Collagen types, associated-diseases and mouse models.
The extracellular matrix (ECM) is the cell structural environment in tissues and organs. The ECM is a dynamic structure that it is constantly remodelled. It contributes to tissue integrity and mechanical properties. It is also essential for maintaining tissue homeostasis, morphogenesis and differentiation, which it does, through specific interactions with cells. The ECM is composed of a mixture of water and macromolecules classified into four main categories: collagens, proteoglycans, elastic proteins, and non-collagenous glycoproteins (also called adhesive glycoproteins). The nature, concentration and ratio of the different ECM components are all important factors in the regulation of the assembly of complex tissue-specific networks tuned to meet mechanical and biological requirements of tissues.
Collagens form a superfamily of 28 trimeric proteins, distinguishable from the other ECM components by their particular abundance in tissues (collagens represent up to 80-90% of total proteins in skin, tendon and bones) and their capacity to self-assemble into supramolecular organized structures (the best known being the banded fibers). The collagen superfamily is highly complex and shows a remarkable diversity in structure, tissue distribution and function (Ricard-Blum and Ruggiero, 2005).
The importance of collagens has been illustrated by the wide range of mutations in collagen genes that result in minor and severe human diseases. Various mutations (point, null or structural mutations, insertions, exon skipping, deletions) in genes encoding collagens are known to be responsible for a large spectrum of human disorders (
The aim of this chapter is to describe the use of targeted mutagenesis in the understanding of the physiopathology of inherited connective tissue disorders. Specifically we are concerned with mutations in collagen genes. We will focus on the use of site-directed mutagenesis to analyze the causative effects of human-identified collagen gene mutations. Recombinant molecules were used to analyze the effects of these mutations on collagen structure, biosynthesis, posttranslational modifications and interactions with binding partners and cells. This work has considerably improved our knowledge in development and in human disorders. These results will then be compared with the limited information about the introduction of subtle targeted mutations into murine collagen genes.
2. The collagen superfamily at a glance
The 28 members of the collagen superfamily exhibit considerable complexity and diversity in structure, assembly and function. However, collagens also share common features. (i) All members are modular proteins composed of collagenous (COL) domains flanked by non collagenous (NC) domains or linker regions. (ii) They are trimeric molecules formed by the association of three identical or different α-chains, which are characterized by repetitions of the G-x-y tripeptide (with the x and y positions often occupied by proline and hydroxyproline, respectively). (Abbreviations and single-letter codes for amino acids are given in Table 1 of the chapter by Figurski
Based on their structure and supramolecular organization, collagens have been divided into several subfamilies (Myllyharju and Kivirikko, 2001). They are (i) the fibril-forming collagens I, II, III, V, XI, XXIV and XVII, which share the capacity to assemble into organized fibrils; (ii) the network-forming collagens IV, VIII and X and the FACIT (Fibril-Associated Collagen with Interrupted Triple-helix collagens) collagens IX, XII, XIV, XVI, XIX, XX, XI and XXII, which are known to mediate protein-protein interactions; (iii) the basement membrane multiplexin (multiple triple-helix domains and interruptions) collagens XV and XVIII; (iv) the transmembrane collagens, including the neuronal XXV collagen and types XIII, XVII, XXIII; and finally (v) other unconventional collagens, such as the anchoring fibrils collagen VII and the ubiquitous collagen VI, which assembles into characteristic beaded filaments (Table 1).
The length of the triple helical domains varies noticeably among different collagen types. Fibril-forming collagens consist of a long central COL domain with about 1000 amino acids (330 G-x-y tripeptide repeats), flanked by small terminal globular extensions (NC domains). After proteolytic processing of the N and C-terminal extensions, the mature molecules aggregate into highly ordered fibrils with a banded pattern observable by transmission electron microscopy. In other collagens, the COL domains are shorter and/or contain interruptions. The NC domains can represent the main part of the molecule, as for the FACIT collagen XII. Most, if not all, collagen types are recognized by specific cell receptors, such as the major ECM integrin receptors, collagen-specific discoidin domain receptors (DDR) and the transmembrane proteoglycan syndecans (Humphries et al., 2006; Xian et al., 2010; Leitinger et al., 2007). Through various interactions with these cell receptors, collagens can induce intracellular pathways directly or indirectly and regulate cell functions, such as migration, proliferation and differentiation. Certain collagens can also bind to growth factors and control their bioavailability by acting as reservoirs. The controlled release of growth factors by proteolytic activity or expression of a splice variant that does not contain the binding site controls morphogenesis, as described for the cartilage collagen II (Zhu et al., 1999).
