Download Collagen and Collagen Disorders

FABAD J. Pharm. Sci., 32, 139-144, 2007
SCIENTIFIC REVIEW
Collagen and Collagen Disorders
Açelya YALOVAÇ *, N. Nuray ULUSU**°
Collagen and Collagen Disorders
Summary
Collagen has been studied extensively by a large number of
research laboratories since the beginning of the 20th century.
Collagens are the major fibrous glycoproteins present in the
extracellular matrix and in connective tissue such as tendons,
cartilage, the organic matrix of bone, and the cornea, and they
maintain the strength of these tissues. Collagen has a triplehelical structure. This molecule consists of repeating unusual
amino acids 35% glycine, 11% alanine, 21% proline, and
hydroxyproline. The importance of collagens was clearly defined
after the inherited collagen disorder studies. Mutations that alter
folding of the triple helix result in identifiable genetic disorders,
such as: osteogenesis imperfecta, Ehlers-Danlos syndromes,
Alport syndrome, Bethlem myopathy, some subtypes of
epidermolysis bullosa, Knobloch syndrome, some osteoporoses,
arterial aneurysms, osteoarthrosis, and intervertebral disc diseases.
The collagen family will be one of the most important research
topics in future years because of its many important functions.
Key Words: Collagen, osteogenesis imperfecta, Ehlers-Danlos
syndrome, Alport syndrome, Bethlem myopathy
Received
: 01.04.2009
Revised
: 09.06.2009
Accepted : 29.07.2009
Kollajen ve Kollajen Bozukluklar›
Özet
20. yüzy›l›n bafllar›ndan beri, kollajen çok say›da araflt›rma
laboratuarlar›nda yayg›n olarak çal›fl›lmaktad›r. Kollajenler,
ekstraselüler matrikste ve tendon, k›k›rdak, kemi¤in organik
matriksi ve kornea gibi ba¤ dokularda bulunan bafll›ca fibröz
glikoproteinlerdir ve bu dokular›n dayan›kl›l›¤›n› artt›r›rlar.
Kollajenin yap›s› üçlü heliksdir. Bu molekül, %35 glisin, %11
alanin, %21 prolin ve hidroksiprolin olmak üzere, nadir
aminoasitlerin tekrarlar›ndan oluflur. Kollajenlerin önemi, kal›tsal
kollajen bozukluklar› çal›fl›lmalar›ndan sonra aç›kça ç›km›flt›r.
Üçlü heliksin katlanmas›n› de¤ifltiren mutasyonlar, tan›mlanabilen
genetik hastal›klarla sonuçlan›rlar. Bu hastal›lardan baz›lar›;
Osteogenesiz imperfekta, Ehlers-Danlos sendromlar›, Alport
sendromu, Bethlem myopatisi, Epidermolizis bullosan›n baz› alt
tipleri, Knobloch sendromu, baz› osteoporozlar, arteriyal
anevrizmalar, osteoarthrozis ve intervertebral disk hastal›klar›d›r.
Gelecekte, kollajen ailesi birçok önemli fonksiyonlar›ndan dolay›,
en önemli araflt›rma konular›ndan biri olacakt›r.
Anahtar kelimeler: Kollajen; Osteogenesis imperfecta; EhlersDanlos Sendromu; Alport Sendromu; Bethlem myopatisi
INTRODUCTION
Enzymopathies affect humanity and our health in a multitude
of ways. These disorders may cause life-threatening
pathophysiological problems, structuropathies and various
morbidities and mortalities. Some of these enzymopathies
are quite common, such as glucose-6-phosphate deficiency.
This enzyme defect is the most common enzymopathy in
humans (1). On the other hand, there are various other
enzymopathies including 6-phosphogluconate
dehydrogenase deficiency (2). Collagen gene mutations
and collagen modifying enzyme defects are rarely
encountered. In this review, we discuss some recent data
about collagen diseases.
