Basement membranes and human disease

TLDR: In 1990, the role of basement membranes in human disease was established by the identification of COL4A5 mutations in Alport’s syndrome, and exciting progress has recently been made with potential treatment options for some of these so far incurable diseases.

Abstract: In 1990, the role of basement membranes in human disease was established by the identification of COL4A5 mutations in Alport’s syndrome. Since then, the number of diseases caused by mutations in basement membrane components has steadily increased as has our understanding of the roles of basement membranes in organ development and function. However, many questions remain as to the molecular and cellular consequences of these mutations and the way in which they lead to the observed disease phenotypes. Despite this, exciting progress has recently been made with potential treatment options for some of these so far incurable diseases.

Figures

Table 2 Phenotypes of mouse models of BM components covered in text

Table 1: Basement membrane protein targets in inherited human diseases

Full text

Van Agtmael, T. and Bruckner-Tuderman, L. (2010) Basement
membranes and human disease. Cell and Tissue Research, 339 (1). pp.
167-188. ISSN 0302-766X
http://eprints.gla.ac.uk/35275/
Deposited on: 30 August 2010
Enlighten – Research publications by members of the University of Glasgow
http://eprints.gla.ac.uk

Basement membranes and human disease
Tom van Agtmael§ and Leena Bruckner-Tuderman*
§ Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow, U.K.
and * Dept. of Dermatology, University Medical Center Freiburg and Freiburg Institute for
Advanced Studies, Freiburg, Germany
Corresponding authors: Tom Van Agtmael Faculty of Biomedical and Life Sciences,
Davidson Building, University of Glasgow, University Avenue, Glasgow UK,
tom.van.agtmael@bio.gla.ac.uk,. Leena Bruckner-Tuderman Department of Dermatology,
University Medical Center Freiburg, Hauptstr. 7, 79104 Freiburg, Germany. E-mail:
bruckner-tuderman@uniklinik-freiburg.de
Keywords: basement membrane, laminin, collagen, laminin, nidogen
Abbreviations
BM: basement membrane, NMJ neuromuscular junction, DEJ dermo epidermal junction,
SJS Schwartz Jampel syndrome, DDSH Dyssegmental dysplasia silverman handmaker
type, EB epidermolysis bullosa, GBM glomerular basement membrane
1

Abstract
In 1990 the role of basement membranes in human disease was established by the
identification of COL4A5 mutations in Alport’s syndrome. Since then the number of
diseases caused by mutations in basement membrane components has steadily increased as
has our understanding of the roles of basement membranes in organ development and
function. However, many questions remain as to the molecular and cellular consequences
of these mutations and how they lead to the observed disease phenotypes. Despite this,
exciting progress has recently been made with potential treatment options for some of these
so far incurable diseases.
Introduction
Basement membranes (BM) are specialised extracellular matrices that provide tissue
structure and influence cell behaviour. They are present throughout the body and form
compartments within tissues by separating endothelial and epithelial cells from underlying
mesenchyme. In general BMs are composed of collagens, perlecan, nidogens and laminins,
but individual BMs differ in their composition leading to an abundance of different
interacting partners and added complexity. Consequently BMs are crucial to life and
mutations in their components lead to a wide variety of clinical phenotypes affecting
different organs. In this review we will cover after a short overview of the main BM
components, the current knowledge of diseases caused by abnormalities of these molecules
in the eye, kidney, vasculature, skin and neuro-muscular junction.
2

