duplication and sustained clinical improvement. Ann Neurol 2001, 50:747–754.

    Article  PubMed  CAS  Google Scholar 

  10. Hurst S, Garbern J, Trepanier A, Gow A: Quantifying the carrier female phenotype in Pelizaeus-Merzbacher disease. Genet Med 2006, 8:371–378.

    Article  PubMed  Google Scholar 

  11. Lee JA, Carvalho CM, Lupski JR: A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 2007, 131:1235–1247.

    Article  PubMed  CAS  Google Scholar 

  12. Bonnet-Dupeyron MN, Combes P, Santander P, et al.: PLP1 splicing abnormalities identified in Pelizaeus-Merzbacher Disease and SPG2 fibroblasts are associated with different types of mutations. Hum Mutat 2008 (in press).

  13. Wang E, Dimova N, Cambi F: PLP/DM20 ratio is regulated by hnRNPH and F and a novel G-rich enhancer in oligodendrocytes. Nucleic Acids Res 2008, 35:4164–4178.

    Article  CAS  Google Scholar 

  14. Karim SA, Barrie JA, McCulloch MC, et al.: PLP overexpression perturbs myelin protein composition and myelination in a mouse model of Pelizaeus-Merzbacher disease. Glia 2007, 55:341–351.

    Article  PubMed  Google Scholar 

  15. Dhaunchak AS, Nave KA: A common mechanism of PLP/DM20 misfolding causes cysteine-mediated endoplasmic reticulum retention in oligoden drocytes and Pelizaeus-Merzbacher disease. Proc Natl Acad Sci U S A 2007, 104:17813–17818.

    Article  PubMed  CAS  Google Scholar 

  16. Krämer-Albers EM, Gehrig-Burger K, Thiele C, et al.: Perturbed interactions of mutant proteolipid protein/DM20 with cholesterol and lipid rafts in oligodendroglia: implications for dysmyelination in spastic paraplegia. J Neurosci 2006, 26:11743–11752.

    Article  PubMed  CAS  Google Scholar 

  17. Werner HB, Kuhlmann K, Shen S, et al.: Proteolipid protein is required for transport of sirtuin 2 into CNS myelin. J Neurosci 2007, 27:7717–7730.

    Article  PubMed  CAS  Google Scholar 

  18. Vaurs-Barriere C, Bonnet-Dupeyron MN, Combes P, et al.: Golli-MBP copy number analysis by FISH, QMPSF and MAPH in 195 patients with hypomyelinating leukodystrophies. Ann Hum Genet 2006, 70:66–77.

    Article  PubMed  CAS  Google Scholar 

  19. Uhlenberg B, Schuelke M, Rüschendorf F, et al.: Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease. Am J Hum Genet 2004, 75:251–260.

    Article  PubMed  CAS  Google Scholar 

  20. Henneke M, Combes P, Diekmann S, et al.: GJA12 mutations are a rare cause of Pelizaeus Merzbacher-like disease. Neurology 2008, 70:748–754.

    Article  PubMed  CAS  Google Scholar 

  21. Bugiani M, Al Shahwan S, Lamantea E, et al.: GJA12 mutations in children with recessive hypomyelinating leukoencephalopathy. Neurology 2006, 67:273–279.

    Article  PubMed  CAS  Google Scholar 

  22. Pingault V, Bondurand N, Le Caignec C, et al.: The SOX10 transcription factor: evaluation as a candidate gene for central and peripheral hereditary myelin disorders. J Neurol 2001, 248:496–499.

    Article  PubMed  CAS  Google Scholar 

  23. Zara F, Biancheri R, Bruno C, et al.: Deficiency of hyccin, a newly identified membrane protein, causes hypomyelination and congenital cataract. Nat Genet 2006, 38:1111–1113.

    Article  PubMed  CAS  Google Scholar 

  24. Biancheri R, Zara F, Bruno C, et al.: Phenotypic characterization of hypomyelination and congenital cataract. Ann Neurol 2007, 62:121–127.