Collagens, which account for one-third of the body’s
proteins, are the biggest protein family of connective tissue
and the extracellular matrix. The collagen family has various
physiological functions. This superfamily includes 28
different types. These groups can also be classified into
subtypes according to their structural and functional
properties (3). The primary structure of the collagen
molecule was identified as (Gly-X-Y)(n). The collagen
structure is frequently characterized by the Gly-Pro-Hyp
tripeptide (4). Glycine makes up one-third of all the amino
acid residues, and the repetitive structure consists of many
amino acids (5). Although this structure can theoretically
* Hacettepe University, Faculty of Pharmacy, Department of Biochemistry, 06100 Ankara, Turkey
** Hacettepe University, Faculty of Medicine, Department of Biochemistry, 06100 Ankara, Turkey
° Corresponding author e-mail: [email protected]
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Yalovaç, Ulusu
include more than 400 different compositions, when they
are analyzed, only a limited number of differences can be
determined (4). The triple-helix structure is important for
some cellular functions such as adhesion and extracellular
matrix activation and for enzymatic functions such as
hydroxylation of collagen’s Lys and Pro residues (6). Even
though its catabolism by matrix metalloproteinases is not
fully understood, it is accepted that the triple-helix structure
is required for the catabolism of both the collagen molecule
and the cell surface receptors of macrophages (6,7). Collagen
is usually found in fibril form in the extracellular matrix.
The fibril-forming collagens are 300 nm in length and 67
nm in diameter (8). Each collagen chain consists of
approximately 1000 amino acid residues. Fibril-forming
collagens are types I, II, III, V, and XI, and these types of
collagens are most common in the body (9). Type I collagen
is the most abundant protein in humans (10). The collagen
biosynthesis requires eight specific post-translational
enzymes (11).
The critical roles of collagens are identified with the diseases
that are caused by the mutations on the genes coding them,
among which are osteogenesis imperfecta, chondroplasias,
some subtypes of Ehlers-Danlos syndrome, Alport
syndrome, Bethlem myopathy, some subtypes of
epidermolysis bullosa, Knobloch syndrome, some
osteoporoses, arterial aneurysms, osteoarthrosis, and
intervertebral disc diseases. In this review, we intend to
present the most prevalent diseases caused by several
mutations.
Osteogenesis Imperfecta
Osteogenesis imperfecta, also known as “brittle bone
disease”, is the most common (estimated prevalence is
1/10000 and 1/20000) autosomal dominant disease of the
connective tissue (12,13).
The disease is characterized by extremely fragile bones,
reduced bone mass, blue sclera, dentinogenesis imperfecta,
hearing loss, and scoliosis (14). The bone fragility in this
disease is caused by reduced bone mass, degenerated
organization of bone tissue and altered bone geometry in
size and shape (15).
The first classification of osteogenesis imperfecta was
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made by Sillience in 1979, and it was divided into four
groups (types I-IV) due to the defects in the collagen gene.
However, today this disease is divided into seven groups
with the discovery of types V-VII (14,16).
Most of the cases are related with the mutations in two
genes that encode the proalpha1 or proalpha2 polypeptide
chains of type I collagen. A small proportion of these
diseases are from a mutation in a cartilage protein or the
expression of 3-prolyl-hydroxylase (17). Type I collagen
is known to be the main structural protein of bone and
skin. However, type I collagen gene mutations cause a
bone disease. It has been shown previously that mutant
collagen expression is different in bone and in skin (13).
Clinical manifestation of this disease ranges from normal
to lethal (18). If the mutations affect the amount of type I
collagen, clinical manifestation of the disease will result
in mild forms. Mutations in COL1A1 or COL1A2 genes
result in more severe and lethal forms. Glycine has a critical
role in the formation of collagen triple-helix. The most
common mutations of this disease are seen in the substation
of glycine with a bigger amino acid (13). The mutations
seen in types V, VI and VII are recently defined types (15).
