Disease relevance of CHM

• Mutations in members of this family, such as REP-1, lead to abnormalities, including progressive retinal degradation (choroideremia) in humans [1].
• The REP-1 was found to be toxic for yeast cells and its toxicity is proposed to be associated with the formation of unproductive Ypt:REP-1 complexes [2].
• Choroideremia, an X-linked form of retinal degeneration, results from defects in the Rab escort protein-1 (REP-1) gene [3].
• Mutations in the REP-1 gene in humans lead to an X-chromosome-linked defect known as choroideremia--a debilitating disease that inevitably culminates in complete blindness [4].
• PCR using REP1/REP2 and ERIC2 primers may provide a more reliable and reproducible alternative method for fingerprinting Gram negative bacteria [5].

Psychiatry related information on CHM

• Molecular analysis of four males with mental retardation and deletions of Xq21 places the putative MR region in Xq21.1 between DXS233 and CHM [6].
• To clarify the pathophysiological differences of the cerebrovascular reserve capacity in relation to cerebral cognitive impairments between vascular dementia (VaD) and persistent vegetative state (PVS), we evaluated acetazolamide (ACZ) vasoreactivity testing by transcranial harmonic perfusion imaging (HPI) and Doppler sonography (TCD) [7].
• HDT alters cerebral lateralization for motor control and this may be responsible for slowing in perceptual-motor performance in Space. TCD monitoring may be required for motor performance tasks in Space [8].
• A significantly (p < 0.05) decrease in TCD measures was found in right and left MCA and BA of dementia patients with respect to controls [9].
• High nicotine dependence combined with TCD pathological finding significantly discriminated successes and failures, suggesting that smokers with pathological TCD need specific therapeutic approach with more social support, individualized coping skills and cognitive restructuring [10].

High impact information on CHM

• Sequence-conserved regions common to GDI and the choroideraemia gene product, which delivers Rab to catalytic subunits of Rab geranylgeranyltransferase II, are clustered on one face of the molecule [11].
• Choroideraemia (tapetochoroidal dystrophy, TCD), a common form of X-linked blindness, is characterized by progressive dystrophy of the choroid, retinal pigment epithelium and retina [12].
• The cDNAs encompass an open reading frame of 948 base pairs that is structurally altered in eight TCD patients with deletions, and in a female patient with a balanced translocation involving Xq21 [12].
• Posttranslational geranylgeranylation of Rab GTPases is catalyzed by Rab geranylgeranyltransferase (RabGGTase), which consists of a catalytic alpha/beta heterodimer and an accessory Rab escort protein (REP) [13].
• Comparing the structure of REP-1 with the closely related RabGDI, we conclude that the specificity of the REP:RabGGTase interaction is defined by differently positioned phenylalanine residues conserved in the REP and GDI subfamilies [13].

Chemical compound and disease context of CHM

• Thermotolerant Gluconobacter frateurii CHM 43 was selected for L-erythrulose production from mesoerythritol at higher temperatures [14].
• In this single-center study, a consecutive cohort of 59 adult patients transplanted with HLA-identical bone marrow and receiving graft-versus-host disease (GVHD) prophylaxis with either standard cyclosporine/methotrexate (n = 33) or partial T cell depletion (E-rosetting) (TCD, n = 26 were analyzed) [15].
• TCD can be used to detect vessel narrowing from a variety of causes, including vasospasm, and also can be used to detect cerebral emboli and to evaluate CO2 reactivity, autoregulation, and the response to certain medications, as well as to indicate progressive obstruction of the cerebral circulation as seen in conditions leading to brain death [16].

Biological context of CHM

• REP functions as a molecular chaperone that presents Rab proteins to the RabGGTase and after prenylation delivers them to their target membrane [17].
• Finally, in an affected male who did not have a mutation in any of the CHM exons or their splice sites, the deletion of a complete exon from the CHM mRNA was observed [18].
• Choroideremia (CHM) is a progressive chorioretinal degeneration caused by mutations in the widely expressed CHM gene on chromosome Xq21 [18].
• These included two partial CHM gene deletions and an insertion of a full-length L1 retrotransposon into the coding region of the CHM gene, a type of mutation that has not been previously reported as a cause of CHM [18].
• We have searched for mutations of the CHM gene in patients with choroideremia by analysis of individual CHM exons and adjacent intronic sequences PCR-amplified from genomic DNA and by reverse transcription (RT)-PCR analysis of the coding region of the CHM mRNA [18].

