COL11A1
Collagen alpha-1(XI) chain precursor [COLL6]
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Fibrochondrogenesis is documented to be a neonatally lethal rare recessively inherited disorder characterized by short-limbed skeletal dysplasia. Here we report two patients from two unrelated consanguineous Emirati families who have unexpectedly survived till the ages of 3 and 6 years. These patients show additional symptoms which include developmental delay, profound sensory-neural deafness, severe myopia and progressive severe skeletal abnormalities. Linkage of fibrochondrogenesis in the Emirati families to chromosome 1 has been established using homozygosity mapping confirming recent findings by Tompson et al. in 2010. Screening of the COL11A1 gene revealed two null homozygous mutations [c.4084C>T (p.R1362X) and c.3708 437T>G] in the aforementioned two families. The c.4084C>T mutation is predicted to introduce a stop codon at position Arg1362, whereas the c.3708 437T>G mutation causes the activation of an intronic pseudoexon between exons 48 and 49. This resulted in the insertion of 50 nucleotides into the mRNA. The carriers of these mutations display ocular defects with normal hearing. In conclusion, our data shall improve the overall understanding of fibrochondrogenesis especially in surviving homozygous patients and, at least partly, explain the phenotypic variability associated with COL11A1 gene mutations.
MeSH Terms
- Child
- Child, Preschool
- Chondrodysplasia Punctata, Rhizomelic
- Chromosome Mapping
- Collagen Type XI
- Consanguinity
- Family
- Female
- Homozygote
- Humans
- Infant
- Infant, Newborn
- Life Expectancy
- Male
- Mutation
- Pedigree
- Phenotype
- United Arab Emirates
Skeletal tissues of mice with an inactivated allele of the Col2a1 gene for Type II collagen ("heterozygous knockout") were studied. To determine whether a heterozygous inactivation of the Col2a1 gene has a role in the etiology of spine disorders such as disc degeneration. Mutations in the COL2A1, COL11A1, COL11A2, and COL9A2 genes have been linked to spine disorders. However, the mechanism by which genetic factors lead to disc degeneration still are largely unknown. Spine tissues were studied using radiograph analyses; conventional, quantitative, and polarized light microscopy; immunohistochemistry for the major extracellular components, and in situ hybridization for procollagens alpha1(I) and alpha1(II). Voluntary running activity also was monitored in half of the mice. As the findings showed, 1-month-old heterozygous knockout mice had shorter limb bones, skulls, and spines, as well as thicker and more irregular vertebral endplates, which calcified earlier than in the control mice. They also had a lower concentration of glycosaminoglycans in the anulus fibrosus, in the endplates, and in the vertebral bone than the controls. These features in the heterozygous knockout mice were compensated by the age of 15 months. However, the long bones and skulls of the mature heterozygous mice remained shorter than those of the controls. Gene-deficient mice used the running wheel less. However, physical exercise did not induce any marked structural changes in the skeleton. Mice with heterozygous knockout of Col2a1 show subtle early skeletal manifestations that bear some resemblance to those of human spine disorders.
MeSH Terms
- Aging
- Alleles
- Animals
- Bone and Bones
- Collagen Type II
- Gene Silencing
- Glycosaminoglycans
- Heterozygote
- Intervertebral Disc
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Motor Activity
- Ossification, Heterotopic
- Radiography
- Reference Values
- Skull
- Spinal Diseases
- Spine
- Tissue Distribution