The Human COL11A2 Gene Structure Indicates that the Gene Has Not Evolved with the Genes for the Major Fibrillar Collagens

Abstract

The human COL11A2 gene was analyzed from two overlapping cosmid clones that were previously isolated in the course of searching the human major histocompatibility region (Janatipour, M., Naumov, Y., Ando, A., Sugimura, K., Okamoto, N., Tsuji, K., Abe, K., and Inoko, H. (1992) Immunogenetics 35, 272-278). Nucleotide sequencing defined over 28,000 base pairs of the gene. It was shown to contain 66 exons. As with most genes for fibrillar collagens, the first intron was among the largest, and the introns at the 5-end of the gene were in general larger than the introns at the 3-end. Analysis of the exons coding for the major triple helical domain indicated that the gene structure had not evolved with the genes for the major fibrillar collagens in that there were marked differences in the number of exons, the exon sizes, and codon usage. The gene was located close to the gene for the retinoic X receptor ␤ in a head-to-tail arrangement similar to that previously seen with the two mouse genes (P. Vandenberg and D. J. Prockop, submitted for publication). Also, there was marked interspecies homology in the intergenic sequences. The amino acid sequences and the pattern of charged amino acids in the major triple helix of the ␣2(XI) chain suggested that the chain can be incorporated into the same molecule as ␣1(XI) and ␣1(V) chains but not into the same molecule as the ␣3(XI)/␣1(II) chain. The structure of the carboxyl-terminal propeptide was similar to the carboxyl-terminal propeptides of the pro␣1(XI) chain and pro␣ chains of other fibrillar collagens, but it was shorter because of internal deletions of about 30 amino acids.Over 19 types of collagens are known, each with an apparently unique biological function (1-3). A major subclass is the fibrillar collagens that form ordered extracellular fibrils and that include type I, type II, type III, type V, and type XI collagens. Type I and type III collagens are found in most non-cartilaginous tissues. Type II is found primarily in cartilage where it is the most abundant protein, but it is also present in the vitreous humor and several other tissues in early embryonic development. Type XI collagen was originally recognized as a minor fibrillar collagen in cartilage that was similar to type II collagen. The protein was considered to consist of three ␣ chains referred to as ␣1(XI), ␣2(XI), and ␣3(XI) (4 -6). The ␣3(XI) chain was subsequently shown to be derived from the same gene as the ␣1(II) chain of type II collagen that, by an unknown mechanism, was assembled with the ␣1(XI) and ␣2(XI) chain to form a unique procollagen molecule (4 -9). In further analyses, type XI collagen was found to be closely related in structure to type V collagen, and both type V and type XI collagens were found in small amounts in a variety of cartilaginous and non-cartilaginous connective tissues (10, 11). Amino acid sequencing of fragments of collagen fibrils from mammalian vitreous humor demonstrated that fibrils were assembled from molecules containing ␣1(XI) and ␣2(V) chains (12). Also, during th...

Collagen XI sequence variations in nonsyndromic cleft palate, Robin sequence and micrognathia

“…10 The corresponding mouse genes have the same orientation and it has been demonstrated that some transcripts from Rxr-b extend into Col11a2. 24 Excess administration of retinoic acids to pregnant women is known to cause micrognathia and cleft palate, 25,26 possibly by upregulating the expression of RXR-b, resulting in downregulation of COL11A2 and thereby producing a phenotype similar to those seen in connection with mutations in collagen XI genes.…”

“…1,2,[6][7][8] Collagen XI is a heterotrimer of a1(XI), a2(XI) and a3(XI) chains encoded by three distinct genes; COL11A1, COL11A2 and COL2A1. [9][10][11] The COL2A1 gene also codes for the a1 chain of collagen II, but the a3(XI) chain undergoes more extensive post-translational modification than the a1(II) chain. 12 Collagens II and XI are present throughout Meckel's cartilage, which provides mechanical support for the developing mandible.…”

Evolution of collagens

“…3A). More recently, the exon-intron organizations of COL5A1 and COL11A2 were determined (Takahara et al, 1995;Vuoristo et al, 1995) (COLxAy refers to the human gene encoding the pro␣y(x) collagen chain), and these match the structure proposed for an ancestral fibrillar collagen gene. The relative conservation of the exon-intron organization of the region encoding the major triple helix of metazoan fibrillar ␣ chains argues for a strong selection pressure preserving both the size and the perfect Gly-Xaa-Yaa repeat necessary for the formation of fibrils.…”

Stickler syndrome: further mutations in COL11A1 and evidence for additional locus heterogeneity

“…Indeed the deleted region in MS40 alone, at 40 kb, is larger than the 28 kb COL11A2 gene. 31 Another 54 bp exon-skipping mutation in COL11A1 caused Marshall syndrome 38 and it was suggested that this was due to the more disruptive type of mutation compared with the previous glycine substitution seen in this molecule. 16 The skipping mutation and the multi exon deletion described here should be just as disruptive as the mutant described as causing Marshall syndrome.…”

“…For the larger cDNAs Superscript™ (Life Sciences) was used in the reverse transcription reactions and TaqPlus™ (Stratagene) was used in the amplification reactions, as recommended by the manufacturers. Amplification of various regions of COL11A1 from genomic DNA was undertaken using TaqPlus, primers derived from the COL11A1 cDNA sequence (Genbank accession number J04177; J05407, 22 ), and the gene structure of COL11A2 31 as a guide to the exon/intron organisation of COL11A1. All amplified genomic products were partially sequenced to confirm the location of introns, and detect mutations in affected individuals.…”