Type VII osteogenesis imperfecta arises from the mutations
in “cartilage-associated protein” gene (19).
Osteogenesis imperfecta has many phenotypic differences
and can be seen in every age, and diagnosis of the disease
is difficult (16). Prenatal diagnosis can be made using
clinical, radiographic, biochemical or genetic methods; the
remainder are diagnosed after birth (20). Today, only
symptomatic treatment is available - nonsurgical treatment
consists of physical therapy and rehabilitation; surgical
treatment and drugs used for increasing bone strength are
the other treatment options (21). Treatments with
bisphosphonates have led to significant improvements in
adolescents and increased patient quality of life (12,22).
A potent inhibitor of bone resorption drug and growth
hormone have also been used in recent years (21,23).
Animal studies and laboratory studies consisting of somatic
gene therapy that aims at the inactivation of the mutations
are still being evaluated (24).
Marfan Syndrome
Marfan syndrome is an autosomal dominant, multisystemic
disease of the connective tissue (25). It does not have a
FABAD J. Pharm. Sci., 32, 139-144, 2007
particular gender, racial or geographic tendency (26). This
syndrome affects approximately 1 in 5000 to 1 in 10,000
individuals (27). It results from the mutations in the FBN1
gene, which encodes the fibrilin-1 (28). More than 500
FBN1 mutations have been determined for this syndrome
(29). For clinical diagnosis, 86% of the cases can be
diagnosed clearly by using Ghent nosology, but for certain
diagnosis, genetic test should be performed (30).
Its characteristics are aortic dilatation that progresses with
aortic valve failure, mitral valve prolapsus and failure, lens
dislocation and myopia, long and slim body and long limbs
due to excessive bone growth, arachnodactyly, chest
deformations, defects in skeletal system, skin, nervous
system and lungs, and sometimes scoliosis (31-33).
One of the reasons for sudden cardiac death in athletes is
the rupture of the aortic root due to Marfan syndrome (34).
Furthermore, it can lead to various surgical pathologies
such as hernia, ileus and abdominal vein aneurysms. These
pathologies can sometimes be life- threatening (35).
Individuals with Marfan syndrome are often tall and agile
and they can unwittingly join physical activities and sports
(27). Symptoms related to muscle and skeleton are very
common (30).
Ehlers-Danlos Syndrome
The estimated prevalence of Ehlers-Danlos syndrome
ranges from 1/10000 to 1/25000 [36]. However, this disease
can be seen on all continents and can affect all races and
both genders (37). At least 10 subtypes are classified based
upon genetic, biochemical and clinical features (38). The
syndrome is characterized by fragile and tender skin, easy
bruising and atrophic injury. In approximately half of the
cases, mutations in the COL5A1 and COL5A2 genes
encoding the alpha1 and alpha2 chains of type V are defined
(39).
Type IV Ehlers-Danlos syndrome accounts for
approximately 5 to 10% of cases, and this disease is caused
by 19 different mutations in the COL3A1 gene coding for
type III procollagen (36,40). Characteristic features of the
disease are easy bruising, serious vein, uterus and digestion
complications, acrogeria, and translucent skin with highly
visible subcutaneous vessels. The vascular type can result
in fatal bleedings (36,41). Type VI is a result of the
homozygote and heterozygote mutations in the lysyl
hydroxylase gene (38). The expression of the disorder is
changeable in different tissues. In skin, a complete lack of
hydroxylysine was observed, but in some tissues such as
lung, tendon, kidney or bone it is less expressed (42). The
skin of type VI patients are hyperelastic but bruise easily
and heal difficultly and slowly (43). Type VII is related
with the defect in the process of transformation of
procollagen to collagen. Inadequate procollagen amino
protease activity is seen (44). On the other hand, many
types of this disorder have been described, some of which
are rarely seen, such as types V, VII and X (45). Types I
and III result from decreasing lysyl hydroxylase activity
(38). Very little is known about the genetic or biochemical
defects responsible for the other subtypes of Ehlers-Danlos
syndrome, but they are still being researched (38,46).
