Increasing prevalence of coeliac disease over time.

BACKGROUND: The number of coeliac disease diagnoses has increased in the recent past and according to screening studies, the total prevalence of the disorder is around 1%. AIM: To establish whether the increased number of coeliac disease cases reflects a true rise in disease frequency. METHODS: The total prevalence of coeliac disease was determined in two population-based samples representing the Finnish adult population in 1978-80 and 2000-01 and comprising 8000 and 8028 individuals, respectively. Both clinically-diagnosed coeliac disease patients and previously unrecognized cases identified by serum endomysial antibodies were taken into account. RESULTS: Only two (clinical prevalence of 0.03%) patients had been diagnosed on clinical grounds in 1978-80, in contrast to 32 (0.52%) in 2000-01. The prevalence of earlier unrecognized cases increased statistically significantly from 1.03% to 1.47% during the same period. This yields a total prevalence of coeliac disease of 1.05% in 1978-80 and 1.99% in 2000-01. CONCLUSIONS: The total prevalence of coeliac disease seems to have doubled in Finland during the last two decades, and the increase cannot be attributed to the better detection rate. The environmental factors responsible for the increasing prevalence of the disorder are issues for further studies.

SAP30L interacts with members of the Sin3A corepressor complex and targets Sin3A to the nucleolus.

Histone acetylation plays a key role in the regulation of gene expression. The chromatin structure and accessibility of genes to transcription factors is regulated by enzymes that acetylate and deacetylate histones. The Sin3A corepressor complex recruits histone deacetylases and in many cases represses transcription. Here, we report that SAP30L, a close homolog of Sin3-associated protein 30 (SAP30), interacts with several components of the Sin3A corepressor complex. We show that it binds to the PAH3/HID (Paired Amphipathic Helix 3/Histone deacetylase Interacting Domain) region of mouse Sin3A with residues 120-140 in the C-terminal part of the protein. We provide evidence that SAP30L induces transcriptional repression, possibly via recruitment of Sin3A and histone deacetylases. Finally, we characterize a functional nucleolar localization signal in SAP30L and show that SAP30L and SAP30 are able to target Sin3A to the nucleolus.

A novel deletion in a Pearson syndrome infant with hypospadias and cleft lip and palate.

Pearson syndrome is a rare multiorgan mitochondrial disorder that causes substantial disability and usually leads to premature death. We describe an infant with Pearson syndrome who showed, in addition to the typical features of the syndrome, cleft lip and palate and hypospadias.

STAM/EAST/Hbp adapter proteins--integrators of signalling pathways.

STAM/EAST/Hbp family of proteins consists of eight members well conserved from yeast to mammals. The basic domain architecture is comprised of an N-terminal Vps27, Hrs and STAM homology domain, a ubiquitin-interacting motif and a central Src homology-3 domain. Vertebrate members also carry an immunoreceptor tyrosine-based activation motif. STAM/EAST/Hbp proteins become tyrosine-phosphorylated by a variety of cytokines and growth factors. STAM 1 and STAM 2A are involved in cytokine-mediated signalling for DNA synthesis and c-myc induction. EAST and STAM 2A/Hbp play a role in receptor-mediated endo- and exocytosis and probably also in the regulation of actin cytoskeleton. Knockout experiments implicate a role for STAM 1 in neural cell survival. A picture is emerging of STAM/EAST/Hbp proteins acting as integrators of thus far mechanistically disparate cellular signalling events.

Vear, a novel Golgi-associated protein with VHS and gamma-adaptin "ear" domains.

The molecular basis of the selectivity and the details of the vesicle formation in endocytic and secretory pathways are still poorly known and most probably involve as yet unidentified components. Here we describe the cloning, expression, and tissue and cell distribution of a novel protein of 67 kDa (called Vear) that bears homology to several endocytosis-associated proteins in that it has a VHS domain in its N terminus. It is also similar to gamma-adaptin, the heavy subunit of AP-1, in having in its C terminus a typical "ear" domain. In immunofluorescence microscopy, Vear was seen in the Golgi complex as judged by a typical distribution pattern, a distinct colocalization with the Golgi marker gamma-adaptin, and a sensitivity to treatment of cells with brefeldin A. In cell fractionation, Vear partitioned with the post-nuclear membrane fraction. In transfection experiments, hemagglutinin-tagged full-length Vear and truncated Vear lacking the VHS domain assembled on and caused compaction of the Golgi complex. Golgi association without compaction was seen with the ear domain of Vear, whereas the VHS domain alone showed a diffuse membrane- and vesicle-associated distribution. The Golgi association and the bipartite structure along with the differential targeting of its domains suggest that Vear is involved in heterotypic vesicle/suborganelle interactions associated with the Golgi complex. Tissue-specific function of Vear is suggested by its high level of expression in kidney, muscle, and heart.

EAST, a novel EGF receptor substrate, associates with focal adhesions and actin fibers.

