ABSTRACT
Research to date has identified several genes that are implicated in the etiology of ossification of the posterior longitudinal ligament of the spine (OPLL); however, their pathogenetic relevance remains obscure. The aim of this study is to identify susceptibility genes for OPLL through a large-scale case-control association study and to re-examine previously reported associations. A total of 109 single nucleotide polymorphisms (SNPs) in 35 candidate genes were genotyped for 711 sporadic OPLL patients and 896 controls. The differences in allelic and genotypic distribution between patients and controls were assessed using the chi (2) test with Bonferroni's correction. We also analyzed the association by separating patients into subgroups according to sex, age and the number of ossified vertebrae. The nominal P values fell below 0.05 for five SNPs in three genes. An intronic SNP in the TGF3 gene (P=0.00040) showed the most significant association. Previously reported associations of COL11A2, NPPS and TGFB1 with OPLL could not be reproduced. Further, no significant associations were detected in stratified analyses based on sex, age or the number of ossified vertebrae. TGFB3 warrants further investigation because it is located within a genomic region that has been positively linked with OPLL.
Subject(s)
Genetic Predisposition to Disease , Ossification of Posterior Longitudinal Ligament/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Case-Control Studies , Child , Child, Preschool , Female , Humans , Male , Middle Aged , Polymorphism, Single NucleotideSubject(s)
Extracellular Matrix Proteins/genetics , Mutation , Osteochondrodysplasias/genetics , von Willebrand Factor/genetics , Adult , DNA Mutational Analysis , Genotype , Humans , Male , Matrilin Proteins , Mutation, Missense , Osteochondrodysplasias/diagnostic imaging , Phenotype , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , RadiographyABSTRACT
Intergenic splicing, the joining of exons from separate genes, has been observed only rarely in mammals. While the matrilin (MATN) and lysosomal-associated protein transmembrane (LAPTM) genes comprise distinct gene families, we have demonstrated intergenic splicing between two sets of family genes, the matrilin-3 (MATN3) and lysosomal-associated protein transmembrane 4alpha (LAPTM4A), and the matrilin-2 (MATN2) and lysosomal-associated protein transmembrane 4beta (LAPTM4B). The expression pattern and sub-cellular localization of the MATN-LAPTM hybrid transcripts differ from those of the original genes, suggesting unique functions for the products. Our observations indicate that intergenic splicing is a common and well-regulated phenomenon and underscore the fundamental challenges in defining the gene (transcriptional unit). Given these findings, the number of gene in the human genome may be smaller than present estimates suggest.
Subject(s)
Extracellular Matrix Proteins/metabolism , Membrane Proteins/metabolism , Oncogene Proteins/metabolism , Trans-Splicing , Cell Line , Extracellular Matrix Proteins/genetics , Gene Fusion , Glycoproteins/genetics , Glycoproteins/metabolism , Humans , Matrilin Proteins , Membrane Proteins/genetics , Oncogene Proteins/genetics , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolismABSTRACT
Preaxial polydactyly (PPD) is a common limb malformation in human. A number of polydactylous mouse mutants indicate that misexpression of Shh is a common requirement for generating extra digits. Here we identify a translocation breakpoint in a PPD patient and a transgenic insertion site in the polydactylous mouse mutant sasquatch (Ssq). The genetic lesions in both lie within the same respective intron of the LMBR1/Lmbr1 gene, which resides approximately 1 Mb away from Shh. Genetic analysis of Ssq reveals that the Lmbr1 gene is incidental to the phenotype and that the mutation directly interrupts a cis-acting regulator of Shh. This regulator is most likely the target for generating PPD mutations in human.