Laminins
Laminin is besides collagen type IV the most abundant basement membrane component
and is present in all BMs. A laminin network links the BM to the cell surface through
interactions with cell surface receptors, which enables it to influence cell signalling and
behaviour besides providing a structural role. Laminins are heterotrimeric glycoproteins
consisting of an α, β and γ chain, and 5 α, 3 β and 3 γ chains are encoded by the genes
LAMA1-5, LAMB1-3 and LAMC1-3 (Durbeej 2009). The chains can assemble into at least
15 laminin proteins (Miner 2008) which are named in the new nomenclature according to
their composition such that LM-111 consists of the α 1, β 1 and γ 1 chains (Aumailley et al.
2005). As some chains are components of multiple laminins, e.g. laminin α5 chain is a
component of LM-511, LM-521 and LM-523, characterising the role of individual laminins
is difficult as mutations may affect multiple laminins.
Generally, laminins are cruciform shaped proteins (Fig. 1), although rod- or Y-shaped
laminin molecules occur (Durbeej 2009).The N-terminal end of the chains contains
globular domains separated by laminin epidermal growth factor-like repeats (LEa, LEb,
LEc). All chains contain laminin N-terminal (LN) domains which are important for laminin
network formation. The α chain also contain the L4a and L4b globular domains whilst β
and γ chains contain the LF and L4 domains respectively. The central coiled coil region is
flanked by the C-terminal end of the α chain which forms the globular LG domain,
consisting of five LG domains which mediate cell adhesion through binding receptors
including integrins, dystroglycan, syndecan and heparin (Miner 2008). These interactions
can be modulated by the proteolytical cleavage of LG domains 3-5.
3

Because laminin, collagen type IV, nidogen and perlecan are key BM components, one can
imagine that aberrations in any of these components would prohibit BM formation. The
absence of BM formation in mice deficient for laminin γ1 or β1 (Miner et al. 2004; Smyth
et al. 1999) shows indeed that laminin is required for initial BM formation and early
development. In contrast, collagen type IV (Poschl et al. 2004), nidogen (Bader et al. 2005)
and perlecan (Arikawa-Hirasawa et al. 1999) are required for BM maintenance rather than
initial formation. Laminin’s role in development is not limited to early development as both
the interaction between nidogen and laminin γ1 and laminin α5 are required for kidney
formation (Miner and Li 2000; Willem et al. 2002). In addition, laminin α5 plays a role in
the development of placenta, brain, limb and lung (Miner 2008), and elegant rescue
experiments have begun to address how laminin α5 functions. These data showed that
during development its role is mediated through the LG1-2 domains whilst the LG3-5
domains functions in the glomerular filtration barrier (Kikkawa and Miner 2006).
One of the central concepts observed following laminin deficiency is the induced
expression of other laminins. The effectiveness of this for organ function depends on the
redundancy of the different laminin molecules as illustrated by the successful compensatory
expression in notochord development of laminin α4 following laminin α1 deficiency in
zebrafish (Pollard et al. 2006). However this compensation may not always restore organ
function as laminin β1 expression in the glomerular basement membrane (GBM) of Lamb2
-
/-
mice does not rescue filtration barrier function despite producing a structurally intact
BM
(Noakes et al. 1995b).
4

Frequently asked questions

Q1. What are the contributions mentioned in the paper "Basement membranes and human disease" ?

In this review the authors will cover after a short overview of the main BM components, the current knowledge of diseases caused by abnormalities of these molecules in the eye, kidney, vasculature, skin and neuro-muscular junction. 

Q2. What is the role of the ectodomain in the formation of collagen type VII?

Both keratinocytes and fibroblasts can synthesize collagen type VII and interactions between collagen VII and laminin 332 (Chen et al. 

Q3. What are the main components of collagen?

The interactions of collagens with extracellular matrix proteins and cell surface receptors are important during processes such as development, growth, tissue remodelling and disease pathologies. 

Q4. What are the main structural components of the extracellular matrix?

Collagens are the major structural component of the extracellular matrix but are also important for tissue architecture organisation and cellular processes such as adhesion and migration. 

Q5. What are the clinical symptoms of epidermolysis bullosa?

The clinical symptoms vary from mild to severe and include continuous skin blistering, persistent erosions and mucosal involvement, nail dystrophy, alopecia, progressive soft tissue scarring, mutilating deformities and increased risk of epithelial cancer. 

Q6. What is the role of collagen type IV in the formation of mature synapses?

