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PMID: 16775369 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

Molecular genetics of autosomal-recessive axonal Charcot-Marie-Tooth neuropathies.

Neuromolecular medicine ·Vol. 8 ·No. 1-2 ·2006-00-00 ·Pages 87-106

Bernard R, De Sandre-Giovannoli A, Delague V, Lévy N

Abstract

Autosomal-recessive forms of Charcot-Marie-Tooth (ARCMT) account for less than 10% of the families with CMT. On the other hand, in countries with a high prevalence of consanguinity this mode of inheritance accounts, likely, for the vast majority of CMT phenotypes. Like dominant forms, autosomal-recessive forms are generally subdivided into demyelinating forms (autosomal-recessive CMT1: ARCMT1 or CMT4) and axonal forms (ARCMT2). Until now, demyelinating ARCMT were more extensively studied at the genetic level than the axonal forms. Although the latter are undoubtedly the rarest forms among the heterogeneous group of CMT, three distinct forms have been genetically mapped and recent studies in the past 4 yr provided evidence that their respective causing genes have been characterized. Indeed, gene defects in encoding A-type lamins (LMNA), encoding Ganglioside-induced Differentiation-Associated Protein-1 (GDAP1) and encoding the mediator of RNA polymerase II transcription, subunit 25 homolog (MED25) have been identified in ARCMT2 subtypes. Given the clinical, electrophysiological and histological heterogeneity of CMT2, it is likely that unreported forms of ARCMT2, related to novel genes, remain to be discovered, leading to an even more complex classification. However, our goal in this review is to provide the reader with a clear view on the known genes and mechanisms involved in ARCMT2 and their associated phenotypes.

MeSH Terms
Animals Charcot-Marie-Tooth Disease/genetics,pathology,physiopathology Chromosome Disorders/genetics,pathology,physiopathology Chromosomes, Human, Pair 19 Disease Models, Animal Electrophysiology Genes, Recessive/genetics Humans Lamin Type A/genetics,metabolism Molecular Biology Mutation Nerve Tissue Proteins/genetics,metabolism Phenotype
Chemicals
GDAP protein LMNA protein, human Lamin Type A Nerve Tissue Proteins
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Bernard Rafaëlle
Departement de Genetique Medicale Hopital d'enfants de la Timone, Marseille, France.
De Sandre-Giovannoli Annachiara
Delague Valérie
Lévy Nicolas
References (97)
97 references, click to expand
  1. Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies.
    Hum Mol Genet. 2005 Jan 1;14(1):155-69 PMID: 15548545
  2. Lamin a truncation in Hutchinson-Gilford progeria.
    Science. 2003 Jun 27;300(5628):2055 PMID: 12702809
  3. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A.
    Nat Genet. 2004 May;36(5):449-51 PMID: 15064763
  4. A novel mutation of GDAP1 associated with Charcot-Marie-Tooth disease in three Italian families: evidence for a founder effect.
    J Neurol Neurosurg Psychiatry. 2004 Oct;75(10):1495-8 PMID: 15377708
  5. Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy.
    Am J Hum Genet. 2000 Apr;66(4):1407-12 PMID: 10739764
  6. Linkage of a new locus for autosomal recessive axonal form of Charcot-Marie-Tooth disease to chromosome 8q21.3.
    Neuromuscul Disord. 2001 Jan;11(1):27-34 PMID: 11166163
  7. Fine localization of the CMT4A locus using a PAC contig and haplotype analysis.
    Neurogenetics. 1998 Dec;2(1):18-23 PMID: 9933296
  8. Mitochondrial respiratory chain diseases and mutations in nuclear DNA: a promising start?
    Brain Pathol. 2000 Jul;10(3):442-50 PMID: 10885663
  9. Loss of ZMPSTE24 (FACE-1) causes autosomal recessive restrictive dermopathy and accumulation of Lamin A precursors.
    Hum Mol Genet. 2005 Jun 1;14(11):1503-13 PMID: 15843403
  10. Decreased mechanical stiffness in LMNA-/- cells is caused by defective nucleo-cytoskeletal integrity: implications for the development of laminopathies.
    Hum Mol Genet. 2004 Nov 1;13(21):2567-80 PMID: 15367494
  11. Behavioural profiling of a murine Charcot-Marie-Tooth disease type 1A model.
    Eur J Neurosci. 2001 Apr;13(8):1625-34 PMID: 11328356
  12. Differential timing of nuclear lamin A/C expression in the various organs of the mouse embryo and the young animal: a developmental study.
    Development. 1989 Feb;105(2):365-78 PMID: 2680424
  13. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome.
    Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):8963-8 PMID: 15184648
  14. Charcot-Marie-Tooth disease (CMT): distinctive phenotypic and genotypic features in CMT type 2.
    J Neurol Sci. 2001 Feb 15;184(1):1-9 PMID: 11231025
  15. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy.
    Nat Genet. 2000 Feb;24(2):153-6 PMID: 10655060
  16. Autosomal-recessive Charcot-Marie-Tooth diseases.
    J Neuropathol Exp Neurol. 2005 May;64(5):363-70 PMID: 15892292
  17. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome.
    Nature. 2003 May 15;423(6937):293-8 PMID: 12714972
  18. A transgenic rat model of Charcot-Marie-Tooth disease.
    Neuron. 1996 May;16(5):1049-60 PMID: 8630243
  19. 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 Jan;21(1):176-87 PMID: 14595091
  20. A new clinical condition linked to a novel mutation in lamins A and C with generalized lipoatrophy, insulin-resistant diabetes, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy.
    J Clin Endocrinol Metab. 2003 Mar;88(3):1006-13 PMID: 12629077
  21. LMNA mutations in atypical Werner's syndrome.
    Lancet. 2003 Nov 8;362(9395):1585; author reply 1586 PMID: 14615128
  22. A locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 1q21.2-q21.3.
    Am J Hum Genet. 1999 Sep;65(3):722-7 PMID: 10441578
  23. Classical infantile spinal muscular atrophy with SMN deficiency causes sensory neuronopathy.
    Neurology. 2003 Mar 25;60(6):983-7 PMID: 12654964
  24. Proteins that bind A-type lamins: integrating isolated clues.
    J Cell Sci. 2004 Mar 1;117(Pt 7):979-87 PMID: 14996929
  25. The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease.
    Nat Genet. 2002 Jan;30(1):22-5 PMID: 11743580
  26. Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy.
    Hum Mol Genet. 2004 Oct 15;13(20):2493-503 PMID: 15317753
  27. Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy.
    Neurology. 2002 Dec 24;59(12):1865-72 PMID: 12499475
  28. A new mutation of the lamin A/C gene leading to autosomal dominant axonal neuropathy, muscular dystrophy, cardiac disease, and leuconychia.
    J Med Genet. 2004 Mar;41(3):e29 PMID: 14985400
  29. Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy.
    Brain. 2003 Mar;126(Pt 3):642-9 PMID: 12566285
  30. Further evidence that neurofilament light chain gene mutations can cause Charcot-Marie-Tooth disease type 2E.
    Ann Neurol. 2001 Feb;49(2):245-9 PMID: 11220745
  31. Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect.
    J Med Genet. 2005 Apr;42(4):358-65 PMID: 15805163
  32. Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. I. Neurologic, genetic, and electrophysiologic findings in hereditary polyneuropathies.
    Arch Neurol. 1968 Jun;18(6):603-18 PMID: 4297451
  33. Extreme variability of skeletal and cardiac muscle involvement in patients with mutations in exon 11 of the lamin A/C gene.
    Muscle Nerve. 2005 May;31(5):602-9 PMID: 15770669
  34. Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction.
    J Clin Invest. 2004 Feb;113(3):370-8 PMID: 14755334
  35. Genomic instability in laminopathy-based premature aging.
    Nat Med. 2005 Jul;11(7):780-5 PMID: 15980864
  36. A progeroid syndrome in mice is caused by defects in A-type lamins.
    Nature. 2003 May 15;423(6937):298-301 PMID: 12748643
  37. Correlation between varying levels of PMP22 expression and the degree of demyelination and reduction in nerve conduction velocity in transgenic mice.
    Hum Mol Genet. 1998 Mar;7(3):449-58 PMID: 9467003
  38. Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B).
    Hum Mol Genet. 2000 May 22;9(9):1453-9 PMID: 10814726
  39. GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria.
    Hum Mol Genet. 2005 Apr 15;14(8):1087-94 PMID: 15772096
  40. The novel neurofilament light (NEFL) mutation Glu397Lys is associated with a clinically and morphologically heterogeneous type of Charcot-Marie-Tooth neuropathy.
    Neuromuscul Disord. 2004 Feb;14(2):147-57 PMID: 14733962
  41. Hereditary motor and sensory neuropathy of neuronal type with onset in early childhood.
    J Neurol Sci. 1981 Aug;51(2):181-97 PMID: 6268756
  42. Nuclear envelopathies--raising the nuclear veil.
    Pediatr Res. 2005 May;57(5 Pt 2):8R-15R PMID: 15817509
  43. A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene.
    Am J Hum Genet. 2000 Jul;67(1):37-46 PMID: 10841809
  44. Vocal cord and diaphragm paralysis, as clinical features of a French family with autosomal recessive Charcot-Marie-Tooth disease, associated with a new mutation in the GDAP1 gene.
