The human keratins: biology and pathology

The keratins are the typical intermediate filament proteins of epithelia, showing an outstanding degree of molecular diversity. Heteropolymeric filaments are formed by pairing of type I and type II molecules. In humans 54 functional keratin genes exist. They are expressed in highly specific patterns related to the epithelial type and stage of cellular differentiation. About half of all keratins--including numerous keratins characterized only recently--are restricted to the various compartments of hair follicles. As part of the epithelial cytoskeleton, keratins are important for the mechanical stability and integrity of epithelial cells and tissues. Moreover, some keratins also have regulatory functions and are involved in intracellular signaling pathways, e.g. protection from stress, wound healing, and apoptosis. Applying the new consensus nomenclature, this article summarizes, for all human keratins, their cell type and tissue distribution and their functional significance in relation to transgenic mouse models and human hereditary keratin diseases. Furthermore, since keratins also exhibit characteristic expression patterns in human tumors, several of them (notably K5, K7, K8/K18, K19, and K20) have great importance in immunohistochemical tumor diagnosis of carcinomas, in particular of unclear metastases and in precise classification and subtyping. Future research might open further fields of clinical application for this remarkable protein family.     

Wilms' tumour: reconciling genetics and biology.

Wilms' tumour, a paediatric malignancy of the kidney, is a striking example of the relationship between aberrant development and cancer. Several different genetic loci have been implicated in the aetiology of the tumour; genomic imprinting also plays a role. One Wilms' tumour predisposition gene (WT1), encoding a zinc finger protein, is expressed in a limited set of tissues, including developing nephrons and gonads. The biology and genetics of Wilms' tumour underline the developmental relationship between kidneys and gonads.     

Peroxisome biogenesis disorders: genetics and cell biology

Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease and rhizomelic chondrodysplasia punctata are progressive disorders characterized by loss of multiple peroxisomal metabolic functions. These diseases are inherited in an autosomal recessive manner, are caused by defects in the import of peroxisomal matrix proteins and are referred to as the peroxisome biogenesis disorders (PBDs). Recent studies have identified the PEX genes that are mutated in 11 of the 12 known complementation groups of PBD patients. This article reviews these advances in PBD genetics and discusses how studies of human PEX genes, their protein products and PBD cell lines are shaping current models of peroxisome biogenesis.     

PTEN: from pathology to biology

The PTEN tumour suppressor gene is mutated frequently in many malignancies and its importance in the development of cancer is probably underestimated. As the primary phosphatase of phosphatidylinositol (3,4,5)-trisphosphate, PTEN has a central role in reigning in the phosphoinositide 3-kinase (PI 3-kinase) network to control cellular homeostasis. Cells that lack PTEN are unable to regulate the PtdIns 3-kinase programme, which stimulates a variety of cellular phenotypes that favour oncogenesis. As well as the well-known role as tumour suppressor, recent studies show that PTEN is involved in the regulation of several basic cellular functions, such as cell migration, cell size, contractility of cardiac myocytes and chemotaxis. Here, we review the roles of PTEN in normal cellular functions and disease development.     

Alpha1-antitrypsin: Physiology,genetics and pathology

Summary Alpha₁-antitrypsin (₁) is a glycoprotein in human serum that inhibits the enzymatic activity of trypsin and other proteolytic enzymes. Its concentration in normal serum is 200–250 mg/100 ml. In certain physiological and pathological situations, such as pregnancy, under contraceptive medication and during inflammation, the level of ₁-at is elevated. The physiological role of ₁ is not known, but the interaction with proteolytic enzymes from white blood cells is probably important. Electrophoretic techniques distinguish several phenotypes, which can be explained by the existence of several codominant alleles at one locus (probably the structural locus). Two alleles Pi^Z and Pi^S cause low concentrations of ₁-at in serum: the approximate concentrations of ₁-at for the different phenotypes are Z/Z 10%, M/Z 50–60%, S/S 60%, M/S 80%, where the level of 212 mg/100 ml found in the M/M phenotype is taken as 100%; thus the effect of these alleles on the ₁-at concentration is additive. Homozygosity for the Pi^Z allele is strongly associated with chronic obstructive lung disease and there is also an association of COPD and heterozygosity for the Pi^Z or Pi^S or both, but to a lesser degree.

