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Home , Epidermolysis bullosa, Knobloch syndrome

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

SCIENTIFIC REVIEW

Collagen and Disorders

Açelya YALOVAÇ *, N. Nuray ULUSU**°

Collagen and Collagen Disorders Kollajen ve Kollajen Bozukluklar› Summary Özet Collagen has been studied extensively by a large number of 20. yüzy›l›n bafllar›ndan beri, kollajen çok say›da araflt›rma research laboratories since the beginning of the 20th century. laboratuarlar›nda yayg›n olarak çal›fl›lmaktad›r. Kollajenler, are the major fibrous glycoproteins present in the ekstraselüler matrikste ve tendon, k›k›rdak, kemi¤in organik and in connective tissue such as tendons, matriksi ve kornea gibi ba¤ dokularda bulunan bafll›ca fibröz cartilage, the organic matrix of bone, and the , and they glikoproteinlerdir ve bu dokular›n dayan›kl›l›¤›n› artt›r›rlar. maintain the strength of these tissues. Collagen has a triple- Kollajenin yap›s› üçlü heliksdir. Bu molekül, %35 glisin, %11 helical structure. This molecule consists of repeating unusual alanin, %21 prolin ve hidroksiprolin olmak üzere, nadir amino acids 35% glycine, 11% alanine, 21% proline, and aminoasitlerin tekrarlar›ndan oluflur. Kollajenlerin önemi, kal›tsal hydroxyproline. The importance of collagens was clearly defined kollajen bozukluklar› çal›fl›lmalar›ndan sonra aç›kça ç›km›flt›r. after the inherited collagen disorder studies. that alter Üçlü heliksin katlanmas›n› de¤ifltiren mutasyonlar, tan›mlanabilen folding of the triple helix result in identifiable genetic disorders, genetik hastal›klarla sonuçlan›rlar. Bu hastal›lardan baz›lar›; such as: , Ehlers-Danlos syndromes, Osteogenesiz imperfekta, Ehlers-Danlos sendromlar›, Alport , , some subtypes of sendromu, Bethlem myopatisi, Epidermolizis bullosan›n baz› alt epidermolysis bullosa, Knobloch syndrome, some osteoporoses, tipleri, Knobloch sendromu, baz› osteoporozlar, arteriyal arterial aneurysms, osteoarthrosis, and intervertebral disc diseases. anevrizmalar, osteoarthrozis ve intervertebral disk hastal›klar›d›r. The collagen family will be one of the most important research Gelecekte, kollajen ailesi birçok önemli fonksiyonlar›ndan dolay›, topics in future years because of its many important functions. en önemli araflt›rma konular›ndan biri olacakt›r. Key Words: Collagen, osteogenesis imperfecta, Ehlers-Danlos Anahtar kelimeler: Kollajen; Osteogenesis imperfecta; Ehlers- syndrome, Alport syndrome, Bethlem myopathy Danlos Sendromu; Alport Sendromu; Bethlem myopatisi Received : 01.04.2009 Revised : 09.06.2009 Accepted : 29.07.2009

INTRODUCTION Enzymopathies affect humanity and our health in a multitude Collagens, which account for one-third of the body’s of ways. These disorders may cause life-threatening , are the biggest family of connective tissue pathophysiological problems, structuropathies and various and the extracellular matrix. The collagen family has various morbidities and mortalities. Some of these enzymopathies physiological functions. This superfamily includes 28 are quite common, such as glucose-6-phosphate deficiency. different types. These groups can also be classified into This enzyme defect is the most common enzymopathy in subtypes according to their structural and functional humans (1). On the other hand, there are various other properties (3). The primary structure of the collagen enzymopathies including 6-phosphogluconate molecule was identified as (Gly-X-Y)(n). The collagen dehydrogenase deficiency (2). Collagen gene mutations structure is frequently characterized by the Gly-Pro-Hyp and collagen modifying enzyme defects are rarely tripeptide (4). Glycine makes up one-third of all the amino encountered. In this review, we discuss some recent data acid residues, and the repetitive structure consists of many about collagen diseases. 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]