    Neuromuscul Disord. 2004 Apr;14(4):261-4 PMID: 15019704
  45. 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 May;13(4):341-6 PMID: 12868504
  46. Phenotypical features of a Moroccan family with autosomal recessive Charcot-Marie-Tooth disease associated with the S194X mutation in the GDAP1 gene.
    Arch Neurol. 2003 Apr;60(4):598-604 PMID: 12707075
  47. Neuronal differentiation of NT2/D1 teratocarcinoma cells is accompanied by a loss of lamin A/C expression and an increase in lamin B1 expression.
    Exp Neurol. 1999 Jun;157(2):241-50 PMID: 10364436
  48. Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy.
    J Cell Biol. 1999 Nov 29;147(5):913-20 PMID: 10579712
  49. Frequent low penetrance mutations in the Lamin A/C gene, causing Emery Dreifuss muscular dystrophy.
    Neuromuscul Disord. 2002 Dec;12(10):958-63 PMID: 12467752
  50. A second locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 19q13.3.
    Am J Hum Genet. 2001 Jan;68(1):269-74 PMID: 11112660
  51. Clinical and electrophysiological characteristics of autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2B) that maps to chromosome 19q13.3.
    Neuromuscul Disord. 2004 May;14(5):301-6 PMID: 15099588
  52. The regulation of bidirectional mitochondrial transport is coordinated with axonal outgrowth.
    J Cell Sci. 1993 Mar;104 ( Pt 3):917-27 PMID: 8314882
  53. Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice.
    J Clin Invest. 2004 Feb;113(3):357-69 PMID: 14755333
  54. Dominant LMNA mutations can cause combined muscular dystrophy and peripheral neuropathy.
    J Neurol Neurosurg Psychiatry. 2005 Jul;76(7):1019-21 PMID: 15965218
  55. Electrophysiological findings including single fibre EMG in a family with mitochondrial myopathy.
    J Neurol Sci. 1982 Feb;53(2):397-410 PMID: 7057217
  56. The phenotypic manifestations of autosomal recessive axonal Charcot-Marie-Tooth due to a mutation in Lamin A/C gene.
    Neuromuscul Disord. 2003 Jan;13(1):60-7 PMID: 12467734
  57. Extreme variability of phenotype in patients with an identical missense mutation in the lamin A/C gene: from congenital onset with severe phenotype to milder classic Emery-Dreifuss variant.
    Arch Neurol. 2004 May;61(5):690-4 PMID: 15148145
  58. Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse.
    Am J Hum Genet. 2002 Mar;70(3):726-36 PMID: 11799477
  59. Autosomal recessive forms of Charcot-Marie-Tooth disease.
    Curr Neurol Neurosci Rep. 2004 Sep;4(5):413-9 PMID: 15324608
  60. Autosomal recessive forms of hereditary motor and sensory neuropathy.
    J Neurol Neurosurg Psychiatry. 1980 Aug;43(8):669-78 PMID: 7431027
  61. Mapping of a new locus for autosomal recessive demyelinating Charcot-Marie-Tooth disease to 19q13.1-13.3 in a large consanguineous Lebanese family: exclusion of MAG as a candidate gene.
    Am J Hum Genet. 2000 Jul;67(1):236-43 PMID: 10848494
  62. Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. II. Neurologic, genetic, and electrophysiologic findings in various neuronal degenerations.
    Arch Neurol. 1968 Jun;18(6):619-25 PMID: 5652992
  63. Prelamin A endoproteolytic processing in vitro by recombinant Zmpste24.
    Biochem J. 2005 Apr 1;387(Pt 1):129-38 PMID: 15479156
  64. The nuclear lamina comes of age.
    Nat Rev Mol Cell Biol. 2005 Jan;6(1):21-31 PMID: 15688064
  65. Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity.
    J Biol Chem. 2003 May 9;278(19):17190-7 PMID: 12598526
  66. The nuclear muscular dystrophies.
    Semin Pediatr Neurol. 2002 Jun;9(2):100-7 PMID: 12138994
  67. Mutations in the mouse Lmna gene causing progeria, muscular dystrophy and cardiomyopathy.
    Novartis Found Symp. 2005;264:246-58; discussion 258-63 PMID: 15773758
  68. Periaxin mutations cause recessive Dejerine-Sottas neuropathy.
    Am J Hum Genet. 2001 Feb;68(2):325-33 PMID: 11133365
  69. New insights into neuron-glia communication.
    Science. 2002 Oct 18;298(5593):556-62 PMID: 12386325
  70. Identification of novel GDAP1 mutations causing autosomal recessive Charcot-Marie-Tooth disease.
    Neuromuscul Disord. 2003 Nov;13(9):720-8 PMID: 14561495
  71. Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy.
