Abstract
Mutations in the EGR2 gene cause a spectrum of Charcot–Marie–Tooth disease and related inherited peripheral neuropathies. We ascertained ten consecutive patients with various EGR2 mutations, report a novel de novo mutation, and provide longitudinal clinical data to characterize the natural history of the peripheral neuropathy. We confirmed that respiratory compromise and cranial nerve dysfunction are commonly associated with EGR2 mutations and can be useful in guiding molecular diagnosis. We also contrast morphological studies in the context of the I268N homozygous recessive mutation affecting the NAB repressor binding site and the R359W dominant-negative mutation in the zinc-finger domain.
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Topilko P, Schneider-Maunoury S, Levi G et al (1994) Krox-20 controls myelination in the peripheral nervous system. Nature 371:796–799
Le N, Nagarajan R, Wang JY et al (2005) Analysis of congenital hypomyelinating Egr2Lo/Lo nerves identifies Sox2 as an inhibitor of Schwann cell differentiation and myelination. Proc Natl Acad Sci USA 102:2596–2601
Sherman DL, Brophy PJ (2005) Mechanisms of axon ensheathment and myelin growth. Nat Rev Neurosci 6:683–690
LeBlanc SE, Ward RM, Svaren J (2007) Neuropathy-associated Egr2 mutants disrupt cooperative activation of myelin protein zero by Egr2 and Sox10. Mol Cell Biol 27:3521–3529
Decker L, Desmarquet-Trin-Dinh C, Taillebourg E et al (2006) Peripheral myelin maintenance is a dynamic process requiring constant Krox20 expression. J Neurosci 26:9771–9779
Vandenberghe N, Upadhyaya M, Gatignol A et al (2002) Frequency of mutations in the early growth response 2 gene associated with peripheral demyelinating neuropathies. J Med Genet 39:e81
Warner LE, Mancias P, Butler IJ et al (1998) Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies. Nat Genet 18:382–384
Numakura C, Shirahata E, Yamashita S et al (2003) Screening of the early growth response 2 gene in Japanese patients with Charcot-Marie-Tooth disease type 1. J Neurol Sci 210:61–64
Timmerman V, De Jonghe P, Ceuterick C et al (1999) Novel missense mutation in the early growth response 2 gene associated with Dejerine-Sottas syndrome phenotype. Neurology 52:1827–1832
Bellone E, Di Maria E, Soriani S et al (1999) A novel mutation (D305V) in the early growth response 2 gene is associated with severe Charcot–Marie–Tooth type 1 disease. Hum Mutat 14:353–354
Mikesova E, Huhne K, Rautenstrauss B et al (2005) Novel EGR2 mutation R359Q is associated with CMT type 1 and progressive scoliosis. Neuromuscul Disord 15:764–767
Pareyson D, Taroni F, Botti S et al (2000) Cranial nerve involvement in CMT disease type 1 due to early growth response 2 gene mutation. Neurology 54:1696–1698
Yoshihara T, Kanda F, Yamamoto M et al (2001) A novel missense mutation in the early growth response 2 gene associated with late-onset Charcot–Marie–Tooth disease type 1. J Neurol Sci 184:149–153
Warner LE, Svaren J, Milbrandt J, Lupski JR (1999) Functional consequences of mutations in the early growth response 2 gene (EGR2) correlate with severity of human myelinopathies. Hum Mol Genet 8:1245–1251
Svaren J, Sevetson BR, Golda T et al (1998) Novel mutants of NAB corepressors enhance activation by Egr transactivators. Embo J 17:6010–6019
Le N, Nagarajan R, Wang JY et al (2005) Nab proteins are essential for peripheral nervous system myelination. Nat Neurosci 8:932–940
Dytrych L, Sherman DL, Gillespie CS, Brophy PJ (1998) Two PDZ domain proteins encoded by the murine periaxin gene are the result of alternative intron retention and are differentially targeted in Schwann cells. J Biol Chem 273:5794–5800
Boerkoel CF, Takashima H, Bacino CA et al (2001) EGR2 mutation R359W causes a spectrum of Dejerine-Sottas neuropathy. Neurogenetics 3:153–157
Mechta-Grigoriou F, Garel S, Charnay P (2000) Nab proteins mediate a negative feedback loop controlling Krox-20 activity in the developing hindbrain. Development 127:119–128
Schneider-Maunoury S, Topilko P, Seitandou T et al (1993) Disruption of Krox-20 results in alteration of rhombomeres 3 and 5 in the developing hindbrain. Cell 75:1199–1214
Schneider-Maunoury S, Seitanidou T, Charnay P, Lumsden A (1997) Segmental and neuronal architecture of the hindbrain of Krox-20 mouse mutants. Development 124:1215–1226
Inoue K, Khajavi M, Ohyama T et al (2004) Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nat Genet 36:361–369
Szigeti K, Garcia CA, Lupski JR (2006) Charcot-Marie-Tooth disease and related hereditary polyneuropathies: molecular diagnostics determine aspects of medical management. Genet Med 8:86–92
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Szigeti, K., Wiszniewski, W., Saifi, G.M. et al. Functional, histopathologic and natural history study of neuropathy associated with EGR2 mutations. Neurogenetics 8, 257–262 (2007). https://doi.org/10.1007/s10048-007-0094-0
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DOI: https://doi.org/10.1007/s10048-007-0094-0