    Article  PubMed  Google Scholar 

  25. Ugur SA, Tolun A: A deletion in DRCTNNB1A associated with hypomyelination and juvenile onset cataract. Eur J Hum Genet 2008, 16:261–264.

    Article  PubMed  CAS  Google Scholar 

  26. van der Knaap MS, Linnankivi T, Paetau A, et al.: Hypomyelination with atrophy of the basal ganglia and cerebellum: follow-up and pathology. Neurology 2007, 69:166–171.

    Article  PubMed  Google Scholar 

  27. Wolf NI, Harting I, Innes AM, et al.: Ataxia, delayed dentition and hypomyelination: a novel leukoencephalopathy. Neuropediatrics 2007, 38:64–70.

    Article  PubMed  CAS  Google Scholar 

  28. Timmons M, Tsokos M, Asab MA, et al.: Peripheral and central hypomyelination with hypogonadotropic hypogonadism and hypodontia. Neurology 2006, 67:2066–2069.

    Article  PubMed  CAS  Google Scholar 

  29. Mignot C, Boespflug-Tanguy O, Gelot A, et al.: Alexander disease: putative mechanisms of an astrocytic encephalopathy. Cell Mol Life Sci 2004, 61:369–385.

    Article  PubMed  CAS  Google Scholar 

  30. van der Knaap MS, Naidu S, Breiter SN, et al.: Alexander disease: diagnosis with MR imaging. Am J Neuroradiol 2001, 22:541–552.

    PubMed  Google Scholar 

  31. Brenner M, Johnson AB, Boespflug-Tanguy O, et al.: Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet 2001, 27:117–120.

    Article  PubMed  CAS  Google Scholar 

  32. Li R, Johnson AB, Salomons GS, et al.: Propensity for paternal inheritance of de novo mutations in Alexander disease. Hum Genet 2006, 119:137–144.

    Article  PubMed  Google Scholar 

  33. Rodriguez D, Gauthier F, Bertini E, et al.: Infantile Alexander disease: spectrum of GFAP mutations and genotype-phenotype correlation. Am J Hum Genet 2001, 69:1134–1140.

    Article  PubMed  CAS  Google Scholar 

  34. Li R, Johnson AB, Salomons G, et al.: Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease. Ann Neurol 2005, 57:310–326.

    Article  PubMed  CAS  Google Scholar 

  35. Balbi P, Seri M, Ceccherini I, et al.: Adult-onset Alexander disease: report on a family. J Neurol 2008, 255:24–30.

    Article  PubMed  CAS  Google Scholar 

  36. Mignot C, Delarasse C, Escaich S, et al.: Dynamics of mutated GFAP aggregates revealed by real-time imaging of an astrocyte model of Alexander disease. Exp Cell Res 2007, 313:2766–2779.

    Article  PubMed  CAS  Google Scholar 

  37. Salvi F, Aoki Y, Della Nave R, et al.: Adult Alexander’s disease without leukoencephalopathy. Ann Neurol 2005, 58:813–814.

    Article  PubMed  Google Scholar 

  38. van der Knaap MS, Salomons GS, Li R, et al.: Unusual variants of Alexander’s disease. Ann Neurol 2005, 57:327–338.

    Article  PubMed  Google Scholar 

  39. van der Knaap MS, Ramesh V, Schiffmann R, et al.: Alexander disease: ventricular garlands and abnormalities of the medulla and spinal cord. Neurology 2006, 66:494–498.

    Article  PubMed  Google Scholar 

  40. Huttner HB, Richter G, Hildebrandt M, et al.: Acute onset of fatal vegetative symptoms: unusual presentation of adult Alexander disease. Eur J Neurol 2007, 14:1251–1255.

    Article  PubMed  CAS  Google Scholar 

  41. van der Knaap MS, Barth PG, Stroink H, et al.: Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children. Ann Neurol 1995, 37:324–334.

