REVIEWS Genetic diseases of connective tissues: cellular and extracellular effects of ECM mutations John F. Bateman*, Raymond P. Boot-Handford‡ and Shireen R. Lamandé* Abstract | Tissue-specific extracellular matrices (ECMs) are crucial for normal development and tissue function, and mutations in ECM genes result in a wide range of serious inherited connective tissue disorders. Mutations cause ECM dysfunction by combinations of two mechanisms. First, secretion of the mutated ECM components can be reduced by mutations affecting synthesis or by structural mutations causing cellular retention and/or degradation. Second, secretion of mutant protein can disturb crucial ECM interactions, structure and stability. Moreover, recent experiments suggest that endoplasmic reticulum (ER) stress, caused by mutant misfolded ECM proteins, contributes to the molecular pathology. Targeting ER stress might offer a new therapeutic strategy. Osteogenesis imperfecta The major connective tissues of the body, such as might pave the way to new therapeutic opportunities. (OI). A genetic bone disorder skin, tendon, ligaments, cartilage and bone, provide Comprehensive information about gene mutations caused by abnormalities of the structural and informational framework that is has been covered in earlier reviews and is available collagen I structure or synthesis necessary for development. The extensive extracellu- in online databases, so rather than repeating infor- that results in poorly formed and fragile bones. Multiple lar matrix (ECM) of connective tissues is a complex mation we provide a summary of the mutation types distinct clinical manifestations interacting network of proteins, glycoproteins and and diseases that result from ECM gene mutations. range in severity from mild to proteoglycans providing the dynamic and essential Our main aim is to bring together a discussion of the congenital lethal. three-dimensional environment that supports the molecular pathways of pathophysiology that have maintenance, growth and differentiation of cells. In been elucidated by studies using cells from patients, addition to providing a highly organized framework, genetically manipulated cell lines or mutant mouse the ECM mediates signals to and from cells that are disease models. In particular, we highlight the realiza- involved in important biological processes such as cell tion that ECM mutations exert important pathogenic differentiation and migration during development, and effects inside the cell, as well as in the ECM outside repair processes. the cell. *Murdoch Childrens The diversity and functional importance of the ECM Research Institute and is illustrated by the occurrence of numerous genetic and ECM integrates cells into functional assemblies Department of Paediatrics, acquired connective tissue disorders. Mutations in indi- The ECM is diverse, with precisely regulated combi- University of Melbourne, vidual ECM genes cause conditions such as osteogenesis nations of molecular components providing tissue- Royal Childrens Hospital, imperfecta chondrodysplasias Ehlers– Parkville, Victoria 3052, (OI), numerous , specific properties ranging from the rock-hard nature Australia. Danlos syndrome and Marfan syndrome, and although of bone to the elasticity of ligament and skin, and from ‡Wellcome Trust Centre for these conditions are individually rare, collectively they the longevity of adult articular cartilage to the transient Cell-Matrix Research, Faculty are a considerable health burden. Furthermore, studies nature of growth plate cartilage. ECM components can of Life Sciences, University of Manchester, Oxford Road, on these conditions have been of considerable impor- be broadly placed into groups: structural components; Manchester M13 9PT, tance in understanding fundamental aspects of ECM matricellular proteins that have little structural role but United Kingdom. assembly and function. modulate cell–ECM interactions and growth factor Correspondence to J.B. Here we will review recent advances in our under- and protease activity; cell surface receptors and ancil- e-mail: standing of the molecular genetics and pathophysiol- lary proteins that interact with the ECM and perform [email protected] doi:10.1038/nrg2520 ogy of diseases caused by mutations in ECM genes, signalling and structural roles; and proteins involved Published online including insights into the important pathogenic in ECM homeostasis and remodelling, such as pro- 10 February 2009 role of endoplasmic reticulum (ER) stress, which teinases and their inhibitors. Although the different NATURE REVIEWS | GENETICS VOLUME 10 | MARCH 2009 | 173 © 2009 Macmillan Publishers Limited. All rights reserved REVIEWS Chondrodysplasia connective tissue matrices vary in composition and Molecular