collagen disorders.pdf

7/27/2019 collagen disorders.pdf

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FABAD J. Pharm. Sci., 32, 139-144, 2007

SCIENTIFIC REVIEW

Aelya YALOVA *, N. Nuray ULUSU**

Collagen and Collagen Disorders

Summary

Kollajen ve Kollajen Bozukluklar

zet

Collagen and Collagen Disorders

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 theextracellular matrix and in connective tissue such as tendons,cartilage, the organic matrix of bone, and the cornea, and theymaintain the strength of these tissues. Collagen has a triple-helical structure. This molecule consists of repeating unusualamino acids 35% glycine, 11% alanine, 21% proline, andhydroxyproline. The importance of collagens was clearly definedafter the inherited collagen disorder studies. Mutations that alterfolding of the triple helix result in identifiable genetic disorders,such as: osteogenesis imperfecta, Ehlers-Danlos syndromes,Alport syndrome, Bethlem myopathy, some subtypes ofepidermolysis bullosa, Knobloch syndrome, some osteoporoses,arterial aneurysms, osteoarthrosis, and intervertebral disc diseases.The collagen family will be one of the most important researchtopics in future years because of its many important functions.Key Words: Collagen, osteogenesis imperfecta, Ehlers-Danlossyndrome, Alport syndrome, Bethlem myopathyReceived : 01.04.2009Revised : 09.06.2009Accepted : 29.07.2009

20. yzyln bafllarndan beri, kollajen ok sayda arafltrma

laboratuarlarnda yaygn olarak alfllmaktadr. Kollajenler,ekstraseller matrikste ve tendon, kkrdak, kemiin organikmatriksi ve kornea gibi ba dokularda bulunan bafllca fibrzglikoproteinlerdir ve bu dokularn dayanklln arttrrlar.Kollajenin yaps l heliksdir. Bu molekl, %35 glisin, %11alanin, %21 prolin ve hidroksiprolin olmak zere, nadiraminoasitlerin tekrarlarndan oluflur. Kollajenlerin nemi, kaltsalkollajen bozukluklar alfllmalarndan sonra aka kmfltr.l heliksin katlanmasn deifltiren mutasyonlar, tanmlanabilengenetik hastalklarla sonulanrlar. Bu hastallardan bazlar;Osteogenesiz imperfekta, Ehlers-Danlos sendromlar, Alportsendromu, Bethlem myopatisi, Epidermolizis bullosann baz alttipleri, Knobloch sendromu, baz osteoporozlar, arteriyalanevrizmalar, osteoarthrozis ve intervertebral disk hastalklardr.Gelecekte, kollajen ailesi birok nemli fonksiyonlarndan dolay,en nemli arafltrma konularndan biri olacaktr .Anahtar kelimeler:Kollajen; Osteogenesis imperfecta; Ehlers-Danlos Sendromu; Alport Sendromu; Bethlem myopatis i

* 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]

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 bodys

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


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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 extracellularmatrix activation and for enzymatic functions such as

hydroxylation of collagens 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 ofepidermolysis 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 theconnective 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

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 inadolescents 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


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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 isthe 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 andmucous 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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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 XVIIcollagen 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

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 theincreasing 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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