Fibrochondrogenesis results from mutations in the COL11A1 type XI collagen gene

Abstract

Fibrochondrogenesis is a severe, autosomal-recessive, short-limbed skeletal dysplasia. In a single case of fibrochondrogenesis, whole-genome SNP genotyping identified unknown ancestral consanguinity by detecting three autozygous regions. Because of the predominantly skeletal nature of the phenotype, the 389 genes localized to the autozygous intervals were prioritized for mutation analysis by correlation of their expression with known cartilage-selective genes via the UCLA Gene Expression Tool, UGET. The gene encoding the α1 chain of type XI collagen (COL11A1) was the only cartilage-selective gene among the three candidate intervals. Sequence analysis of COL11A1 in two genetically independent fibrochondrogenesis cases demonstrated that each was a compound heterozygote for a loss-of-function mutation on one allele and a mutation predicting substitution for a conserved triple-helical glycine residue on the other. The parents who were carriers of missense mutations had myopia. Early-onset hearing loss was noted in both parents who carried a loss-of-function allele, suggesting COL11A1 as a locus for mild, dominantly inherited hearing loss. These findings identify COL11A1 as a locus for fibrochondrogenesis and indicate that there might be phenotypic manifestations among carriers.

Figure 1

Radiographs of Fibrochondrogenesis Case R00-394 at 32 Weeks Gestation (A) Anterior-posterior view. (B) Lateral view. Note the short long bones with broad metaphyses, short ribs with metaphyseal cupping, and flat vertebral bodies with hypoplastic posterior and rounded anterior ends.

Figure 2

Histologic Analysis of Distal Femur Cartilage from Case R00-394 and Control (A and B) Light microscopy. Cartilage was decalcified, embedded in paraffin, and stained with von Kossa trichrome. The fibrochondrogenesis case (A, 32 weeks gestation) exhibits fibroblastic chondrocytes and a fibrous intercellular matrix not present in the 28-weeks-gestation control (B). Magnification is 40×. (C) Transmission electron microscopy showing frayed and irregular collagen fibrils.

Figure 3

Allele-Specific Expression Based on the c.3124G>A Missense Mutation in Case R00-394 On the left, the sequence trace of an amplified genomic DNA fragment containing the c.3124A missense mutation is shown. On the right, the sequence trace of an amplified cDNA fragment containing the same region is shown, demonstrating the absence of the c.3124G nucleotide derived from the c.1786dupG allele.

Figure 4

Clinical Photograph and Radiographs of Fibrochondrogenesis Cases from Family R06-573 (A) The surviving boy (R06-573C) at 19 months of age, presenting with a flat midface, small nose with anteverted nares, and a small bell-shaped thorax. (B) An anterior-posterior chest radiograph of the boy at 2 months of age shows short and wide ribs with metaphyseal cupping. (C) A lateral-view radiograph of the spine shows flat vertebral bodies. (D) An anterior-posterior radiograph of the femurs shows short long bones with broad metaphyses. (E) Anterior-posterior radiograph of the first affected fetus (R06-573A) in the family at 24 weeks gestation.