139 Yalovaç, Ulusu include more than 400 different compositions, when they made by Sillience in 1979, and it was divided into four are analyzed, only a limited number of differences can be groups (types I-IV) due to the defects in the collagen gene. determined (4). The triple-helix structure is important for However, today this disease is divided into seven groups some cellular functions such as adhesion and extracellular with the discovery of types V-VII (14,16). matrix activation and for enzymatic functions such as hydroxylation of collagen’s Lys and Pro residues (6). Even Most of the cases are related with the mutations in two though its catabolism by matrix metalloproteinases is not genes that encode the proalpha1 or proalpha2 polypeptide fully understood, it is accepted that the triple-helix structure chains of . A small proportion of these is required for the catabolism of both the collagen molecule diseases are from a in a cartilage protein or the and the cell surface receptors of macrophages (6,7). Collagen expression of 3-prolyl-hydroxylase (17). Type I collagen is usually found in fibril form in the extracellular matrix. is known to be the main structural protein of bone and The fibril-forming collagens are 300 nm in length and 67 . However, type I collagen gene mutations cause a nm in diameter (8). Each collagen chain consists of bone disease. It has been shown previously that mutant approximately 1000 amino acid residues. Fibril-forming collagen expression is different in bone and in skin (13). collagens are types I, II, III, V, and XI, and these types of Clinical manifestation of this disease ranges from normal collagens are most common in the body (9). Type I collagen to lethal (18). If the mutations affect the amount of type I is the most abundant protein in humans (10). The collagen collagen, clinical manifestation of the disease will result biosynthesis requires eight specific post-translational in mild forms. Mutations in COL1A1 or COL1A2 genes enzymes (11). result in more severe and lethal forms. Glycine has a critical role in the formation of collagen triple-helix. The most The critical roles of collagens are identified with the diseases common mutations of this disease are seen in the substation that are caused by the mutations on the genes coding them, of glycine with a bigger amino acid (13). The mutations among which are osteogenesis imperfecta, chondroplasias, seen in types V, VI and VII are recently defined types (15). some subtypes of Ehlers-Danlos syndrome, Alport Type VII osteogenesis imperfecta arises from the mutations syndrome, Bethlem myopathy, some subtypes of in “cartilage-associated protein” gene (19). epidermolysis bullosa, Knobloch syndrome, some osteoporoses, arterial aneurysms, osteoarthrosis, and Osteogenesis imperfecta has many phenotypic differences intervertebral disc diseases. In this review, we intend to and can be seen in every age, and diagnosis of the disease present the most prevalent diseases caused by several is difficult (16). Prenatal diagnosis can be made using mutations. clinical, radiographic, biochemical or genetic methods; the remainder are diagnosed after birth (20). Today, only Osteogenesis Imperfecta symptomatic treatment is available - nonsurgical treatment consists of physical therapy and rehabilitation; surgical Osteogenesis imperfecta, also known as “brittle bone treatment and drugs used for increasing bone strength are disease”, is the most common (estimated prevalence is the other treatment options (21). Treatments with 1/10000 and 1/20000) autosomal dominant disease of the bisphosphonates have led to significant improvements in connective tissue (12,13). adolescents and increased patient quality of life (12,22). A potent inhibitor of bone resorption drug and growth The disease is characterized by extremely fragile bones, hormone have also been used in recent years (21,23). reduced bone mass, blue sclera, dentinogenesis imperfecta, Animal studies and laboratory studies consisting of somatic hearing loss, and scoliosis (14). The bone fragility in this that aims at the inactivation of the mutations disease is caused by reduced bone mass, degenerated are still being evaluated (24). organization of bone tissue and altered bone geometry in size and shape (15). Marfan Syndrome Marfan syndrome is an autosomal dominant, multisystemic The first classification of osteogenesis imperfecta was disease of the connective tissue (25). It does not have a