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Zusammenfassung ₁-Antitrypsin (₁-at) ist ein Glykoprotein des menschlichen Serums. Es hemmt die enzymatische Aktivität von Trypsin und anderen proteolytischen Enzymen. Die Konzentration in normalem Serum beträgt etwa 200–250 mg/100 ml. Unter bestimmten physiologischen und pathologischen Bedingungen, z. B. während der Schwangerschaft, nach Verabreichung von Ovulationshemmern und während einer Infektion, ist der Serumspiegel des ₁-at erhöht. Die genaue physiologische Funktion des ₁-at ist unbekannt, wahrscheinlich ist aber die Hemmung von proteolytischen Enzymen aus Leukocyten von Bedeutung. Mit Hilfe elektrophoretischer Methoden kann man einige Phänotypen unterscheiden. Diese Phänotypen können durch mehrere codominante Allele an einem Locus, wahrscheinlich dem Strukturlocus, erklärt werden. Zwei Allele, Pi^Z und Pi^S, verursachen niedrige Konzentrationen von ₁ im Serum: Die ungefähren Serumkonzentrationen von ₁-at der verschiedenen Phänotypen sind: Z/Z 10%, M/Z 50–60%, S/S 60%, M/S 80%; die Konzentration von 212 mg/100 ml des M/M-Phänotyps ist hier gleich 100% gesetzt. Die Wirkung der verschiedenen Allele auf die ₁-at ist also additiv. Homozygotie für das Pi^Z-Allel ist statistisch signifikant mit chronisch obstruktivem Lungenemphysem assoziiert. Eine geringere, aber ebenfalls statistisch signifikante Assoziation mit chronisch obstruktivem Lungenemphysem besteht auch für die Heterozygotie Pi^M/Pi^Z und Pi^M/Pi^S oder nur für eine von beiden Heterozygotien.

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Recipient of a stipendium from Deutsche Forschungsgemeinschaft.     

From classical genetics to quantitative genetics to systems biology: modeling epistasis

Gene expression data has been used in lieu of phenotype in both classical and quantitative genetic settings. These two disciplines have separate approaches to measuring and interpreting epistasis, which is the interaction between alleles at different loci. We propose a framework for estimating and interpreting epistasis from a classical experiment that combines the strengths of each approach. A regression analysis step accommodates the quantitative nature of expression measurements by estimating the effect of gene deletions plus any interaction. Effects are selected by significance such that a reduced model describes each expression trait. We show how the resulting models correspond to specific hierarchical relationships between two regulator genes and a target gene. These relationships are the basic units of genetic pathways and genomic system diagrams. Our approach can be extended to analyze data from a variety of experiments, multiple loci, and multiple environments.     

Chemical genetics: tailoring tools for cell biology

Chemical genetics is a research approach that uses small molecules as probes to study protein functions in cells or whole organisms. Here, I review the parallels between classical genetic and chemical-genetic approaches and discuss the merits of small molecules to dissect dynamic cellular processes. I then consider the pros and cons of different screening approaches and specify strategies aimed at identifying and validating cellular target proteins. Finally, I highlight the impact of chemical genetics on our current understanding of cell biology and its potential for the future.     

Quantitative genetics in conservation biology

Most of the major genetic concerns in conservation biology, including inbreeding depression, loss of evolutionary potential, genetic adaptation to captivity and outbreeding depression, involve quantitative genetics. Small population size leads to inbreeding and loss of genetic diversity and so increases extinction risk. Captive populations of endangered species are managed to maximize the retention of genetic diversity by minimizing kinship, with subsidiary efforts to minimize inbreeding. There is growing evidence that genetic adaptation to captivity is a major issue in the genetic management of captive populations of endangered species as it reduces reproductive fitness when captive populations are reintroduced into the wild. This problem is not currently addressed, but it can be alleviated by deliberately fragmenting captive populations, with occasional exchange of immigrants to avoid excessive inbreeding. The extent and importance of outbreeding depression is a matter of controversy. Currently, an extremely cautious approach is taken to mixing populations. However, this cannot continue if fragmented populations are to be adequately managed to minimize extinctions. Most genetic management recommendations for endangered species arise directly, or indirectly, from quantitative genetic considerations.     

Myosins: a diverse superfamily

Myosins constitute a large superfamily of actin-dependent molecular motors. Phylogenetic analysis currently places myosins into 15 classes. The conventional myosins which form filaments in muscle and non-muscle cells form class II. There has been extensive characterization of these myosins and much is known about their function. With the exception of class I and class V myosins, little is known about the structure, enzymatic properties, intracellular localization and physiology of most unconventional myosin classes. This review will focus on myosins from class IV, VI, VII, VIII, X, XI, XII, XIII, XIV and XV. In addition, the function of myosin II in non-muscle cells will also be discussed.