    Nat Genet. 1999 Mar;21(3):285-8 PMID: 10080180
  72. The giant axonal neuropathy--clinical and hisotological aspects, differential diagnosis and a new case.
    Clin Neuropathol. 2001 Sep-Oct;20(5):200-11 PMID: 11594505
  73. LMNA mutations in atypical Werner's syndrome.
    Lancet. 2003 Aug 9;362(9382):440-5 PMID: 12927431
  74. Phenotypic variability in autosomal recessive axonal Charcot-Marie-Tooth disease due to the R298C mutation in lamin A/C.
    Brain. 2004 Jan;127(Pt 1):154-63 PMID: 14607793
  75. Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice.
    Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18111-6 PMID: 15608054
  76. Clinicopathological and genetic study of early-onset demyelinating neuropathy.
    Brain. 2004 Nov;127(Pt 11):2540-50 PMID: 15469949
  77. LMNA mutations in atypical Werner's syndrome.
    Lancet. 2003 Nov 8;362(9395):1585-6; author reply 1586 PMID: 14615129
  78. Hereditary motor and sensory neuropathy of neuronal type with onset in early childhood.
    Brain. 1991 Aug;114 ( Pt 4):1855-70 PMID: 1884182
  79. A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease.
    Hum Mol Genet. 2001 Feb 15;10(4):415-21 PMID: 11157804
  80. High incidence of SMN1 gene deletion in Moroccan adult-onset spinal muscular atrophy patients.
    J Neurol. 2003 Oct;250(10):1209-13 PMID: 14586604
  81. Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21.
    Nat Genet. 2002 Jan;30(1):21-2 PMID: 11743579
  82. A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies.
    Hum Mol Genet. 2002 Apr 1;11(7):769-77 PMID: 11929849
  83. Charcot-Marie-Tooth disease: an update.
    Curr Opin Neurol. 2004 Oct;17 (5):579-85 PMID: 15367862
  84. CMT4A: identification of a Hispanic GDAP1 founder mutation.
    Ann Neurol. 2003 Mar;53(3):400-5 PMID: 12601710
  85. Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease.
    Brain. 2003 Mar;126(Pt 3):590-7 PMID: 12566280
  86. Mitochondrial neuropathy.
    Clin Neurol Neurosurg. 2005 Apr;107(3):181-6 PMID: 15823672
  87. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease.
    N Engl J Med. 1999 Dec 2;341(23):1715-24 PMID: 10580070
  88. ATP: an extracellular signaling molecule between neurons and glia.
    Trends Neurosci. 2000 Dec;23(12):625-33 PMID: 11137153
  89. Complex formation between lamin A and the retinoblastoma gene product: identification of the domain on lamin A required for its interaction.
    Oncogene. 1994 Sep;9(9):2649-53 PMID: 8058329
  90. Phenotypic and genetic exploration of severe demyelinating and secondary axonal neuropathies resulting from GDAP1 nonsense and splicing mutations.
    J Med Genet. 2003 Jul;40(7):e87 PMID: 12843336
  91. In vivo and in vitro interaction between human transcription factor MOK2 and nuclear lamin A/C.
    Nucleic Acids Res. 2002 Nov 1;30(21):4634-42 PMID: 12409453
  92. Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C.
    Am J Hum Genet. 2002 Aug;71(2):426-31 PMID: 12075506
  93. Expression of an LMNA-N195K variant of A-type lamins results in cardiac conduction defects and death in mice.
    Hum Mol Genet. 2005 Aug 1;14(15):2167-80 PMID: 15972724
  94. Linkage of a locus (CMT4A) for autosomal recessive Charcot-Marie-Tooth disease to chromosome 8q.
    Hum Mol Genet. 1993 Oct;2(10):1625-8 PMID: 8268915
  95. Clinical, electrophysiological and morphological findings of Charcot-Marie-Tooth neuropathy with vocal cord palsy and mutations in the GDAP1 gene.
    Brain. 2003 Sep;126(Pt 9):2023-33 PMID: 12821518
  96. Expression of a mutant lamin A that causes Emery-Dreifuss muscular dystrophy inhibits in vitro differentiation of C2C12 myoblasts.
    Mol Cell Biol. 2004 Feb;24(4):1481-92 PMID: 14749366
  97. Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia.
    Hum Mol Genet. 2003 Aug 15;12(16):1995-2001 PMID: 12913070
Article Info
Journal
Neuromolecular medicine
Abbr.
Neuromolecular Med
ISSN
1535-1084
DOI
10.1385/nmm:8:1-2:87
Published
2006-00-00
Pages
87-106
Language
English
Region
United States
NLM ID
101135365
Subset
IM
External Links
PubMed source DOI: 10.1385/nmm:8:1-2:87 View journal details
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