3. A large spectrum of mutations in collagen genes causes inherited disorders
A myriad of mutations has been characterized in collagen genes (Table 1). The function of the gene product and its tissue localization are criteria that lead to a number of inherited connective tissues disorders (reviewed in Bruckner-Tuderman and Bruckner, 1998; Bateman et al., 2009). Typically mutations in collagen genes are null-mutations,
The presence of a glycine in every third position is critical for triple-helix formation, since only glycine, the smallest amino acid, fits into the center of the triple helix. The majority of dominant-negative mutations in collagen genes are due to replacements of one of the glycines in the collagenous domains of the α-chains with a larger amino acid. Glycine substitution mutations in collagen genes underlie heritable connective tissue diseases, such as osteogenesis imperfecta (OI), chondrodysplasias, certain subtypes of Ehlers-Danlos syndrome (EDS), or Alport’s syndrome (reviewed in Bruckner-Tuderman and Bruckner, 1998; Bateman et al., 2009). Since a non-glycine amino acid does not easily fit into the interior space of the triple helix, helix formation is distorted, thereby affecting its structure and stability and impeding fibrillogenesis. Delay in triple-helix formation can result in over-modification and may affect collagen function.
Osteogenesis imperfecta (OI), also known as brittle bone disease, is caused by mutations in genes for collagen I, the most abundant collagen in organisms. OI is characterized by fragile bones that break easily and reduced bone mass. Most OI cases are believed to be associated with glycine substitution mutations in the
Collagen VII, encoded by
Mutations in the
Collagen V is a quantitatively minor fibril-forming collagen that co-polymerizes with collagen I to form heterotypic fibrils (Fichard et al., 1995). Co-polymerisation has a critical role in the nucleation and growth of fibrils in tissues. A collagen V feature is to retain in the mature molecule a major part of the α1(V) N-propeptide which projects beyond the surface of collagen fibrils. This domain was proposed to limit heterotypic fibril growth by steric hindrance and electrostatic interactions (Linsenmayer et al., 1993). Skin biopsies revealed abnormalities in fibril formation (altered diameter, contour, or shape of dermal fibrils). However, abnormalities of fibril structure affected less than 5% of fibrils (reviewed in Fichard et al., 2003). Moreover, the clinical phenotype of classical EDS supports an important role of collagen V in the biomechanical integrity of the skin, tendon and ligaments, although collagen V is only a minor component of the affected tissues. Thus, collagen V may be involved in functions other than the control of fibril growth in classical EDS. A likely hypothesis is that collagen V might be involved in the physiopathology of EDS through interactions with other fibril-associated components and/or with cell receptors. Along this line, it has been shown that mutations in the genes for the collagen V-binding partners, tenascin-X (
Although mutant gene products are thought to impair matrix structure and assembly that eventually alters tissue function, growing evidence links ER stress and the unfolded protein response (UPR) to the initiation and progression of a broad repertoire of connective tissue disorders, including those caused by collagen gene mutations. Some mutant chains cannot be incorporated into procollagen molecules, consequently causing protein degradation with important downstream effects. Misfolded or slowly folding collagens are retained within the endoplasmic reticulum (ER) and ultimately targeted for degradation by a mechanism initially called “protein suicide.” Because connective-tissue cells typically produce large quantities of collagens, the contribution of ER stress induced by misfolded collagens in disease pathogenesis has certainly been underrated. The current knowledge on the implications of unfolded protein response and ER stress in connective tissue diseases has been recently reviewed, and readers are referred to these reviews for further reading (Boot-Handford and Briggs, 2010; Tsang et al., 2010). Notably, mutations in genes encoding collagen I (
Mutations in the three major collagen VI genes (
The paucity of evidence-based data regarding correlations of genotype and phenotype is in part due to the large spectrum of mutations reported for the collagen genes [
A powerful approach to study the biochemical consequences of mutation and the protein structure/function relationship is to engineer a specific mutation into a functional domain of the molecule. Targeted mutagenesis approaches, including the use of alanine-scanning mutagenesis techniques, have led to important insights into the effects of collagen mutations on protein structure and function. A major limitation of mutagenesis strategies to investigate collagens is the large number of collagen gene mutations to be investigated in order to have a better understanding of the molecular mechanisms of “collagenopathies.” Knowledge about the impact of collagen mutations has also been hampered by the technical difficulty of introducing targeted mutations of very large collagen genes into mice.
4. Lessons from site-directed mutagenesis of recombinant collagen genes and derived fragments
Production of a recombinant collagen gene represents a powerful technique to introduce a human mutation into the gene of interest by site-directed mutagenesis. It allows one to analyze the impact of the mutation on collagen assembly and secretion. Collagen biosynthesis is a complex multistep process that takes place in the intracellular and extracellular space and includes various post-translationnal modifications, such as prolyl- and lysyl-hydroxylation, glycosylation, trimerization, proteolytic processing, polymerization and cross-links. Because of recombinant technology, these large multimeric proteins have been produced in large amounts in almost all existing expression systems (Ruggiero and Koch, 2008). This technological breakthrough enabled researchers to analyze in detail the effects of collagen mutations on biosynthesis, molecular and cell interactions, processing and, in some cases, self-assembly. Researchers can also address the question of the correlation of genotype, protein structure and function.