140 FABAD J. Pharm. Sci., 32, 139-144, 2007 particular gender, racial or geographic tendency (26). This hydroxylase gene (38). The expression of the disorder is syndrome affects approximately 1 in 5000 to 1 in 10,000 changeable in different tissues. In skin, a complete lack of individuals (27). It results from the mutations in the FBN1 hydroxylysine was observed, but in some tissues such as gene, which encodes the fibrilin-1 (28). More than 500 lung, tendon, kidney or bone it is less expressed (42). The FBN1 mutations have been determined for this syndrome skin of type VI patients are hyperelastic but bruise easily (29). For clinical diagnosis, 86% of the cases can be and heal difficultly and slowly (43). Type VII is related diagnosed clearly by using Ghent nosology, but for certain with the defect in the process of transformation of diagnosis, genetic test should be performed (30). procollagen to collagen. Inadequate procollagen amino Its characteristics are aortic dilatation that progresses with protease activity is seen (44). On the other hand, many aortic valve failure, mitral valve prolapsus and failure, types of this disorder have been described, some of which dislocation and , long and slim body and long limbs are rarely seen, such as types V, VII and X (45). Types I due to excessive bone growth, arachnodactyly, chest and III result from decreasing lysyl hydroxylase activity deformations, defects in skeletal system, skin, nervous (38). Very little is known about the genetic or biochemical system and lungs, and sometimes scoliosis (31-33). defects responsible for the other subtypes of Ehlers-Danlos One of the reasons for sudden cardiac death in athletes is syndrome, but they are still being researched (38,46). the rupture of the aortic root due to Marfan syndrome (34). Furthermore, it can lead to various surgical pathologies Alport Syndrome such as hernia, ileus and abdominal vein aneurysms. These pathologies can sometimes be life- threatening (35). Alport syndrome is caused by deletion mutations in Individuals with Marfan syndrome are often tall and agile COL4A5 and COL4A6 genes or COL4A3 and COL4A4 and they can unwittingly join physical activities and sports genes encoding the alpha3(IV) and alpha4(IV) chains. (27). Symptoms related to muscle and skeleton are very Eighty percent of Alport syndrome cases are X-linked and common (30). its prevalence is 1/5000 (47,48). This syndrome affects some of the basal membranes and is characterized by renal Ehlers-Danlos Syndrome failure, loss of hearing and lens abnormalities (49). The first pathological sign in this disease is the loss of type IV The estimated prevalence of Ehlers-Danlos syndrome collagen network formed by alpha3, alpha4 and alpha5(IV) ranges from 1/10000 to 1/25000 [36]. However, this disease chains (47). The damage of collagen IV due to mutations can be seen on all continents and can affect all races and causes dysfunction of bound epithelium and results in both genders (37). At least 10 subtypes are classified based organ damage (50). Diagnosis of this disease is upon genetic, biochemical and clinical features (38). The predominantly based on histological studies (47). syndrome is characterized by fragile and tender skin, easy bruising and atrophic injury. In approximately half of the Epidermolysis Bullosa cases, mutations in the COL5A1 and COL5A2 genes encoding the alpha1 and alpha2 chains of type V are defined Epidermolysis bullosa is a heterogeneous group of heritable (39). disorders. It is characterized by blistering of the skin and mucous membranes as a result of a small injury (51,52). Type IV Ehlers-Danlos syndrome accounts for It has been demonstrated that 10 genes are responsible for approximately 5 to 10% of cases, and this disease is caused the different forms of this disease (51). by 19 different mutations in the COL3A1 gene coding for type III procollagen (36,40). Characteristic features of the Epidermolysis bullosa has been classified under three disease are easy bruising, serious vein, uterus and digestion anatomic groups: epidermolytic, junctional, and dermolytic complications, acrogeria, and translucent skin with highly types. These groups can be divided into subtypes based on visible subcutaneous vessels. The vascular type can result histological and clinical criteria (53). Genetic abnormalities in fatal bleedings (36,41). Type VI is a result of the have been examined in different subtypes: in dominant homozygote and heterozygote mutations in the lysyl simplex type, mutations in the K5 or K14 genes cause

