Biomedical subjects

M Vikkula

Publications and source records attributed to M Vikkula.

45 records · Page 3Linked to original sources

PubMed1995

A gene for familial venous malformations maps to chromosome 9p in a second large kindred.

Venous malformations are a common form of vascular anomaly that cause pain and disfigurement and can be life threatening if they involve critical organs. They occur sporadically or in a familial form, where multiple lesions are usually present. We have identified a large kindred showing autosomal dominant inheritance of venous malformations. Using this family we confirm linkage of a familial form of venous malformations to chromosome 9p. We suggest that blue rubber bleb naevus syndrome can be considered a particular manifestation of this form of familial venous malformations. The candidate region for this gene encompasses the interferon gene cluster and the MTS1 (p16) tumour suppressor gene.

Chromosome Mapping↗

PubMed1994

Assignment of a locus for dominantly inherited venous malformations to chromosome 9p.

Venous malformation is the most common type of vascular anomaly. Depending upon size and location, these slow-flow anomalies may cause pain, anatomic distortion, or threaten life. Most venous malformations occur sporadically and present as solitary lesions. They also occur in several syndromes, some of which demonstrate Mendelian inheritance. We have mapped the locus for an autosomal dominant disorder in a three generation family that manifests as multiple cutaneous and mucosal venous malformations. This locus lies within a 24 cM interval on chromosome 9p, defined by the markers D9S157 and D9S163. The alpha and beta interferon gene cluster and the putative tumor suppressor genes MTS1 and MTS2 are also in this region. Characterization of the gene responsible for this disorder should yield insights into the precise pathogenic mechanisms for venous malformations.

Abnormalities, Multiple↗

PubMed1994

Type II collagen mutations in rare and common cartilage diseases.

Cartilage diseases include a wide variety of clinical phenotypes from common osteoarthrosis to several different types of chondrodysplasias, i.e. 'disorders of cartilage', of which more than 100 different have been described. Patients frequently suffer from various symptoms affecting their joints and/or the growth of their long bones. The amount of hyaline cartilage at articular surfaces is often diminished and structurally abnormal. The surface of the cartilage may have an irregular appearance with defects extending into the subchondral bone. The major constituents of this hyaline cartilage are collagens and proteoglycans, the most abundant protein being type II collagen. It is a homotrimer of three identical alpha-chains, which are encoded by a single gene on human chromosome 12. The gene for type II collagen therefore became a likely candidate for some forms of chondrodysplasias and cartilage degeneration. Recently, both linkages and exclusions between this gene and various cartilage diseases have been reported and a growing number of mutations within the gene have also been identified.

Animals↗

PubMed1993

Early-onset osteoarthritis linked to the type II procollagen gene. Detailed clinical phenotype and further analyses of the gene.

OBJECTIVE: To specify in detail the clinical phenotype in 2 Finnish families demonstrating linkage between the type II procollagen gene (COL2A1) and osteoarthritis (OA). We also reevaluated the linkage and screened the exon sequences of the COL2A1 gene for mutations. METHODS: We used single-stranded conformation polymorphism and denaturing gradient-gel electrophoresis techniques for the analyses. RESULTS: The patients' phenotype represented typical, but early-onset, OA. There was no clinical or radiographic evidence of chondrodysplasia. No mutation in the protein-coding regions of the COL2A1 gene could be identified. However, the linkage analysis with a new multiallelic marker resulted in a statistically more significant logarithm of odds (LOD) score than has been reported. CONCLUSION: Familial OA with classic clinical and radiographic findings is tightly linked to the COL2A1 gene. Systematic screening of the 54 exons did not, however, reveal any mutations; this suggests that the mutation may lie in the promoter region or within the introns of this 35-kb gene.

Adolescent↗

PubMed1993

A mutation in the amino-terminal end of the triple helix of type II collagen causing severe osteochondrodysplasia.

Type II collagen is coded by a large gene (COL2A1) consisting of 54 exons on chromosome 12. During the past few years several cartilage disorders have been linked to this gene, and some specific nucleotide changes have been identified in patients. In a spondyloepiphyseal form of chondrodysplasia, the three mutations found so far are all in exon 48 in the region coding for the carboxyl-terminal end of the triple helix. Since folding of the type II collagen polypeptides to the triple helix is initiated from the carboxyl-terminal end, it has been suggested that mutations in this region typically result in severe cartilage diseases. Here we report a novel mutation located in the area coding for the amino-terminal part of the triple helix in a sporadic patient with spondyloepiphyseal dysplasia (SED). The mutation, a substitution of G1063 to A, which results in the conversion of Gly154 to Arg, was identified using exon-specific amplification of genomic DNA and subsequent analyses with denaturing gradient gel electrophoresis and single-strand conformation polymorphism. The substitution was not found in any other SED patient in Finland. This novel mutation demonstrates that amino acid substitutions in the amino-terminal part of the type II collagen triple helix can also result in SED.