pathology of ECM gene mutations A disturbance in the detailed architecture, there are basic similarities in the Many mutations have been characterized in the struc- development of cartilage, types of molecular components and how these compo- tural components of the ECM and in the enzymes primarily affecting the long nents form interacting structural networks. The major involved in their post-translational processing and bones. More than 200 forms are recognized, presenting a ECM components include collagens, proteoglycans and folding. The molecular basis of how these mutations clinical range from mild to a large number of non-collagenous glycoproteins cause the myriad of connective tissue disorders depends severe arrested growth and and proteins1–8 (BOX 1). on the function of the gene product, its tissue distribu- dwarfism, to congenital lethal. Many ECM structural components assemble into tion and the nature of the mutation. Despite this phe- multimers in the cell. This intracellular assembly is an notypic diversity, unifying features in the molecular Ehlers–Danlos syndrome A group of inherited disorders important prerequisite for the multivalent extracellular mechanisms that lead to tissue pathology are emerging of collagen synthesis and fibril interactions that occur between the ECM components from recent studies. This Review will focus on human formation that result in a range which generate the architecturally precise matrix that is disease mutations (TABLE 1) and related mouse models of pathologies, including joint crucial for function. It can also be an important deter- (Supplementary information S1 (table)). A compre- laxity and hypermobility, and skin and blood vessel fragility. minant of how ECM gene mutations cause disease, as hensive description of ECM gene-targeted knockouts we discuss below. The details of the biosynthetic path- is provided by Aszodi et al.14. Marfan syndrome way and multilevel assembly are best understood for An inherited disorder the collagen family, and for this reason much of our Loss-of-function mutations presenting with long bone discussion will focus on collagen as the prototypical The most common genetic causes of reduced synthe- overgrowth, and defects of the heart valves and aorta. It is ECM protein to illustrate common themes in ECM sis of a gene product are mutations that result in the caused by mutations in the assembly and disease mechanisms. The central fea- introduction of premature termination codons (PTCs). microfibrillar protein fibrillin 1. tures of intracellular synthesis and assembly of several The presence of a PTC triggers an mRNA surveillance collagen types and cartilage oligomeric matrix protein process and nonsense mediated decay (NMD), whereby Articular cartilage The permanent cartilage that (COMP, also known as thrombospondin 5, TSP5) are aberrant mRNAs are distinguished from normal mRNAs 15–18 forms the smooth articulating presented in FIG. 1. and are rapidly degraded (FIG. 2). There are many PTC surface of joints. It is a dense The interactions of ECM with cells integrates them mutations in ECM structural genes, and for several of connective tissue with an into functional assemblies and provides two-way con- these it has been directly shown that the PTC mutations extracellular matrix rich duits for signalling and mechanotransduction9,10. ECM result in NMD and haploinsufficiency. These include PTC in collagen II and the 19,20 proteoglycan aggrecan. components interact with cells, and thus connect to the mutations in collagen I in OI , collagen II in Stickler cytoskeleton through a range of cell surface receptors, syndrome21,22, collagen VI in Bethlem myopathy23 and predominantly integrins11. In addition to these direct collagen X in metaphyseal chondrodysplasia, Schmid type24. roles in signalling, many ECM components bind Recessive PTC mutations lead to the absence of collagen growth factors and thus act as a reservoir controlling VI in Ullrich’s congenital muscular dystrophy25,26 and their bioavailablity. These important regulatory roles of collagen VII in dystrophic epidermolysis bullosa27,28. It is ECM function are beyond the scope of this article and likely that the majority of other PTC mutations in ECM are covered in several recent reviews6,12,13. genes will also be shown to cause NMD of the mRNA transcribed from the mutant allele. Although NMD can be 100% efficient29, more com- Box 1 | Extracellular matrix organization monly it reduces the abundance of PTC-containing transcripts to approximately 5–25% of the normal allele A diverse range of extracellular matrix (ECM) structural components have been transcript, so there can be small amounts of mutant described, including 28 distinct collagen subtypes, hyalectins, proteoglycans and a large number