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than that of the Bmp1 knockout cells. PICP processing was
nearly undetectable in double knockout Bmp1 −/− ;Tll1 −/−
fibroblasts and thus Tll1 is the protein designated to be
accountable for the remaining PICP activity of Bmp1 −/−
MEFs. Bmp1 −/− ;Tll1 −/− mice are embryonic lethal owing to
cardiac failure and so evaluation of skeletal abnormalities
in this genotype was not achieved. 32 A possible explana-
tion for the human/mouse phenotypic differences could
be a more essential role for BMP1 in protein processing
in the human skeletal system than in mice, or in other
words TLD-like proteases could compensate less in the
human skeleton. It is also possible that the process of col-
lagen fibril assembly in mice is more resilient to the pres-
ence of unprocessed type I procollagen molecules. There
is, however, one phenotypic aspect in common between
Bmp1 knockout mice and the human phenotype. Bmp1 −/−
mice were reported with consistent herniation of the gut
and both the proband and her affected brother have large
umbilical hernias with intestinal content. It was suggested
that this mouse phenotype could be due to lack of tensile
strength in the ventral body wall secondary to abnormal
collagen fibril formation. 29 Additionally, since BMP1 is
involved in processing dorso-ventral patterning factors
such as chordin, this could also play a role in this particu-
lar phenotypic feature. 23,33 Bmp1 could potentially affect
the ossification process through proteolytic cleavage pro-
cesses involving a number of targets. Among these, its
ability to cleave and inactivate the BMP2/4 inhibitor chor-
din is well documented and has the potential to affect the
ossification process. 28
Asharani et  al. characterized a zebrafish bone mutant
harboring lesions in Bmp1a , demonstrating conserva-
tion of BMP1 function in osteogenesis across species. 28
Genetic, biochemical and histological analyses of this
mutant revealed that Bmp1a is critically required for
mature collagen generation, downstream of osteoblast
maturation, in bone. The authors supported our previ-
ous findings on the role, molecular and cellular bases of
BMP1-dependent osteogenesis and reinforce the impor-
tance of this protein for bone formation and stability. 28,29
FIGURE 19.5 (A) X-ray of the spine of the proband showing
S-curve scoliosis of thoracic and lumbar spine and platyspondyly.
(B) X-ray of the left leg of the proband showing serpentine bowing
and osteoporosis of tibia and fibula. (C) X-ray of the right humerus
showing healed fractures, angulations and lack of bone modeling in
the proband. (D) X-ray of the pelvis and both femora of patient II-6
showing multiple healed fractures, with bowing and lack of bone
modeling (modified from reference 29 ).
COMPARISON OF FINDINGS IN
MUTATED PATIENTS AND
TRANSGENIC ANIMALS
The phenotype resulting from diminished function
of BMP1 in humans diverges from that of Bmp1 −/− mice.
Bmp1 homozygous knockout mice are perinatal lethal
but do not show gross skeletal abnormalities except for
reduced ossification of some skull bones. In contrast, in
one of our patients ( Figures 19.3-19.5 ) we detected fem-
oral bowing during intrauterine examination and bone
fractures were noted at birth in both patients. C-terminal
processing of type I procollagen secreted into the media
by Bmp1 −/− mouse embryonic fibroblasts (MEFs) was
reduced; nevertheless these cells were still producing
fully processed type I collagen chains. 32 We also detected
residual PICP-protease activity in the fibroblasts from
our patients, but further experiments comparing human
and mouse cells under the same methodology are nec-
essary to understand whether the remaining PICP-
protease activity in mutant human fibroblasts is lower
FINAL COMMENTS
BMP1 expands the growing number of genes
involved in AR-OI and demonstrates the high genetic
complexity characteristic of disorders of the collagen
I pathway. So far there are at least two different groups
that have described patients with this form of the dis-
ease, supporting the notion that probably more patients
are going to be described in the near future. The initial
suggestion that patients with mutations in the signal
peptide may show increased bone mineral density and
those with mutations in other parts of the protein tend to
show osteopenia 28 might not always be so exact. Current
 
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