Investigations of genetic diseases such as cystic fibrosis, α‐1‐antitrypsin deficiency, phenylketonuria, mitochondrial acyl‐CoA dehydrogenase deficiencies, and many others have shown that enhanced proteolytic degradation of mutant proteins is a common molecular pathological mechanism. Detailed studies of the fate of mutant proteins in some of these diseases have revealed that impaired or aberrant folding of mutant polypeptides typically results in prolonged interaction with molecular chaperones and degradation by intracellular proteases before the functional conformation is acquired. This appears to be the case for many missense mutations and short in‐frame deletions or insertions that represent a major fraction of the mutations detected in genetic diseases. In some diseases, or under some circumstances, the degradation system is not efficient. Instead, aberrant folding leads to accumulation of protein aggregates that damage the cell. Mechanisms by which misfolded proteins are selected for degradation have first been delineated for the endoplasmatic reticulum; this process has been termed "protein quality control." Similar mechanisms appear to be operative in all cellular compartments in which proteins fold. Within the context of genetic diseases, we review knowledge on the molecular processes underlying protein quality control in the various subcellular compartments. The important impact of such systems for variability of the expression of genetic deficiencies is emphasised. Hum Mutat 14:186–198, 1999. © 1999 Wiley‐Liss, Inc.

Background: The role of genetic and environmental factors for developing alexithymia is still unclear, and the aim of this study was to examine these factors in a large population-based sample of twins. Methods: The Toronto Alexithymia Scale-20 (TAS-20) was included in a mail survey of 46,418 individuals born between 1931 and 1982 and registered with the Danish Twin Registry. The response rate was 75.3%. A total of 8,785 twin pairs, where both cotwins had completed all items of the TAS-20, were selected for this study. Analyses were conducted for total TAS-20 scores and the subscales of (1) difficulties in identifying feelings, (2) difficulties in describing feelings, and (3) externally oriented thinking. The phenotypes were analyzed both as categorical and continuous data. Results: All measures of similarity suggested that genetic factors added to all facets of alexithymia. Structural equation modeling of the noncategorical data, an ACE model including additive genetic, shared environmental and nonshared environmental effects, provided the best fit for all three facets of alexithymia as well as total alexithymia scores, with heritabilities of 30–33% and the remaining variance being explained by shared (12–20%) and nonshared environmental effects (50–56%). Conclusion: The results from this large population-based sample suggest that genetic factors have a noticeable and similar impact on all facets of alexithymia. While the results suggested a moderate influence of shared environmental factors, our results are in concordance with the general finding that environmental influences on most psychological traits are primarily of the nonshared rather than the shared type.

The low density lipoprotein (LDL) receptor is responsible for removing the majority of the LDL cholesterol from the plasma. Mutations in the LDL receptor gene cause the disease familial hypercholesterolemia (FH). Approximately 50% of the mutations in the LDL receptor gene in patients with FH lead to receptor proteins that are retained in the endoplasmic reticulum (ER). Misfolding of mutant LDL receptors is a probable cause of this ER retention, resulting in no functional LDL receptors at the cell surface. However, the specific factors and mechanisms responsible for retention of mutant LDL receptors are unknown. In the present study we show that the molecular chaperone Grp78/BiP co-immunoprecipitates with both the wild type and two different mutant (W556S and C646Y) LDL receptors in lysates obtained from human liver cells overexpressing wild type or mutant LDL receptors. A pulse-chase study shows that the interaction between the wild type LDL receptor and Grp78 is no longer detectable after 2 1 ⁄2 h, whereas it persists for more than 4 h with the mutant receptors. Furthermore, about five times more Grp78 is co-immunoprecipitated with the mutant receptors than with the wild type receptor suggesting that Grp78 is involved in retention of mutant LDL receptors in the ER. Overexpression of Grp78 causes no major alterations on the steady state level of active LDL receptors at the cell surface. However, overexpression of Grp78 decreases the processing rate of newly synthesized wild type LDL receptors. This indicates that the Grp78 interaction is a rate-limiting step in the maturation of the wild type LDL receptor and that Grp78 may be an important factor in the quality control of newly synthesized LDL receptors. The low density lipoprotein (LDL)1 receptor is a transmembrane glycoprotein that binds and internalizes circulating particles of LDL by receptor-mediated endocytosis (1). Mutations in the LDL receptor gene cause familial hypercholesterolemia (FH), which is an autosomal dominant inherited disorder of lipoprotein metabolism. Heterozygous FH is a common disorder with an estimated frequency of about 1 in 500. Today, more than 500 different mutations have been identified in the LDL receptor gene. About 50% of the characterized mutations result in LDL receptor proteins that are retained in the endoplasmic reticulum (ER) (2). Since the existence of an ER quality control system ensures that only correctly folded, newly synthesized proteins are transported to the plasma membrane or secreted, it is likely that protein misfolding contributes to the pathogenesis of FH.Protein misfolding is implicated in the pathogenesis of many genetic diseases (reviewed in Refs. 3 and 4). Missense mutations and small in frame deletions or insertions rarely affect the function of a given protein directly. Mostly these diseasecausing mutations affect the ability of the proteins to fold into a correct conformation, and they often give rise to premature degradation or aggregation of the mutant proteins. Diseases caused by this kind of molecula...

Previously found higher repression in cancer patients vs. controls could be a response to the threat associated with cancer diagnosis and may not necessarily reflect premorbid differences.

The present study provides direct evidence that hyperoxia reduces basal release of NO leading to depletable endothelium-dependent vasoconstriction in porcine coronary arteries independent of changes in eNOS phosphorylation.