Alport Syndrome
Alport syndrome is caused by deletion mutations in
COL4A5 and COL4A6 genes or COL4A3 and COL4A4
genes encoding the alpha3(IV) and alpha4(IV) chains.
Eighty percent of Alport syndrome cases are X-linked and
its prevalence is 1/5000 (47,48). This syndrome affects
some of the basal membranes and is characterized by renal
failure, loss of hearing and lens abnormalities (49). The
first pathological sign in this disease is the loss of type IV
collagen network formed by alpha3, alpha4 and alpha5(IV)
chains (47). The damage of collagen IV due to mutations
causes dysfunction of bound epithelium and results in
organ damage (50). Diagnosis of this disease is
predominantly based on histological studies (47).
Epidermolysis Bullosa
Epidermolysis bullosa is a heterogeneous group of heritable
disorders. It is characterized by blistering of the skin and
mucous membranes as a result of a small injury (51,52).
It has been demonstrated that 10 genes are responsible for
the different forms of this disease (51).
Epidermolysis bullosa has been classified under three
anatomic groups: epidermolytic, junctional, and dermolytic
types. These groups can be divided into subtypes based on
histological and clinical criteria (53). Genetic abnormalities
have been examined in different subtypes: in dominant
simplex type, mutations in the K5 or K14 genes cause
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Yalovaç, Ulusu
basal cell damage and blistering, while in recessive simplex
types, muscular dystrophy results from abnormal plectin
and skin fragility syndrome from PKP1 mutations. The
junctional form results from the laminin 5, type XVII
collagen and alpha-6-beta-4 integrin gene mutations. The
dystrophic type is related with mutations in the type VII
gene (54). The cause of squamous cell carcinoma
development in epidermolysis bullosa patients is still
unknown (55).
Current treatment of the disease includes nursing of the
skin and other organs, infection care for chronic wounds,
nutritional support and surgical treatment if needed (56).
Knobloch Syndrome
Knobloch syndrome is an autosomal recessive disorder
characterized by high myopia, vitreoretinal degeneration,
occipital bone damage, and congenital encephalocele (57).
Genetical analysis of families with Knobloch syndrome is
heterogeneous (58). In these families, pathological mutations
in the COL18A1 gene at 21q22.3 have been identified
(57). These mutations cause the loss of one or all collagen
COL18A1 isoforms or endostatin (58).
Bethlem Myopathy
Bethlem myopathy is an autosomal dominant inherited
relatively mild disease that is characterized by muscle
weakness and distal joint contractures. It is supposed that
type VII collagen plays a role in connecting cells and
extracellular matrix and that mutations in genes encoding
collagen VI result in Bethlem myopathy (59,60). While it
is reported that the first attack in this disease is seen in
early childhood, two-thirds of patients are over 50 years
of age because of the slow progression of the disease (61).
CONCLUSION
Collagen, the most abundant protein in mammals, is the
main component of the extracellular matrix and as a result
is the main component of connective tissue. It is unavoidable
that the undesirable effects of molecular changes in the
structure of this fibrous protein may affect many systems
of the human body, from the central nervous system to the
musculoskeletal and cardiovascular systems. Collagen
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disorders can affect different systems such as the
cardiovascular or ocular system, making these syndromes
very important, even though the collagen disorders are not
so common in our country. In recent years, despite the
increasing information obtained about the structure and
synthesis of collagen, the genetic and molecular bases of
the collagen disorders, which are still accepted as untreatable
or uncurable clinical syndromes, remain undetermined. In
addition to having the opportunity to understand numerous
molecular disorders, progressive biochemical tests,
molecular findings and also the technological resources
will facilitate an explanation of the systematic and
physiopathologic processes. Molecular studies will help
to explain the different syndromes and clinical entities that
are classified in the same groups. In the future, it will be
possible to treat these patients and improve the quality of
their daily life,
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