    Article  PubMed  Google Scholar 

  42. Leegwater PA, Yuan BQ, Van der Steen J, et al.: Mutations of MLC1 (KIAA0027): encoding a putative membrane protein cause megalencephalic leukoencephalopathy with subcortical cysts. Am J Hum Genet 2001, 68:831–838.

    Article  PubMed  CAS  Google Scholar 

  43. Teijido O, Casaroli-Marano R, Kharkovets T, et al.: Expression patterns of MLC1 protein in the central and peripheral nervous systems. Neurobiol Dis 2007, 26:532–545.

    Article  PubMed  CAS  Google Scholar 

  44. Boor I, Nagtegaal M, Kamphorst W, et al.: MLC1 is associated with the dystrophin-glycoprotein complex at astrocytic endfeet. Acta Neuropathol 2007, 114:403–410.

    Article  PubMed  CAS  Google Scholar 

  45. Ambrosini E, Serafini B, Lanciotti A, et al.: Biochemical characterization of MLC1 protein in astrocytes and its association with the dystrophin-glycoprotein complex. Mol Cell Neurosci 2008, 37:480–493.

    Article  PubMed  CAS  Google Scholar 

  46. Leegwater PA, Vermeulen G, Konst AA, et al.: Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. Nat Genet 2001, 29:383–388.

    Article  PubMed  CAS  Google Scholar 

  47. van der Knaap MS, Pronk JC, Scheper GC: Vanishing white matter disease. Lancet Neurol 2006, 5:413–423

    Article  PubMed  Google Scholar 

  48. Fogli A, Wong K, Eymard-Pierre E, et al.: Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus. Ann Neurol 2002, 52:506–510.

    Article  PubMed  CAS  Google Scholar 

  49. Passemard S, Gelot A, Fogli A, et al.: Progressive megalencephaly due to specific EIF2Bepsilon mutations in two unrelated families. Neurology 2007, 69:400–402.

    Article  PubMed  CAS  Google Scholar 

  50. Fogli A, Rodriguez D, Eymard-Pierre E, et al.: Ovarian failure related to eukaryotic initiation factor 2B mutations. Am J Hum Genet 2003, 72:1544–1550.

    Article  PubMed  CAS  Google Scholar 

  51. Vanderver A, Schiffmann R, Timmons M, et al.: Decreased asialotransferrin in cerebrospinal fluid of patients with childhood-onset ataxia and central nervous system hypomyelination/vanishing white matter disease. Clin Chem 2005, 51:2031–2042.

    Article  PubMed  CAS  Google Scholar 

  52. Fogli A, Boespflug-Tanguy O: The large spectrum of eIF2B-related diseases. Biochem Soc Trans 2006, 34:22–29.

    Article  PubMed  CAS  Google Scholar 

  53. Scheper GC, van der Knaap MS, Proud CG: Translation matters: protein synthesis defects in inherited disease. Nat Rev Genet 2007, 8:711–723.

    Article  PubMed  CAS  Google Scholar 

  54. Fogli A, Schiffmann R, Hugendubler L, et al.: Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients. Eur J Hum Genet 2004, 12:561–566.

    Article  PubMed  CAS  Google Scholar 

  55. van Kollenburg B, van Dijk J, Garbern J, et al.: Glia-specific activation of all pathways of the unfolded protein response in vanishing white matter disease. J Neuropathol Exp Neurol 2006, 65:707–715.

    Article  PubMed  Google Scholar 

  56. Kantor L, Harding HP, Ron D, et al.: Heightened stress response in primary fibroblasts expressing mutant eIF2B genes from CACH/VWM leukodystrophy patients. Hum Genet 2005, 18:99–106.

    Article  Google Scholar 

  57. Dietrich J, Lacagnina M, Gass D, et al.: EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy. Nat Med 2005, 11:277–283.