In addition Col18a1 mutations result in neuromigration and axon guidance defects (Ackley et al. 2001) which may underlie the exencephaly in Knobloch syndrome and collagen type IV is important for clustering of synaptic vesicles and maintenance of mature synapses (Fox et al. 2007). 

Q7. What is the role of collagen type IV in BM?

Once secreted, a complex set of interactions occurs between protomers forming a collagen type IV network in the shape of a lattice. 

Q8. What are the key components of BM?

Because laminin, collagen type IV, nidogen and perlecan are key BM components, one can imagine that aberrations in any of these components would prohibit BM formation. 

Q9. What is the mechanism of endostatin release in BMs?

The release of endostatin, through cleavage of the hinge that separates the C-terminal domain from the triple helical domain occurs in vivo as endostatin can be detected in plasma and tissue extracts (Iozzo 2005). 

Q10. What are the interesting mice with milder phenotypes?

Particularly interesting are mice with milder phenotypes, e.g. the collagen type VII hypomorph or the collagen type XVII knockout mouse, which are useful for testing novel biologically valid therapeutic strategies, including protein, cell and gene based therapies, which have already shown some promising results (Fritsch et al. 

Q11. What is the role of the hemidesmosome in the DEJ?

The molecular components of hemidesmosomes, anchoring filaments, and anchoring fibrils in the DEJ are quite well characterized, and mutations in their genes lead to diminished adhesion of the epidermis and the dermis, and to skin blistering. 

Q12. What is the role of the ectodomain in the formation of the collagen type VII?

During the biosynthesis and the supra-molecular aggregation of the fibrils, pro-collagen type VII is processed to mature collagen via proteolytic processing of the NC-2 domain by BMP-1 (bone morphogenicprotein-1) (Rattenholl et al. 2002). 

Q13. What causes the milder cases of EB?

These milder cases are due to missense mutations in LAMA3, LAMB3, LAMC2 or COL17A1 which result in truncated or misfolded LM-332 or collagen type XII proteins. 

Q14. What is the first long-term clinical success in genetic BM?

The correction of junctional EB by transplantation of genetically modified epidermal stem cells in one patient represents the first long-term clinical therapeutic success in genetic BM disease (Mavilio et al. 2006). 

Q15. What is the phenotype of retinal tortuosities?

The retinal tortuosities is one of a number of vascular phenotypes affecting the eye that include a silvery appearance of the arterioles, retinal bleeding, and neovascularisation (Favor et al. 2007; Van Agtmael et al. 2005). 

Q16. What is the role of perlecan in chondrocyte fibrillogenesis?

The requirement of perlecan for collagen fibrillogenesis in chondroplasts (Kvist et al. 2006) suggest that defective deposition of fibrillar collagen underlies the reduced matrix deposition. 

Q17. What is the definition of a highly complex form of BM?

The dermal-epidermal junction (DEJ) in skin is an example of a highly complex form of BM and of specific divergence in its structure. 

Q18. What is the cause of a prolonged decay of the potential in a DDSH mouse?

This may result in re-excitation of muscle leading to myotonia in SJS and muscle potentiation and a prolonged decay time of the potential in Hspg2C1532Y mice (Stum et al. 2008). 

Q19. What is the role of LM-332 in the formation of oligomers?

In contrast to other laminin molecules, LM-332 may rely on the association with LM-331 to form oligomers as it can not selfpolymerize (Aumailley et al. 2006). 

Q20. What is the role of laminin in the development of placenta?

In addition, laminin α5 plays a role inthe development of placenta, brain, limb and lung (Miner 2008), and elegant rescueexperiments have begun to address how laminin α5 functions. 

Q21. What is the ectodomain of human collagen type XVII?

The ectodomain of human collagen type XVII, contains collagenous domains (Col1-15), interspaced by non-collagenous (NC1 to NC16) segments and its tertiary structure is longitudinal with a C-terminal flexible tail (Franzke et al. 2005) (Fig. 2C).