The first fibrochondrogenesis case, R09-068A, resulted from homozygosity for a COL11A2
splice donor mutation that led to skipping of exon 18. Since homozygosity for null mutations in COL11A2
is associated with otospondylomegaepiphyseal dysplasia (OSMED, OMIM 215150), a non-lethal skeletal dysplasia with much less severe skeletal abnormalities [Melkoniemi et al., 2000
; Temtamy et al., 2006
], we infer that the mutation is not a null allele and that the presence of abnormal chains had a detrimental effect on type XI collagen function. This inference is further supported by the observation that mice deficient for proα2(XI) have skeletal manifestations that markedly resemble OSMED and not fibrochondrogenesis [Li et al., 2001
]. For the exon skipping mutation, transcripts lacking the 54 bp exon are predicted to encode proα2(XI) chains harboring an 18 amino acid deletion at position 556-573 (NP_542411.2), toward the amino-terminal end of the triple helical domain. The carrier parents were phenotypically normal, without abnormalities in either hearing or vision, indicating that heterozygosity for the defect is tolerated. This is in contrast to two fibrochondrogenesis carriers heterozygous for substitutions of two different triple helical glycine residues in COL11A1
, in which mild short stature and myopia were observed [Tompson et al., 2010
The second case studied, R10-691A, was heterozygous for a COL11A2
mutation that predicted a more distal 3 amino acid deletion within the triple helical domain of the proα2(XI) chain, corresponding to amino acids 967-969 (NP_542411.2). No other mutations were identified in COL11A2,
and mutations were not found in either COL11A1
. The mutation was not present in the parental DNA and parentage was confirmed by microsatellite analysis, proving that the mutation was de novo
. These data thus indicate that there is an autosomal dominant form of fibrochondrogenesis. Furthermore, there is precedent for mutations in COL11A2
producing both dominant and recessive forms of the same disorder, with reported cases of dominant and recessive forms of OSMED [Pihlajamaa et al., 1998
; Temtamy et al., 2006
] as well as nonsyndromic hearing loss [McGuirt et al., 1999
; Chen et al., 2005
We cannot exclude the theoretical possibility of digenic inheritance with the de novo COL11A2
mutation inherited with a second mutation from a carrier parent. However, the possibility of compound COL11A1
mutant genotypes has been excluded by sequence analysis. Furthermore, both parents were of normal height and had normal vision and hearing, so the possible second mutation would have to be of no phenotypic consequence. While there are rare examples in the literature for new mutations in recessive disorders, where the affected individuals have inherited a point mutation carried by one parent in addition to a new mutation (Cremonesi et al., 1996
), these have typically been observed for disorders in which the carrier frequency is high. Fibrochondrogenesis is a very rare disorder, perhaps less than 1 in 1,000,000 births in outbred populations, which would imply a carrier frequency of 1 in 500. Consequently, it is more likely that this case resulted solely from the new mutation in COL11A2
, consistent with the conclusion that there are autosomal dominant forms of the disease.
Several dominantly inherited type XI collagenopathies have been reported to result from incorporation of molecules containing abnormal proα2(XI) chains into fibrils. Autosomal dominant forms of OSMED (OMIM 277610) can result from substitution for a triple helical glycine residue [Pihlajamaa et al., 1998
]. In-frame triplet-repeat deletions of 18 amino acids in two cases and 9 amino acids in a third have been described for non-ocular Stickler syndrome (MIM 184840) [Vikkula et al., 1995
; Sirko-Osadsa et al., 1998
; Vuoristo et al., 2004
]. Finally, nonsyndromic hearing loss (OMIM 601868) caused by cysteine for arginine or glutamate for glycine amino acid substitutions within the triple helical domain have been identified in two independent families [McGuirt et al., 1999
]. Thus mutations that lead to the synthesis of abnormal proα2(XI) chains can result in a spectrum of dominantly inherited phenotypes ranging in severity from hearing loss to perinatal lethal fibrochondrogenesis, likely reflecting the nature and location of the molecular defect.
The newborn radiographic phenotype of fibrochondrogenesis, consisting of shortened long bones with metaphyseal flaring leading to a dumbbell-shaped appearance, along with platyspondyly and epiphyseal abnormalities, bears some similarity to the phenotypes of OSMED and Kniest dysplasia (). This similarity is evident in case R10-691A in which, despite perinatal lethality, there was a milder radiographic appearance. In particular, there was less pronounced metaphyseal widening and irregularity of the long bones, reduced anterior cupping of the ribs and a lack of caudally protruding spurs from the basilar portion of the ilia as compared with some fibrochondrogenesis cases, including the recessive case presented here. However, the dominant case exhibited the characteristic clinical findings of fibrochondrogenesis, especially the typical craniofacial abnormalities, distinguishing it from the other, related disorders.
OSMED can result from homozygosity for null mutations in COL11A2
[Temtamy et al., 2006
], heterozygosity for missense mutations in COL11A2
[Pihlajamaa et al., 1998
] or heterozygosity for an in-frame deletion in the triple helical domain of the COL2A1
product [Miyamoto et al., 2005
]. Kniest dysplasia has been shown to result from heterozygosity for mutations in COL2A1
[Winterpacht et al., 1993
]. These genotypic differences distinguish the fibrochondrogenesis cases studied here from the other phenotypes in this spectrum of disease, and provide insight into the effect of discrete mutations and molecular mechanisms that alter the function of the main structural component of cartilage, the type II/XI collagen heterotypic fibril. The phenotypic similarities among these disorders likely arise from the contribution of the gene products affected in all three disorders to the cartilage collagen fibril.
This study has identified COL11A2 as a second locus for fibrochondrogenesis, has indicated that synthesis of structurally abnormal proα2(XI) collagen molecules can produce fibrochondrogenesis, and has extended the spectrum of severity among the type XI collagenopathies resulting from COL11A2 mutations. The data further demonstrate that there are dominant forms of fibrochondrogenesis, and this finding must now be taken into account when counseling families in that recurrence risk will need to consider the possibility of parental germline mosaicism for dominant mutations. Analysis of additional cases will help determine the relative frequencies of mutations in COL11A1 and COL11A2 in fibrochondrogenesis as well as the proportion of cases with dominant and recessive inheritance.