Disease relevance of CST7

• Recombinant cystatin F was produced in a baculovirus expression system and characterized [1].
• Lower monofilament detection and CMAP were independently associated with lower heel BUA (p < 0.01), and monofilament detection was associated with lower hip BMD (p < 0.05) in regression additionally adjusted for lifestyle factors, bone-active medications, and diabetes-related complications [2].
• Of 59 consecutive CTS patient hands, 36 (61%) showed significant reduction in CMAP and/or antidromic SNAP amplitudes at the wrist compared to the palm, indicating the presence of focal demyelination resulting in conduction block vs. pathologic dispersion with phase cancellation [3].
• We compared DCMAP duration and P-D CMAP dispersion in 91 genetically characterized hereditary neuropathies and 33 subjects with CIDP [4].
• We identified 5 of 44 consecutive children (11%) with Guillain-Barré syndrome who had electrophysiologic evidence of severe reduction of the mean amplitude of the compound motor action potentials (mean CMAP amplitude < 10% of lower limit of normal) [5].

High impact information on CST7

• Electrophysiology confirmed unaltered NCV, but less reduced CMAP recordings in the treatment group [6].
• Mammalian cystatin F, which is expressed almost exclusively in hematopoietic cells and accumulates in lysosome-like organelles, has been implicated in the regulation of antigen presentation and other immune processes [7].
• Strikingly, core sugars for one of the two N-linked glycosylation sites of cystatin F are well ordered, and their conformation and interactions with the protein indicate that this unique feature of cystatin F may modulate its inhibitory properties, in particular its reduced affinity toward asparaginyl endopeptidase compared with other cystatins [7].
• Cystatin F is a glycosylated human low molecular weight cysteine proteinase inhibitor [1].
• Six B cell lines in culture secreted barely detectable amounts of cystatin F, but several T cell lines and especially one myeloid cell line secreted significant amounts of the inhibitor [1].

Biological context of CST7

• A previously undescribed human member of the cystatin superfamily called cystatin F has been identified by expressed sequence tag sequencing in human cDNA libraries [1].
• Stimulation with tetradecanoyl phorbol acetate, causing monocytic differentiation, also resulted in down-regulation (two fold to threefold) of cystatin F expression, whereas the cystatin C expression was essentially unaltered in both experiments [8].
• The results suggest that cystatin F as an intracellular cysteine peptidase inhibitor with readily regulated expression, may be a candidate to control the cysteine peptidase activity known to be essential for antigen presentation in different blood cell lineages [8].
• In contrast to the cystatin C promoter, it does not contain multiple Sp1 binding sites, but has a unique site for C/EBPalpha, possibly explaining the restricted expression of the cystatin F gene [8].
• Poor nerve function (lower monofilament detection, higher vibration threshold, lower CMAP, lower NCV) was associated with 1.4-5.7% lower BUA and significant for all but NCV, adjusted for demographics, diabetes, body composition, and physical ability [2].

Anatomical context of CST7

• Northern blot analysis revealed that the cystatin F gene is primarily expressed in peripheral blood cells and spleen [1].
• Tissue expression clearly different from that of the ubiquitous inhibitor, cystatin C, was also indicated by a high incidence of cystatin F clones in cDNA libraries from dendritic and T cells, but no clones identified by expressed sequence tag sequencing in several B cell libraries and in >600 libraries from other human tissues and cells [1].
• Here we show using U937 cells that cystatin F is secreted as a disulfide bridge-linked dimer and is not associated with endosomes intracellularly [9].
• Interestingly, although cystatin F targeting to endosomes or lysosomes is not observed in U937, modification of its C-terminal end by the addition of several amino acids promotes its accumulation in the lysosomes of transfected HeLa cells [9].
• MNCV, SNAP, CMAP, hot and cold thresholds, sensation, tendon reflexes, and muscle strength were assessed by standard tests in upper and lower limbs [10].

Associations of CST7 with chemical compounds

• Unlike other human cystatins, cystatin F has 2 additional Cys residues, indicating the presence of an extra disulfide bridge stabilizing the N-terminal region of the molecule [1].
• Cells stimulated with all-trans retinoic acid to differentiate them towards a granulocytic pathway, showed a strong ( approximately 18-fold) down-regulation of intracellular cystatin F and almost abolished secreted levels of the inhibitor [8].
• In OP patients, pancuronium did not alter the amplitude of the single CMAP, whereas its repetitive discharges were reduced [11].
• The concentration of cystatin F in benign effusions correlated significantly with diagnostic parameters and inflammation (total protein; lactate dehydrogenase; C-reactive protein) [12].
• The administration of magnesium sulphate (MgSO4.7H2O, 4 g intravenous) resulted in a decrease in the CMAP amplitude, loss of the repetitive response and conversion of the decrement-increment response at high-rate RNS to an incremental response [13].

Other interactions of CST7

• Changes in cortical threshold and MEP/CMAP ratios to magnetic stimulation also did not differ significantly between the two groups [14].
• This suggests that cystatin F in U937 cells may function as a regulatory inhibitor of proteolytic activity of cathepsin H or, more likely, as a protection against cathepsins misdirected to specific cystatin F containing endosomal/lysosomal vesicles [15].
• The level of cystatin E/M appears to be significantly associated with primary pleural tumours and cystatin F correlates with inflammatory processes of lung disorders [12].

Analytical, diagnostic and therapeutic context of CST7

• An immunoassay for quantification of cystatin F showed that blood contains low levels of the inhibitor (0.9 ng/ml) [1].
• Immunocytochemistry demonstrated a marked cytoplasmic cystatin F staining in a granular pattern [8].
• The exopeptidases, cathepsins C and X were not inhibited by cystatin F. In order to investigate the biological significance of the inhibition data, the intracellular localization of cystatin F and its potential targets, cathepsins B, H, L, S, C and K, were studied by confocal microscopy in U937 promonocyte cells [15].
• Factors associated with an adverse outcome were: age over 15 years, severity of motor electrodiagnostic findings (especially a decreased distal CMAP amplitude and EMG signs of acute denervation), requirement for ventilation and slow progression (>3 weeks) to maximum deficit [16].
• Distal compound muscle action potential (DCMAP) dispersion, defined as a DCMAP duration >/=9 ms, and proximal-distal (P-D) CMAP dispersion are considered useful in the electrodiagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) [4].

References