EAST is a novel epidermal growth factor receptor (EGFR) substrate. It interacts with Eps15, another EGFR substrate which is involved in receptor endocytosis. In this study we show that EAST associates with focal adhesions and actin filaments. First, in immunofluorescence and electron microscopy analysis, an extensive codistribution of EAST with vinculin, paxillin and actin filaments was seen. Second, overexpression of the NH2 terminus of EAST led to a formation of actin-rich microspikes and membrane protrusions. Third, in cosedimentation assay EAST showed a direct association with actin. These results suggest that EAST is involved in the EGFR-regulated reorganization of the actin cytoskeleton and may be part of a link between cytoskeleton and endocytic machinery.

EAST, an epidermal growth factor receptor- and Eps15-associated protein with Src homology 3 and tyrosine-based activation motif domains.

We describe the cloning and characterization of a new cytoplasmic protein designated epidermal growth factor receptor-associated protein with SH3- and TAM domains (EAST). It contains an Src homology 3 domain in its midregion and a tyrosine-based activation motif in its COOH terminus. Antibodies to EAST recognize a 68-kDa protein that is present in most chicken tissues. An epidermal growth factor (EGF)-dependent association between the EGF receptor (EGFR) and EAST was shown by reciprocal immunoprecipitation/immunoblotting studies with specific antibodies. Activated EGFR catalyzed the tyrosine phosphorylation of EAST, as judged by an in vitro kinase assay with both immunoprecipitated and purified EGFR. Immunoprecipitation/immunoblotting experiments also demonstrated an association between EAST and eps15, an EGFR substrate associated with clathrin-coated pits and vesicles, which is essential in the endocytotic pathway. The association between EAST and eps15 was not affected by EGF treatment. In immunofluorescence microscopy, EAST was shown to partially colocalize with clathrin. The sequence of the NH2-terminal portion of EAST shows a high degree of similarity with a group of proteins involved in endocytosis or vesicle trafficking. Thus, EAST is a novel signal transduction component probably involved in EGF signaling and in the endocytotic machinery.

Src phosphorylates EAST, a novel EGF receptor-associated protein.

We have recently found and characterized EAST, a novel EGF receptor-associated protein with SH3 and TAM domains. In this study we show that EAST becomes phosphorylated by Src kinase. This, in conjunction with our earlier observations on the close association between EAST and the endocytic machinery, suggests that EAST could be involved in Src-dependent effects on EGF receptor endocytosis.

VHS domain marks a group of proteins involved in endocytosis and vesicular trafficking.

Endocytosis is driven by a mechanism which is characterized by an orderly congregation of a large number of proteins which effectuate, first, formation of a coated vesicles, second, pinching off the vesicle and, third, regulated transport. True to the nature of many other proteins involved in multimolecular complexes, also endocytosis-associated proteins, such as Eps15, clathrin and AP-2, are characterized by distinct domains which mediate the protein-protein interactions. We now report that a group of well-established endocytosis and/or vesicular trafficking proteins possess a VHS domain, a recently described domain with an unknown function. We suggest that in these proteins VHS serves as a membrane targeting domain which by its specific features together with FYVE, SH3 and/or TAM domains, which are also present in some VHS-containing proteins, is involved in the stage-specific assembly of the endocytic machinery.

ITAM motif in an apoptosis-receptor.

Signal transduction by the T-cell and B-cell antigen receptors and receptors for immunoglobulin Fc regions depends highly on the cytoplasmic immunoreceptor tyrosine-based activation motif (ITAM). After binding of the ligand, phosphorylation of the two conserved tyrosines of ITAM creates binding sites for downstream signalling molecules and thus enables the initiation of signalling events. Here, we report that the recently found apoptosis receptor, WSL-1/DR3/APO-3/LARD/TRAMP also contains this motif. This may imply that the apoptosis receptor uses ways similar to immunoreceptors in relaying the induction/suppression of the apoptotic signal.

Genetic models for the inheritance of the silver colour mutation of foxes.

We consider genetic models for the inheritance of the particular colour patterns of silver foxes. The models are evaluated by computation of statistical likelihoods based on observations of related foxes in extended pedigrees. Problems caused by incomplete paternity information are addressed by inferences based on phenotypic observations. The unreliability of subjective evaluations of fur colour also provides difficulty, in particular crossfoxes emerge as being difficult to differentiate. No evidence of linkage between Agouti locus and Extension locus is found in this dataset.

Genetic polymorphism of esterase in plasma of American mink (Mustela vison L.).

Plasma samples of 412 minks, including 20 families and representing 15 lines, have been investigated by isoelectric focusing for the enzyme esterase (ES). The observed variation of the enzyme may be explained as a result of one locus with at least seven codominant alleles. The segregation of six alleles assumed for the locus in 20 families supports this genetic model. Genetic divergence among the lines is observed and may be due to founder effect and/or selection.