Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The differentiation of the oligodendrocyte from its bipotential progenitor culminates in the production of the myelin-specific proteins and the elaboration of membrane processes that ensheath the axon. Mutations in proteolipid protein (PLP) and its alternatively spliced isoform DM-20, the major protein constituents of central nervous system myelin, are characterized by a significant reduction in the number of mature oligodendrocytes, resulting in severe hypomyelination, tremor and early death. The canine shaking pup carries such a mutation, a single base change that substitutes a proline for a histidine near the first transmembrane region of PLP and DM-20. This mutation hinders oligodendrocyte differentiation, as evidence by a splicing pattern at the PLP locus characteristic of immature oligodendrocytes. The spliced transcript expressed earliest in development, DM-20, continues to be overexpressed in shaking pup oligodendrocytes. The disruption of the normal maturation schedule in these X-linked dysmyelinating disorders suggests that PLP or DM-20 plays a fundamental role in oligodendrocyte development. We propose that, while the more abundant PLP is the primary structural component of myelin, DM-20 may be critical to oligodendrocyte maturation.
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PMID:A point mutation in the proteolipid protein gene of the 'shaking pup' interrupts oligodendrocyte development. 172 45

The quaking viable mice have myelination defects and develop a characteristic tremor 10 d after birth. The quaking gene encodes at least five alternatively spliced QUAKING (QKI) isoforms that differ in their C-terminal 8--30-amino-acid sequence. The reason for the existence of the different QKI isoforms and their function are unknown. Here we show that only one QKI isoform, QKI-7, can induce apoptosis in fibroblasts and primary rat oligodendrocytes. Heterodimerization of the QKI isoforms results in the nuclear translocation of QKI-7 and the suppression of apoptosis. The unique C-terminal 14 amino acids of QKI-7 confers the ability to induce apoptosis to heterologous proteins such as the green fluorescent protein and a QKI-related protein, Caenorhabditis elegans GLD-1. Thus, the unique C-terminal sequences of QKI-7 may function as a life-or-death 'sensor' that monitors the balance between the alternatively spliced QKI isoforms. Moreover, our findings suggest that nuclear translocation is a novel mechanism of inactivating apoptotic inducers.
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PMID:Nuclear translocation controlled by alternatively spliced isoforms inactivates the QUAKING apoptotic inducer. 1129 9

Quaking viable (Qk(v)) mice have developmental defects that result in their characteristic tremor. The quaking (Qk) locus expresses alternatively spliced RNA-binding proteins belonging to the STAR family. To characterize the RNA binding specificity of the QKI proteins, we selected for RNA species that bound QKI from random pools of RNAs and defined the QKI response element (QRE) as a bipartite consensus sequence NACUAAY-N(1-20)-UAAY. A bioinformatic analysis using the QRE identified the three known RNA targets of QKI and 1,430 new putative mRNA targets, of which 23 were validated in vivo. A large proportion of the mRNAs are implicated in development and cell differentiation, as predicted from the phenotype of the Qk(v) mice. In addition, 24% are implicated in cell growth and/or maintenance, suggesting a role for QKI in cancer.
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PMID:Target RNA motif and target mRNAs of the Quaking STAR protein. 1604 88

The quaking viable (qk(v)) mice have attracted attention because of their characteristic tremor caused by their dysmyelination. In the central nervous system, qk(v) mice fail to develop mature myelinating oligodendrocytes and display uncompacted myelin. The genetic defect in the qk(v) mice prevents the proper expression of alternatively spliced KH-type QKI RNA binding proteins. Thus qk(v) mice provide a unique animal model linking RNA binding proteins to defects in oligodendrocyte cell fate and myelination. The fact that QKI proteins are modified post-translationally makes them Signal Transduction Activiators of RNA (STAR) proteins. We have used a gain-of-function approach with the ectopic expression of the separate QKI isoforms using adenoviruses and retroviruses to determine their separate roles in cell fate and myelination. Herein, we discuss the recent advances in characterizing the QKI KH-type proteins as glial cell fate and myelin egulators.
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PMID:QUAKING KH domain proteins as regulators of glial cell fate and myelination. 1713 40