ER-resident proteins must be distinguished from newly synthesized secretory proteins, which pass through this compartment as they transit the secretory pathway toward the extracellular space. One of the mechanisms by which this is achieved is the selective retrograde transport of soluble ER-resident proteins from the cis-Golgi to the ER 
. Receptors in post-ER compartments recognize a C-terminal motif that marks proteins that are to be retained in the ER. The KDEL motif binds to this salvaging receptor (KDEL receptor) in the Golgi, resulting in this ligand-receptor complex being returned to the ER 
. Soluble ER-resident proteins such as molecular chaperones and components of the control quality machinery, e.g. immunoglobulin heavy-chain binding protein, calreticulin, and protein disulfide isomerase, contain the KDEL motif at the carboxyl terminus. P3H1, encoded by LEPRE1
, forms a molecular complex with CRTAP and CypB in the ER, and provides the enzymatic activity of the complex. P3H1 is the only component of the complex with a KDEL ER-retrieval sequence at the carboxyl terminus 
. One splice mutation, c.2055+18G>A, which abolishes the LEPRE1
mRNA splice form of KDEL, has previously been reported 
. This splice mutation results in preferential use of alternative splice donor site, and a significant decrease in the LEPRE1
mRNA splice form containing the KDEL sequence. However, this finding does not provide direct evidence for the importance of the KDEL sequence. The case presented here is therefore the first report of a mutation in LEPRE1
that eliminates only the KDEL ER-retrieval sequence, while all other functional domains remain intact. Without the KDEL ER- retrieval sequence, the c.2155dupC variant will not captured by KDEL receptor in the Golgi. Our report shows, for the first time, that the KDEL ER- retrieval sequence is essential for P3H1 functionality in vivo
. Dysfunction of this KDEL-KDEL receptor interaction will provide us one disease causing mechanism of OI as well as other diseases involved in ER enzyme.
It is noteworthy that our proband’s collagen contained higher percentage (85%) of 3-hydroxylated Pro986 residues than previously reported with LEPRE1
null mutations, which showed severely reduced (0–15%) 3-hydroxylation of Pro986 
. We could not detect mutant P3H1 in the proband cells by western blotting assay or fluorescent microscopy. However, we hypothesize that the P3H1/CRTAP/CyPB complex that includes the mutant P3H1 without KDEL must be transiently present in the ER at some minimal level, which is sufficient for 3-hydroxylating most α1(I) Pro986 residues. Recently, it was reported that the P3H1/CRTAP/CyPB complex has 3 distinct activities: it is a prolyl 3-hydroxylase, a PPIase, and a molecular chaperone 
. In the present patient, despite the higher percentage of 3-hydroxylated Pro986 residues, overmodification of the patient’s type I collagen was observed electrophoretically. This observation implicates the dysfunctional P3H1/CRTAP/CyPB complex in the pathology, with potential roles for absence of its chaperone or PPIase functions. However, since our proband has generally milder OI than described for null LEPRE1
mutations, the OI severity may correlate with the level of type I collagen P986 3-hydroxylation.
In conclusion, our study shows, for the first time, that the KDEL ER- retrieval sequence is important for P3H1 functionality in vivo. In addition, the higher percentage of 3-hydroxylated P986 residues seen in the collagen of our patient correlates with her moderate phenotype, in contrast to the severe/lethal OI of probands with null LEPRE1 mutations and minimal collagen 3-hydroxylation.