141 Yalovaç, Ulusu basal cell damage and blistering, while in recessive simplex disorders can affect different systems such as the types, muscular dystrophy results from abnormal plectin cardiovascular or ocular system, making these syndromes and from PKP1 mutations. The very important, even though the collagen disorders are not junctional form results from the 5, type XVII so common in our country. In recent years, despite the collagen and alpha-6-beta-4 integrin gene mutations. The increasing information obtained about the structure and dystrophic type is related with mutations in the type VII synthesis of collagen, the genetic and molecular bases of gene (54). The cause of squamous cell carcinoma the collagen disorders, which are still accepted as untreatable development in epidermolysis bullosa patients is still or uncurable clinical syndromes, remain undetermined. In unknown (55). addition to having the opportunity to understand numerous molecular disorders, progressive biochemical tests, Current treatment of the disease includes nursing of the molecular findings and also the technological resources skin and other organs, care for chronic wounds, will facilitate an explanation of the systematic and nutritional support and surgical treatment if needed (56). physiopathologic processes. Molecular studies will help to explain the different syndromes and clinical entities that Knobloch Syndrome are classified in the same groups. In the future, it will be possible to treat these patients and improve the quality of Knobloch syndrome is an autosomal recessive disorder their daily life, characterized by high myopia, vitreoretinal degeneration, damage, and congenital (57). Genetical analysis of families with Knobloch syndrome is heterogeneous (58). In these families, pathological mutations REFERENCES in the COL18A1 gene at 21q22.3 have been identified (57). These mutations cause the loss of one or all collagen 1. Ulusu NN, Kus MS, Tezcan EF. Glucose-6-phosphate COL18A1 isoforms or endostatin (58). dehydrogenase molecular and kinetic properties. Biyokimya Dergisi 22: 25-33, 1997. Bethlem Myopathy 2. Tandogan B, Ulusu NN. 6-Phosphogluconate dehydrogenase: molecular and kinetic properties. Turkish Bethlem myopathy is an autosomal dominant inherited J Biochem 28(4): 268-273, 2003. relatively mild disease that is characterized by muscle 3. Heino J. The collagen family members as cell adhesion weakness and distal joint contractures. It is supposed that proteins. Bioessays. 29(10): 1001-1010, 2007. type VII collagen plays a role in connecting cells and 4. Ramshaw JA, Shah NK, Brodsky B. Gly-X-Y tripeptide extracellular matrix and that mutations in genes encoding frequencies in collagen: a context for host-guest triple- collagen VI result in Bethlem myopathy (59,60). While it helical peptides. J Struct Biol. 122(1-2): 86-91, 1998. is reported that the first attack in this disease is seen in 5. Brodsky B, Persikov AV. Molecular structure of the early childhood, two-thirds of patients are over 50 years collagen triple helix. Adv Protein Chem. 70: 301-339, of age because of the slow progression of the disease (61). 2005. 6. Fields GB. The collagen triple-helix: correlation of CONCLUSION conformation with biological activities. Connect Tissue Res. 31(3): 235-243, 1995. Collagen, the most abundant protein in mammals, is the 7. Lauer-Fields JL, Juska D, Fields GB. Matrix main component of the extracellular matrix and as a result metalloproteinases and collagen catabolism Biopolymers. is the main component of connective tissue. It is unavoidable 66(1): 19-32, 2002. that the undesirable effects of molecular changes in the 8. Wess TJ. Collagen fibril form and function. Adv Protein structure of this fibrous protein may affect many systems Chem. 70: 341-374, 2005. of the human body, from the central nervous system to the 9. Ottani V, Martini D, Franchi M, Ruggeri A, Raspanti musculoskeletal and cardiovascular systems. Collagen M. Hierarchical structures in fibrillar collagens. Micron

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