Adolescent↗

PubMed1993

Multiallelic polymorphism of the cartilage collagen gene: no association with osteoarthrosis.

OBJECTIVES: To determine whether any of the type II collagen alleles are associated with generalised osteoarthrosis or osteoarthrosis of the finger joints in the genetically isolated Finnish population. METHODS: Two patient cohorts with evidence for only primary osteoarthrosis and a cohort of healthy control subjects were selected from the Helsinki University Central Hospital and the Rheumatism Foundation Hospital in Finland. Forty one patients with primary generalised osteoarthrosis, 49 patients with osteoarthrosis of the finger joints, and 48 control subjects were included. Two markers of the type II collagen gene, a PvuII polymorphism and a VNTR polymorphism, were analysed from each subject. RESULTS: Four different alleles of the VNTR marker were observed and the relative risks associated with the different VNTR alleles varied between 0.39 and 1.24 among the patients with generalised osteoarthrosis and between 0.67 and 2.33 among the patients with osteoarthrosis of the finger joints. The PvuII polymorphism detected two different alleles and the associated relative risks were 0.82 and 1.82 for the patients with generalised osteoarthrosis, and 1.04 and 0.96 for the patients with osteoarthrosis of the finger joints. CONCLUSIONS: A major predisposing allele of the type II collagen gene as the causative factor for osteoarthrosis could be excluded in this population. A spectrum of mutations associated with different alleles of this gene could not be excluded, however. Further, these two forms of cartilage disease can be caused by gene defects with reduced penetrance and the effect of such an allele is easily masked under the high frequency of normal alleles.

Alleles↗

PubMed1992

Structural analysis of the regulatory elements of the type-II procollagen gene. Conservation of promoter and first intron sequences between human and mouse.

Transcription of the type-II procollagen gene (COL2A1) is very specifically restricted to a limited number of tissues, particularly cartilages. In order to identify transcription-control motifs we have sequenced the promoter region and the first intron of the human and mouse COL2A1 genes. With the assumption that these motifs should be well conserved during evolution, we have searched for potential elements important for the tissue-specific transcription of the COL2A1 gene by aligning the two sequences with each other and with the available rat type-II procollagen sequence for the promoter. With this approach we could identify specific evolutionarily well-conserved motifs in the promoter area. On the other hand, several suggested regulatory elements in the promoter region did not show evolutionary conservation. In the middle of the first intron we found a cluster of well-conserved transcription-control elements and we conclude that these conserved motifs most probably possess a significant function in the control of the tissue-specific transcription of the COL2A1 gene. We also describe locations of additional, highly conserved nucleotide stretches, which are good candidate regions in the search for binding sites of yet-uncharacterized cartilage-specific transcription regulators of the COL2A1 gene.

Amino Acid Sequence↗

PubMed1989

Structural analyses of the polymorphic area in type II collagen gene.

The structure of type II collagen gene is extremely well conserved but contains a cluster of high frequency polymorphisms in a 2.2 kb area. Here we report the nucleotide sequence of this DNA area, essential for the PCR-facilitated RFLP-analyses of this gene. In the structural analyses we found four differences in the deduced human amino acid sequence when compared to the published bovine amino acid sequence. The donor and acceptor signals and branch point signals required for the splicing events were in agreement with mammalian consensus sequences. The frequency of inverted repeats which could provoke the DNA strand to loop formation and consequently to deletion mutations did not differ from that found in other sequenced genes coding for fibrillar collagens. mutations did not differ from that found in other sequenced genes coding for fibrillar collagens.

Collagen↗

PubMed1989

Predisposition to familial osteoarthrosis linked to type II collagen gene.

The genetic background of two families, in whom a predisposition to primary osteoarthrosis is inherited as a dominant trait, was investigated. Use of restriction fragment length polymorphisms within and around the type II collagen gene on chromosome 12 revealed a linkage between this cartilage-specific gene and primary osteoarthrosis.

Adult↗