Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in GDAP1, the ganglioside-induced differentiation-associated protein 1 gene, cause Charcot-Marie-Tooth (CMT) type 4A, a severe autosomal recessive form of neuropathy associated with either demyelinating or axonal phenotypes. Here, we demonstrate that GDAP1 has far greater expression in neurons than in myelinating Schwann cells. We investigated cell localization of GDAP1 in a human neuroblastoma cell line by means of transient overexpression and co-localization with organelle markers in COS-7 cells and by western blot analysis of subcell fractions with anti-GDAP1 polyclonal antibodies. We observed that GDAP1 is localized in mitochondria. We also show that C-terminal transmembrane domains are necessary for the correct localization in mitochondria; however, missense mutations do not change the mitochondrial pattern of the wild-type protein. Our findings suggest that CMT4A disease is in fact a mitochondrial neuropathy mainly involving axons and represents a disease belonging to the new category of mitochondrial disorders caused by mutations in nuclear genes. We postulate that GDAP1 may be related to the maintenance of the mitochondrial network.
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PMID:GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria. 1577 96

Charcot-Marie-Tooth disease (CMT) is a heritable neurodegenerative condition, some types of which (notably CMT4A) are caused by mutations in the GDAP1 gene that encodes a protein of unknown molecular function implicated in regulation of mitochondrial fission. Here we present for the first time a functional analysis of the GDAP1 gene promoter which we found to be transcriptionally regulated by YY1, a broadly studied factor that seems to be involved in regulating many of the same cellular phenomena as GDAP1. We show that GDAP1 is broadly expressed in cancer cell lines of different tissue origin, contrasting with the restricted neuronal distribution reported by some authors. There is a consensus YY1 binding site in the GDAP1 core promoter which we show to be functional in both in vitro binding assays and in living cells. Overexpression of YY1 activated the GDAP1 promoter in a reporter gene system as well as increased the level of endogenous mRNA. RNAi-mediated knockdown of YY1 in HEK293 cells led to decreased GDAP1 expression. While YY1 is known to exert both positive and negative regulatory influences on nuclear-encoded mitochondrial proteins, as well as on neurodegeneration-related genes, in all cell lines we studied (including neuroblastoma) the effect of YY1 on GDAP1 expression is activatory. This leads to interesting conclusions about the possible clinical role of this interaction and suggests a broader regulatory network.
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PMID:YY1-dependent transcriptional regulation of the human GDAP1 gene. 1972 Jan 40