[CITATION][C] Interruption of SOX10 function in myelinopathies

JR Lupski - Annals of neurology, 2010 - Wiley Online Library
Annals of neurology, 2010Wiley Online Library
Tremendous progress in our understanding of myelin development, function, and
maintenance has come from insights provided by patients manifesting myelinopathies.
Mutations affecting peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ), and
gap junction protein beta-1 (GJB1; also known as Cx32, encoding connexin-32) result in
Charcot-Marie-Tooth (CMT) and related peripheral neuropathies such as Dejerine-Sottas
neuropathy and congenital hypomyelinating neuropathy (CHN). 1 Mutations that affect …
Tremendous progress in our understanding of myelin development, function, and maintenance has come from insights provided by patients manifesting myelinopathies. Mutations affecting peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ), and gap junction protein beta-1 (GJB1; also known as Cx32, encoding connexin-32) result in Charcot-Marie-Tooth (CMT) and related peripheral neuropathies such as Dejerine-Sottas neuropathy and congenital hypomyelinating neuropathy (CHN). 1 Mutations that affect proteins of the central nervous system myelin, such as proteolipid protein 1 (PLP1), cause Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia. 2 Interestingly, for the most common forms of de-or dysmyelinating CMT and PMD, there are no mutant proteins at all. Instead, in about 70% of patients with either CMT1 or PMD, myelinopathies are caused by altered dosage due to gene copy number variation, resulting from duplication of either PMP22 or PLP1, respectively. These findings emphasize the importance of nervous system gene regulation and expression for proper myelin function. In this issue of Annals of Neurology, Osaka and colleagues beautifully demonstrate the importance of myelin gene regulation by identifying point mutations in a SOX10 transcription factor binding site upstream of the GJC2 gene in a patient with a central hypomyelinating disorder similar to, but clinically less severe than, PMD. 3 The GJC2 gene encodes a gap junction protein; coding region mutations have been associated with a PMD-like disorder (PMLD; Mendelian Inheritance in Man [MIM]# 311601). Key to our understanding of genes and genetic pathways critical to myelin development and function was the identification of patients with mutations in the transcription factors regulating myelin gene expression. One of the first identified by virtue of mutations that conveyed a neurological phenotype was early growth response 2 (EGR2), 4 in which, perhaps as might have been anticipated because this transcription factor is important for myelin development, mutations can cause a severe CHN. However, a surprise was to find patients with adult onset CMT1 who had mutations in EGR2.
Such a finding suggests that this transcription factor is not only important for myelin development but also essential to maintain proper myelin function. 5 Often a single subject, that is, a case report, can initiate a cascade of insights into neuropathologic mechanisms, as was the case in a patient with CHN, PMD, Waardenburg syndrome, and Hirschsprung disease6 found to have SOX10 mutations. This condition has now been extensively characterized and is referred to as PCWH (peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease; MIM# 609132). 7 The complex neurological disease is caused by apparent gain-offunction mutations that act in neural crest cells during development (Fig 1A). Interestingly, some mutations of SOX10 may have dominant-negative activity restricted to single neural crest-derived cell lineages. 8 Many of the genes downstream of SOX10 that potentially mediate all the phenotypic consequences of PCWH remain to be elucidated.
Wiley Online Library