Collagens, the basic proteins of the human body.

Collagens are structural elements of many tissues in the human body. The family of collagens can be divided into fibrillar and non-fibrillar collagens. The criterion of the classification is the structure of these proteins. Mutations in the genes encoding collagens cause a variety of human diseases that include osteogenesis imperfecta, some forms of osteoporosis, chondrodysplasias, some types of Ehlers-Danlos syndrome, arterial and intracranial aneurysms, epidermolysis bullosa and the renal disease known as Alport syndrome. The detection of mutations is important both scientifically and clinically. Defining the molecular defects underlying a disorder helps in the understanding of not only the properties of the mutated protein but also the function of the normal protein. Even though many mutations in the genes encoding collagens have been described, the pathogenic consequences of some of the mutations are not fully understood. The important rationale for mutation detection is the clinical use of molecular diagnostics in genetic counselling and differential diagnosis.

Novel amino acid substitution in the Y-position of collagen type II causes spondyloepimetaphyseal dysplasia congenita.

We report on monozygotic twins with short stature and severe spondyloepimetaphyseal dysplasia congenita (SEMDC) from the Polish population. Phenotype of the twin girls resembles spondyloepiphyseal dysplasia congenita Spranger-Wiedemann (SEDC-SW), but shortening of the stature is more severe and the cranioface is normal. The distinctive radiographic features, in spite of similarity to SEDC-SW, indicate different spinal and, notably, severe metaphyseal involvement. Molecular analysis of the COL2A1 gene revealed an A to G transition at nucleotide +79 of exon 41 that converted the codon for arginine at amino acid 792 to a codon for glycine (Arg792Gly). The twins were heterozygous for the mutation and neither parent had this change. The Arg792Gly substitution is located at the Y-position of Gly-X-Y triplet, and it is likely that this substitution decreased the thermal stability of the triple helix and may affect fibril growth by replacement of an arginine residue, which is important for a conformation of the triple helix.

[Osteochondrodysplasia determined genetically by a collagen type II gene mutation]. / Osteochondrodysplazje uwarunkowane mutacjami w genie kolagenu typu II.

Chondrodysplasias are a heterogenous group of skeletal dysplasias, affecting the growing cartilage. The main part of chondrodysplasias is caused by mutations in various types of collagen genes. The current classification within this group of disorder relies on clinical, histological and radiographic features. Type II collagenopathies comprise part of chondrodysplasias, consisting of hereditary disorders caused by defects in the type II collagen. Collagen type II is coded by a large gene--COL2A1. The chromosomal location for the human COL2A1 gene is 12q13.11-q13.12. Defects in collagen type II are caused by point mutations in the COL2A1 gene. Type II collagenopathies form a wide spectrum of clinical severity ranging from lethal achondrogenesis type II, hypochondrogenesis, through severe forms like spondyloepiphyseal dysplasia congenita, spondyloepimetaphyseal dysplasia congenita, Marshall syndrome, to the mild forms--Stickler syndrome and early osteoarthritis. The pathological changes in the patients are observed in the growth plate, nucleus pulposus and vitreous body, where the abnormal collagen type II is distributed. This article presents the genetic background of collagenopathies type II and the results of current molecular studies of the patients. Both the molecular and the clinical studies may promise a better understanding of the relationship between the genotype and the phenotype. We present the patients, who were diagnosed at the Department of Medical Genetics and in the Orthopaedic Department in Poznan.

A mutation in COL9A1 causes multiple epiphyseal dysplasia: further evidence for locus heterogeneity.

Multiple epiphyseal dysplasia (MED) is an autosomal dominantly inherited chondrodysplasia. It is clinically highly heterogeneous, partially because of its complex genetic background. Mutations in four genes, COL9A2, COL9A3, COMP, and MATR3, all coding for cartilage extracellular matrix components (i.e., the alpha2 and alpha 3 chains of collagen IX, cartilage oligomeric matrix protein, and matrilin-3), have been identified in this disease so far, but no mutations have yet been reported in the third collagen IX gene, COL9A1, which codes for the alpha1(IX) chain. MED with apparently recessive inheritance has been reported in some families. A homozygous R279W mutation was recently found in the diastrophic dysplasia sulfate transporter gene, DTDST, in a patient with MED who had a club foot and double-layered patella. The series consisted of 41 probands with MED, 16 of whom were familial and on 4 of whom linkage analyses were performed. Recombination was observed between COL9A1, COL9A2, COL9A3, and COMP and the MED phenotype in two of the families, and between COL9A2, COL9A3, and COMP and the phenotype in the other two families. Screening of COL9A1 for mutations in the two probands from the families in which this gene was not involved in the recombinations failed to identify any disease-causing mutations. The remaining 37 probands were screened for mutations in all three collagen IX genes and in the COMP gene. The probands with talipes deformities or multipartite patella were also screened for the R279W mutation in DTDST. The analysis resulted in identification of three mutations in COMP and one in COL9A1, but none in the other two collagen IX genes. Two of the probands with a multipartite patella had the homozygous DTDST mutation. The results show that mutations in COL9A1 can cause MED, but they also suggest that mutations in COL9A1, COL9A2, COL9A3, COMP, and DTDST are not the major causes of MED and that there exists at least one additional locus.