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Genetic diseases of connective tissues: cellular and extracellular effects of ECM mutations

Nature Reviews Genetics volume 10, pages 173–183 (2009)Cite this article

Key Points

  • The extracellular matrices (ECMs) of connective tissues are crucial for normal development and tissue function, and mutations in ECM genes result in a wide range of serious inherited disorders. These include skeletal dysplasias, such osteogenesis imperfecta, and a spectrum of chondrodysplasias, Ehlers–Danlos syndrome, forms of muscular dystrophy, epidermolysis bullosa and Alport syndrome

  • Mutations cause ECM dysfunction by several mechanisms. First, secretion of ECM components can be reduced by mutations affecting synthesis or structural mutations causing cellular retention and/or degradation.

  • The secretion of mutant proteins can also disturb crucial interactions with consequent effects on structure and stability of the ECM.

  • Recent experiments also show that mutant misfolded extracellular matrix proteins such as cartilage oligomeric protein (COMP), collagens and matrilin 3 induce significant endoplasmic reticulum (ER) stress, and trigger the unfolded protein response (UPR). UPR can lead to deleterious downstream consequences, such as apoptosis and altered gene expression, and this can contribute to the molecular pathology of the mutations.

  • The emerging importance of ER stress in the pathology of a range of connective tissue disorders offers the possibility of new treatment strategies. These strategies target ER stress and seek to manipulate this pathway by reducing either the mutant protein load or the deleterious cellular consequences of ER-stress.

  • The pathophysiology of the many inherited connective tissue disorders resulting from ECM protein misfolding mutations most probably results from the combined effects of the extracellular consequences of reduced or abnormal protein on matrix structure and function, and the cellular consequences of ER stress.

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.

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Figure 1: Supramolecular assembly pathways.
Figure 2: The extracellular matrix (ECM) disease paradigm.

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Acknowledgements

This work was supported by grants from National Health and Medical Research Council of Australia. J.F.B. and S.R.L. are National Health and Medical Research Council Research Fellows. We thank C. Little, P. Farlie, A. Fosang and R. Wilson for critical reading of the manuscript.

Author information

Authors and Affiliations

  1. Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Childrens Hospital, Parkville, 3052, Victoria, Australia

    John F. Bateman & Shireen R. Lamandé

  2. Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, United Kingdom

    Raymond P. Boot-Handford

Authors
  1. John F. Bateman
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  2. Raymond P. Boot-Handford
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  3. Shireen R. Lamandé
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Correspondence to John F. Bateman.

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Related links

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FURTHER INFORMATION

Bateman laboratory homepage

Online Medelian Inheritance in Man (OMIM)

The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff

Database of osteogenesis imperfecta and type III collagen mutations

Leiden Muscular Dystrophy pages

Glossary

Osteogenesis imperfecta

(OI). A genetic bone disorder caused by abnormalities of collagen I structure or synthesis that results in poorly formed and fragile bones. Multiple distinct clinical manifestations range in severity from mild to congenital lethal.

Chondrodysplasia

A disturbance in the development of cartilage, primarily affecting the long bones. More than 200 forms are recognized, presenting a clinical range from mild to severe arrested growth and dwarfism, to congenital lethal.

Ehlers–Danlos syndrome

A group of inherited disorders of collagen synthesis and fibril formation that result in a range of pathologies, including joint laxity and hypermobility, and skin and blood vessel fragility.

Marfan syndrome

An inherited disorder presenting with long bone overgrowth, and defects of the heart valves and aorta. It is caused by mutations in the microfibrillar protein fibrillin 1.

Articular cartilage

The permanent cartilage that forms the smooth articulating surface of joints. It is a dense connective tissue with an extracellular matrix rich in collagen II and the proteoglycan aggrecan.

Growth plate cartilage

A transient cartilage type that drives bone growth and is located at one or both ends of long bones between the epiphysis and the diaphysis. The chondrocytes of the growth plate undergo specific maturation steps leading to hypertrophy and replacement with bone during endochondral bone formation before puberty.

Haploinsufficiency

A condition in a diploid organism in which a single functional copy of a gene results in a phenotype, such as a disease.

Stickler syndrome

A mild inherited chondrodysplasia with early degenerative joint and vertebral changes and often retinal detachment and blindness.

Bethlem myopathy

A genetic disease associated with muscle weakness. This congenital form of muscular dystrophy caused by collagen VI mutations is less severe than the allelic disorder, Ullrich congenital muscular dystrophy.

Metaphyseal chondrodysplasia, Schmid type

A form of chondrodysplasia that is caused by mutations in collagen X, a component of growth plate cartilage. Growth plates are structurally altered and the chondrocytes are disorganized, causing mild clinical abnormities of bone growth, such as bowed legs and hip problems.

Dystrophic epidermolysis bullosa

A severe genetic disorder resulting in extremely fragile skin and recurrent blister formation caused by mutations in collagen VII.

Dominant negative

A form of mutation that interferes with the function of its wild-type allele product.

Bruck syndrome

A recessive form of osteogenesis imperfecta, with joint contractures caused by mutations in the collagen-modifying enzyme lysyl hydroxylase 2.

ER-associated degradation

(ERAD). An intracellular quality control pathway that directs retrotranslocation of normal and misfolded proteins from the endoplasmic reticulum to the cytoplasm for proteasomal degradation.

Autophagy

In autophagy the cell is degraded largely from within, with little or no help from phagocytes. Bulk cytoplasm and organelles are sequestered within double-membrane-bound vesicles. These ultimately fuse with the lysosome and their contents are degraded.

Proteasome

A large cytoplasmic protein complex that degrades proteins to which ubiquitin has been added by a process that requires ATP.

Chondrocyte

Cartilage cells that produce the structural components of cartilage.

Osteoblast

A mesenchymal cell with the capacity to differentiate into bone tissue.

Mesenchymal stem cells

Multipotent mesenchymally derived stem cells that can differentiate into a variety of cell types, including osteoblasts, chondrocytes, myocytes and adipocytes.

Allogeneic

In allogeneic transplants, cells, organs or tissues from any human other than self or a monozygotic twin are used for therapeutic purposes.

mTOR

The mammalian target of rapamycin is a serine/threonine protein kinase that regulates cell growth, proliferation, survival, protein synthesis and transcription.

Transforming growth factor-β

(TGFβ). A secreted protein that controls cellular proliferation, differentiation and other functions in most cells. It has a role in immunity, cancer, heart disease and Marfan syndrome.

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Bateman, J., Boot-Handford, R. & Lamandé, S. Genetic diseases of connective tissues: cellular and extracellular effects of ECM mutations. Nat Rev Genet 10, 173–183 (2009). https://doi.org/10.1038/nrg2520

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