title: Dominant and recessive forms of fibrochondrogenesis resulting from mutations at a second locus, COL11A2.
abstract: Fibrochondrogenesis is a severe, recessively inherited skeletal dysplasia shown to result from mutations in the gene encoding the proα1(XI) chain of type XI collagen, COL11A1. The first of two cases reported here was the affected offspring of first cousins and sequence analysis excluded mutations in COL11A1. Consequently, whole-genome SNP genotyping was performed to identify blocks of homozygosity, identical-by-descent, wherein the disease locus would reside. COL11A1 was not within a region of homozygosity, further excluding it as the disease locus, but the gene encoding the proα2(XI) chain of type XI collagen, COL11A2, was located within a large region of homozygosity. Sequence analysis identified homozygosity for a splice donor mutation in intron 18. Exon trapping demonstrated that the mutation resulted in skipping of exon 18 and predicted deletion of 18 amino acids from the triple helical domain of the protein. In the second case, heterozygosity for a de novo 9 bp deletion in exon 40 of COL11A2 was identified, indicating that there are autosomal dominant forms of fibrochondrogenesis. These findings thus demonstrate that fibrochondrogenesis can result from either recessively or dominantly inherited mutations in COL11A2.
authors.affiliation: Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, California, USA.
authors.forename: Stuart W
authors.initials: SW
authors.lastname: Tompson
authors.forename: Eissa Ali
authors.initials: EA
authors.lastname: Faqeih
authors.forename: Leena
authors.initials: L
authors.lastname: Ala-Kokko
authors.forename: Jacqueline T
authors.initials: JT
authors.lastname: Hecht
authors.forename: Rika
authors.initials: R
authors.lastname: Miki
authors.forename: Tara
authors.initials: T
authors.lastname: Funari
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Funari
authors.forename: Lisette
authors.initials: L
authors.lastname: Nevarez
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Cohn
mesh_terms: D024161:Collagen Type XI / Q000235:genetics*; D004392:Dwarfism / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D005091:Exons; D005799:Genes, Dominant; D005808:Genes, Recessive; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D007438:Introns; D010009:Osteochondrodysplasias / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: C499319:COL11A2 protein, human; D024161:Collagen Type XI; D022821:RNA Splice Sites