Total deficiency of collagen proα chains is rare. Complete deficiency of proα1(I) chains appears to be incompatible with life.15
In this report we describe a boy with clinical features reminiscent of mild hypermobility EDS due to a defect in the production of the proα2(I) collagen chains. To date there are only few reports of patients with total α2(I) collagen deficiency, who show markedly different phenotypes (table 1).
Table 1Clinical and molecular findings in reported index patients with total absence of proα2(I) collagen chains
The original patient reported by Nicholls et al
was a 5 year old boy with severe, progressively deforming OI (OI type III) with multiple fractures, skeletal deformities, and popcorn deformity of the epiphyses.6
A homozygous four‐nucleotide frameshift deletion within the carboxy‐terminal propeptide of proα2(I) collagen was identified.8
This mutation prevented incorporation of proα2(I) chains into the normal type I procollagen molecules and resulted in the production of proα1(I) collagen homotrimers.7
No cardiac abnormalities were reported in the index patient. The development of valvular disease later on can, however, not be excluded, since there is no follow‐up report of this patient when he was older.
Subsequently, two Japanese patients were reported with total α2(I) collagen deficiency, both presenting EDS‐like features, including joint hypermobility, hyperextensibility of the skin, and abnormal wound healing.9,10
The first of these patients also suffered from severe aortic regurgitation, necessitating aortic valve replacement in adulthood,9
while the second patient had mitral valve regurgitation.10
In 2001 Nicholls et al
reported a total absence of α2(I) collagen chains in a girl with phenotypic manifestations of both OI, including blue sclerae and slightly increased bone fragility, and EDS, including generalised joint laxity, patellar dislocations, and pedes plano valgi with secondary shortening of the Achilles tendon. Her skin was normal. No cardiovascular anomalies were observed at the age of 9 years. A homozygous splice site mutation in IVS 46 led to the introduction of a PTC.11
Finally, three adult patients with complete α2(I) collagen chain deficiency were reported, all showing features of classic EDS, including hyperextensible skin, hypermobile joints, abnormal wound healing with atrophic scarring, and/or easy bruising. The brother of patient 3 presented more subtle EDS signs, with hypermobility of small joints and soft skin. All three patients developed valvular heart disease in adulthood, involving either the aortic or mitral valve, or both, and necessitating valve replacement surgery. In these patients, homozygous nonsense mutations or compound heterozygous splice site mutations that lead to COL1A2
mRNA instability were identified.12
Because of the severe cardiac valve problems in most adult patients with α2(I) chain deficiency, this phenotype was called the “cardiac valvular form of EDS” by Schwarze et al
Since the patient described here already shows some signs of mitral valve bulging at the age of 6 years, continued cardiac follow up with echocardiography will be necessary.
The difference in clinical phenotype in patients with total lack of α2(I) collagen chains is remarkable, ranging from a very severe OI phenotype with multiple fractures and deformities of the long bones, to a much milder, EDS‐like phenotype, albeit with potentially serious cardiac problems in adulthood. It is well established that, in eukaryotic cells, mRNAs containing a PTC are rapidly degraded by a process called nonsense mediated RNA decay (NMD). Thus, potentially deleterious truncated proteins are not expressed at high levels. Indeed, in the patients with total α2(I) collagen chain deficiency who presented an EDS phenotype, COL1A2
mRNA was shown to be markedly decreased. In vertebrates, it has been shown that PTCs located in the last coding exon do not lead to NMD.16
Hence the stable but mutant mRNA is translated into abnormal protein chains. This may explain the severe phenotypic consequences in the OI patient with the 4 bp deletion located in the last exon of the COL1A2
gene. Indeed, it was shown that the patient's fibroblasts produced structurally abnormal proα2(I) chains, which were not incorporated into procollagen molecules.7
Probably these mutant proteins, although not participating in collagen trimerisation, accumulate intracellularly and exert a deleterious effect on the normal fraction of collagen chains.
In conclusion, in the majority of cases, the underlying COL1A2 mutations result in NMD and a loss of function effect. The phenotypic consequences are those of a form of EDS, with hypermobility in childhood and complicated by cardiac valve disease in adulthood. On the other hand, COL1A2 mutations which do not result in NMD produce a gain of function effect with the production of abnormal collagen type I chains that disturb interaction with the normal collagen chains and lead to a severe OI phenotype.
We show that the autosomal recessive cardiac valvular form of EDS can overlap with a mild EDS hypermobility type during childhood, while the cardiac valvular phenotype may evolve during adulthood. EDS hypermobility type is usually an autosomal dominant disorder, mainly characterised by joint hypermobility and joint dislocations, but usually without major cardiac valvular problems, although mitral valve prolapse and aortic root dilation may be more common than in the general population.2,17
Apart from the association with tenascin‐X haploinsufficiency in a small subset of patients with autosomal dominant hypermobile EDS,18
the underlying defect of this subtype is largely unknown.
Biochemical SDS‐PAGE analysis of collagen extracted from skin fibroblasts can show the absence of proα2(I) collagen chains in patients with cardiac valvular EDS. In this subset of patients, careful clinical and echocardiographic follow up throughout adulthood is mandatory.