    Article  PubMed  CAS  Google Scholar 

  58. van der Knaap MS, van der Voorn P, Barkhof F, et al.: A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate. Ann Neurol 2003, 53:252–258.

    Article  PubMed  Google Scholar 

  59. Labauge P, Roullet E, Boespflug-Tanguy O, et al.: Familial, adult onset form of leukoencephalopathy with brain stem and spinal cord involvement: inconstant high brain lactate and very slow disease progression. Eur Neurol 2007, 58:59–61.

    Article  PubMed  Google Scholar 

  60. Scheper GC, van der Klok T, van Andel RJ, et al.: Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat Genet 2007, 39:534–539.

    Article  PubMed  CAS  Google Scholar 

  61. Dinopoulos A, Cecil KM, Schapiro MB, et al.: Brain MRI and proton MRS findings in infants and children with respiratory chain defects. Neuropediatrics 2005, 36:290–301.

    Article  PubMed  CAS  Google Scholar 

  62. Eldridge R, Anayiotos CP, Schlesinger S, et al.: Hereditary adult-onset leukodystrophy simulating chronic progressive multiple sclerosis. N Engl J Med 1984, 311:948–953.

    PubMed  CAS  Google Scholar 

  63. Coffeen CM, McKenna CE, Koeppen AH, et al.: Genetic localisation of an autosomal dominant leukodystrophy mimicking chronic progressive multiple sclerosis to chromosome 5q31. Hum Mol Genet 2000, 9:787–793.

    Article  PubMed  CAS  Google Scholar 

  64. Padiath QS, Saigoh K, Schiffmann R, et al.: Lamin B1 duplications cause autosomal dominant leukodystrophy. Nat Genet 2006, 38:1114–1123.

    Article  PubMed  CAS  Google Scholar 

  65. Mattout A, Dechat T, Adam SA, et al.: Nuclear lamins, diseases and aging. Curr Opin Cell Biol 2006, 18:335–341.

    Article  PubMed  CAS  Google Scholar 

  66. Crow YJ, Leitch A, Hayward BE, et al.: Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection. Nat Genet 2006, 38:910–916.

    Article  PubMed  CAS  Google Scholar 

  67. Crow YJ, Hayward BE, Parmar R, et al.: Mutations in the gene encoding the 3′–5′ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nat Genet 2006, 38:917–920.

    Article  PubMed  CAS  Google Scholar 

  68. Rice G, Newman WG, Dean J, et al.: Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. Am J Hum Genet 2007, 80:811–815.

    Article  PubMed  CAS  Google Scholar 

  69. Richards A., van den Maagdenberg AM, Jen JC, et al.: C-terminal truncations in human 3-prime-5-prime DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat Genet 2007, 39:1068–1070.

    Article  PubMed  CAS  Google Scholar 

  70. Joutel A, Corpechot C, Ducros A, et al.: Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996, 383:707–710.

    Article  PubMed  CAS  Google Scholar 

  71. Gould DB, Phalan FC, Breedveld GJ, et al.: Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science 2005, 20:1167–1171.

    Article  CAS  Google Scholar 

  72. Gould DB, Phalan FC, van Mil SE, et al.: Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N Engl J Med 2006, 354:1489–1496.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Faculté de Médecine, GReD, INSERM U931 CNRS 6247, 28, place Henri Dunant, 63000, Clermont-Ferrand, France

    Odile Boespflug-Tanguy

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  1. Odile Boespflug-Tanguy
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  2. Pierre Labauge
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  3. Anne Fogli
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  4. Catherine Vaurs-Barriere
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Correspondence to Odile Boespflug-Tanguy.

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Boespflug-Tanguy, O., Labauge, P., Fogli, A. et al. Genes involved in leukodystrophies: A glance at glial functions. Curr Neurol Neurosci Rep 8, 217–229 (2008). https://doi.org/10.1007/s11910-008-0034-x

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