Anatomical context of CHM

• These data suggest that REP-1 is per se sufficient to chaperone newly prenylated rab proteins to their target membranes [19].
• To assess the relative accuracy of p57(KIP2) immunostaining and molecular diagnosis by nuclear DNA microsatellite polymorphisms in discriminating CHM from its mimics, we analyzed archival tissue from 33 case patients (7 with a definitive diagnosis of CHM, 16 with a possible diagnosis of HM, and 10 with normal placentas) by both methods [20].
• The evaluation of AgNORs in cytotrophoblasts contributes to a reliable discrimination of CHM and PHM; this fairly simple and economical method could serve as an useful addition to conventional methods of diagnosis in gestational trophoblastic disease [21].
• Based on structural information and biophysical measurements, we propose mechanistic and thermodynamic models for GDI and Rab escort protein-mediated interaction of RabGTPase with intracellular membranes [22].
• Furthermore, levels of Xi expression varied among cell lines that expressed REP1 [23].

Associations of CHM with chemical compounds

• We demonstrate here that REP-1 can also associate with RabGGTase in the absence of Rab protein and that this interaction is dramatically strengthened by the presence of phosphoisoprenoids such as GGpp [24].
• We previously showed that two major cysteine endopeptidases, REP-1 and REP-2, were present in germinated rice ( Oryza sativa L.) seeds, and that REP-1 was the enzyme that digests seed storage proteins [25].
• In this work, we show that RabGGTase can form a stable complex with Rab7-REP in the absence of its lipid substrate geranylgeranyl pyrophosphate [26].
• Two major endopeptidases, REP-1 and REP-2, were present in the 40-75% saturated ammonium sulfate fraction from day-9 germinated seeds, and could be separated by hydrophobic column chromatography [27].
• (3) Meso-erythritol dehydrogenase has been purified from the membrane fraction of G. frateurii CHM 43 [28].

Physical interactions of CHM

• Crystallization and preliminary X-ray diffraction analysis of monoprenylated Rab7 GTPase in complex with Rab escort protein 1 [17].

Other interactions of CHM

• The REP-1 and REP-2 were purified using a combination of affinity and anion-exchange chromatography [2].
• In the current studies, we produced REP-1 and REP-2 by recombinant DNA methods and showed that both proteins were approximately equal in facilitating the attachment of GG groups to several Rab proteins, including Rab1A, Rab5A, and Rab6 [29].
• Cytosolic RAB3D is associated with RAB escort protein (REP), not RAB-GDP dissociation inhibitor (GDI), in dispersed chief cells from guinea pig stomach [30].
• We demonstrate that the complex formed from semisynthetic monoprenylated Rab7 and REP-1 represents a genuine intermediate of the Rab prenylation reaction and thus provides a unique tool for studies of the Rab prenylation mechanism [31].
• The present study shows that REP-2 is an asparaginyl endopeptidase that acts as an activator of REP-1, and we separated it into two forms, REP-2alpha (39 kDa) and REP-2beta (40 kDa), using ion-exchange chromatography and gel filtration chromatography [25].

Analytical, diagnostic and therapeutic context of CHM

• Finally, gel filtration analysis of cytosolic fractions from 293 cells that were coexpressing T7 epitope-tagged REP with various Myc-Rab1B constructs revealed that mutations in the alpha2 helix of Rab1B prevented the association of nascent (i.e., nonprenylated) Rab1B with REP [32].
• METHODS: The eyes were processed for histopathologic examination, including immunocytochemistry with an antibody against the CHM gene product, REP-1, and retinal cell-specific markers [33].
• The discrimination index for the PCR-based DNA fingerprinting techniques was 0.75 for enterobacterial repetitive intergenic consensus 1, 0.71 for M13, 0.77 for REP-1, 0.77 for REP-2, and 0.87 for multiplex PCR [34].
• PURPOSE: To test the reliability of a corneal radius correcting factor (R factor) in calculating intraocular lens (IOL) power in eyes that developed cataract after refractive surgery and compare it with the clinical history (CHM) and double-K (DKM) methods [35].
• METHODS: Nineteen eyes from the literature that underwent cataract extraction and IOL implantation after refractive surgery were used to compare actual postoperative and expected refractive errors utilizing the R factor, CHM, and DKM [35].

References