Mutations occurring in collagen I genes are the most extensively studied mutations among all collagen types. A first set of experiments substituted glycine 859 of the proα1(I) chain with cysteine or arginine by site-directed mutagenesis to reproduce two mutations identified in OI patients. In order to study the expression of the mutant molecule in the presence or absence of the wild-type proα1(I) chain, the mutated constructs were transfected into normal fibroblasts to look for a dominant-negative effect in the presence of the wild-type gene or in fibroblasts isolated from Mov13 homozygous mice (referred to as Mov13 fibroblasts hereafter), whose cells carry a provirus that prevents transcription initiation of the natural proα1(I) gene (Schnieke et al., 1987). In agreement with observations of collagen I in OI patients, the mutated collagens were poorly secreted from the cells and exhibited reduced thermal stability and increased sensitivity to degradation. This supported the idea that the strict preservation of the G-x-y triplets is absolutely required for proper formation of the triple helix.
The integrity of the C-propeptide is pivotal for the trimerization of all fibril-forming collagens. The C-propeptides of the proα1(I) and proα2(I) chains contain an Asn-Ile-Thr sequence. That sequence fits a consensus sequence for the addition of N-linked oligosaccharides. To analyze the role of this post-translational modification, the asparagine residue of the proα1(I) chain was changed to glycine by site-directed mutagenesis. The expression of the corresponding molecule was analyzed in transfected normal and Mov13 fibroblasts (Lamandé and Bateman, 1995). The mutation did not impair heterotrimeric assembly and secretion of hybrid procollagen I into the extracelllular space. Only a slight effect on C-proteinase cleavage efficiency was observed with the unglycosylated molecule. To circumvent the difficulty of producing a large repertoire of full-length mutated collagens I in order to undertake a genotype/phenotype analysis, a recombinant trimeric mini-collagen I was recently expressed in an
Human collagen IV mutations, thought to affect the biosynthesis of this basement membrane collagen, were extensively investigated. These mutations were known to cause Alport syndrome, a severe renal disease leading eventually to kidney failure. Collagen IV chains, α1(IV)-α6(IV), are encoded by 6 genes,
Collagens undergo a great variety of proteolytic modifications. The fate and functions of the released fragments derived from collagens are still under intensive investigation, but the consequences of mutations in the coding regions for the cleavage sites on collagen structure, self-assembly and function have not been investigated in detail. A large repertoire of proteinases is responsible for these processing interactions. Included among such enzymes are the ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) and the BMP-1/tolloid families of metalloproteinases and more recently the furin-like proprotein convertases (Ricard-Blum and Ruggiero, 2005). To investigate collagen processing, fastidious extraction and purification steps were often necessary to obtain limited amounts of unprocessed proteins and enzymes with full activity in order to undertake
5. Lessons from site-directed mutagenesis in mice
In most cases, the gene of interest was disrupted and knock-out mice were preferably generated. Few transgenic mice harbouring point mutations or small deletion in collagen genes have been generated (Table 1). Naturally occurring mutations in mice disrupting collagen genes have also been identified and characterized. The
Another example concerns collagen V deficiency/dysfunction, which is responsible for Ehlers-Danlos syndrome (EDS). In the absence of the
6. Concluding remarks
Site-directed mutagenesis has been extensively used in collagen engineering and has shed light on collagen structure, expression, folding, secretion, interactions and self-assembly in the extracellular space. It also opened the way for the analysis of specific functional domains. It allowed the study of the wide variety of collagen types, including those expressed in trace amounts in tissues but nevertheless display pivotal functions. While it is true that site-directed mutagenesis has yielded important information on the functional consequences of a range of collagen mutations responsible for human diseases, only few studies have approached the consequences of collagen gene mutations on cell adaptation to ER stress. Collagen gene mutations affect protein synthesis, folding and secretion imbalance, which eventually induces ER stress.
Mouse models are particularly useful for analysing the biological significance of collagens in pathological situations. Knock-out mice often lead to embryonic lethality, which hampers in-depth analysis of the phenotype. A few knock-in mice have been created with subtle mutations or small deletions that reproduce human mutations. The major reason for the paucity of knock-in mice is certainly that collagen genes are very large. Thus, they are difficult to manipulate. The introduction of a small deletion or a single point mutation in murine collagen genes still represents a considerable challenge. Nevertheless, the few examples of knock-in mouse lines tend to prove that mouse models can bring new information about
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