Disease relevance of COL5A1

• Null alleles of the COL5A1 gene of type V collagen are a cause of the classical forms of Ehlers-Danlos syndrome (types I and II) [1].
• In addition, these studies place COL5A1 near the locus for the genetic disorder, nail-patella syndrome (hereditary osteo-onychodysplasia), which also maps to 9q34 [2].
• Here, we describe a balanced translocation between chromosome 9 and an X chromosome that disrupts the minor fibrillar collagen type V gene COL5A1 in a patient with both EDS type I and hypomelanosis of Ito [3].
• This SSR is used to exclude COL5A1 as a candidate gene in hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease) and to add COL5A1 to the existing map of "index" markers of chromosome 9 by evaluation of the COL5A1 locus on the CEPH 40-family reference pedigree set [4].
• CONCLUSIONS: The COL5A1 BstUI RFLP is associated with ATP and more specifically, chronic Achilles tendinopathy [5].

High impact information on COL5A1

• A translocation interrupts the COL5A1 gene in a patient with Ehlers-Danlos syndrome and hypomelanosis of Ito [3].
• The breakpoint occurs at 9q34 within COL5A1 intron 24 and interestingly, within a LINE-1 (L1) element at Xp21 [3].
• This demonstrates that a mutation in a type V collagen gene, COL5A1, results in EDS type I, and shows the involvement of L1 sequences in a constitutional chromosomal translocation [3].
• Two potential candidate genes, COL5A1 and ZNF79, are also located within 9q33-34 [6].
• Mutations in the COL5A1 and COL5A2 genes, which encode type V collagen, have been identified in several individuals [7].

Biological context of COL5A1

• Genetic heterogeneity has been confirmed as an explanation for such failure, since causative mutations have been identified in the COL5A1, COL5A2, and tenascin X genes and since they have been inferred in the COL1A2 gene [1].
• Thus, although as many as one-half of the mutations that give rise to EDS types I and II are likely to lie in the COL5A1 gene, a significant portion of them result in very low levels of mRNA from the mutant allele, as a consequence of nonsense-mediated mRNA decay [1].
• The main triple-helical domain being encoded by 49-50 exons, including the junction exons, in the COL5A1, COL11A1 and COL11A2 genes, but by 43-44 exons in the genes for the major fibrillar collagens [8].
• In 37 patients, the COL5A1/A2 genes were then analyzed by SSCP and conformation sensitive gel electrophoresis (CSGE) [9].
• Using an intragenic COL5A1 polymorphism, we have demonstrated linkage, at zero recombination, to the same allele in two large British EDS type II families (LOD scores 4.1 and 4.3) [10].

Anatomical context of COL5A1

• CONCLUSIONS: In the eye, COL5A1 and COL5A2 mutations manifest as abnormally thin and steep corneas with floppy eyelids [11].
• Products of the two COL5A1 alleles were approximately equal after the addition of cycloheximide to the fibroblast cultures [12].
• We have identified haploinsufficiency of the COL5A1 gene that encodes the proalpha1(V) chain of type V collagen in the classical form of the Ehlers-Danlos syndrome (EDS), a heritable connective-tissue disorder that severely alters the collagen-fibrillar structure of the dermis, joints, eyes, and blood vessels [12].
• Separation of amniotic membranes after amniocentesis in an individual with the classic form of EDS and haploinsufficiency for COL5A1 expression [13].
• The COL5A1 gene and Achilles tendon pathology [5].

Associations of COL5A1 with chemical compounds

• Mutation analysis by means of RNase cleavage and direct sequencing of reverse transcription-polymerase chain reaction products showed in both the presence of a heterozygous G1489E [correction] mutation in the COL5A1 gene, which represents the first report of a glycine substitution in the main triple-helical region of alpha1(V) collagen [14].
• EDS cells with COL5A1 haplo-insufficiency deposited less than one-half of hydroxyproline as collagen compared to control fibroblasts, though total collagen synthesis rates are near-normal because type V collagen represents a small fraction of collagen synthesized [15].

Other interactions of COL5A1

• An additional mutation in either the COL5A1 and COL5A2 genes was excluded [16].
• These studies establish the chromosomal location of the COL5A1 gene, which encodes the pro alpha 1 (V) chain, within segment 9q34.2----q34 [2].
• METHODS: We searched for mutations in the COL5A1 gene in cDNA from cultured fibroblasts of 19 patients with sCAD using single-strand conformational polymorphism analysis and nucleotide sequence analysis of polymerase chain reaction-amplified fragments of the whole COL5A1 coding sequence [17].
• We have employed 3'-untranslated region RFLPs to exclude COL5A1 as a candidate gene in families with tuberous sclerosis 1, Ehlers-Danlos syndrome type II, and nail-patella syndrome [4].

Analytical, diagnostic and therapeutic context of COL5A1

• RTPCR amplification of mRNA covering the whole of this domain of COL5A1 showed a deletion of 54 bp [18].
• METHODS: Seven patients with classic Ehlers-Danlos syndrome (EDS) due to COL5A1 haploinsufficiency and one with an exon-skipping mutation in COL5A2 underwent an ocular examination, corneal topography, pachymetry, and specular microscopy [11].
• Mutations in the COL5A1 coding sequence are not common in patients with spontaneous cervical artery dissections [17].
• The subcloned PCR product (pGC1) presented the same nucleotide sequence as the original fragment from the published sequence of COL5A1 [19].
• In situ hybridization, using pGC1 as a probe, mapped the COL5A1 gene to chromosome 9q34 [19].

References