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et al. 39 that noted decreased cortical thickness in a patient
with an FKBP10 mutation, though the phenotype is more
consistent with OI than BS. Therefore, phenotype/geno-
type correlations in FKBP10 mutations have not been
possible. In a patient presenting with OI and joint con-
tractures both FKBP10 and PLOD2 should be considered
likely candidates. Further complicating the spectrum of
disease due to mutations in FKBP10 , Bale et  al. 40 identi-
ied homozygosity for FKBP10 mutations in Kuskokwim
disease, a skeletal disorder found in Eskimos character-
ized by multiple joint contractures predominantly affect-
ing the knees and ankles, with atrophy or compensatory
hypertrophy of associated muscle groups. 41
significant short stature. The patients have fragile bones,
normal sclerae, no dentinogenesis imperfecta, no hear-
ing loss and normal intelligence. Radiographic features
include Wormian bones in the skull, generalized osteo-
penia, bowing, bending and fractures of the long bones
and osteopenia/platyspondyly of the vertebral bodies.
They typically present with talipes equinous. As noted
in patients with FKBP10 mutations, several studies have
demonstrated no abnormality in the biosynthesis of
type I collagen.
Bank et  al. 36 showed a specific defect underlying
Bruck syndrome resultant from deficiency of a bone-
specific telopeptide lysyl hydroxylase producing aber-
rant crosslinking of bone collagen. They found that in
bone, lysine residues within the telopeptides, but not
helix of type I collagen, were underhydroxylated, lead-
ing to aberrant crosslinking in BS. In their studies, one
large family showed linkage to chromosome 17p12 and
was designated BS type I (BS1), while two BS families
showed linkage to chromosome 3 (BS2). 36 In the latter
two families, mutations were identified in the PLOD2
(lysyl hydroxylase, LH2), which encodes for one isoform
of lysyl hydroxylase, which catalyzes the hydroxylation
of lysine residues. 37 The PLOD2 gene contains 20 exons
and has high homology to PLOD1 and PLOD3 . It has dif-
ferent splice variants; one variant is found in fetal kidney
and pancreas (LH2a) while a longer variant is found in
skin fibroblasts (LH2b). Missense mutations have been
identified in both the short and long form of the mol-
ecule. Interestingly, Puig-Hervas et  al. 38 identified two
families that had homozygosity for a mutation that is
predicted only to affect the long form of LH2, suggesting
that loss of the long form alone produces BS.
FKBP A ND COLLAGEN CROSSLIN KING
In the extracellular matrix, collagen fibrils are stabi-
lized by intermolecular covalent bonds, referred to as
molecular crosslinks. Multiple different crosslinks are
known and the location and number of the crosslinks can
frequently be tissue specific.42-45 42-45
In collagen, lysine (Lys) is the main amino acid residue
involved in crosslinking. The lysyl hydroxylases (LH1,
LH2 and LH3) are the main enzymes responsible for
hydroxylation (adding an -OH group) to lysine within
the helix and amino- and carboxyterminal telopeptide of
type I collagen. Once this occurs, the hydroxylysine (Hyl)
residues in the telopeptide are converted to the aldehyde
hydroxyallysines (Hylald) that are capable of reacting
with a Lys or Hyl residue of the triple helix to form di-,
tri- or tetra-functional crosslinks. 37,46 These mature cross-
links (pyridinolines) are made from either one Hyl and
one Lys residue (lysylpyridinoline crosslinks; LP) or from
two hydroxylysine residues (hydroxylysylpyridinoline
crosslinks; HP), and are found in connective tissues
(bone, tendon and cartilage). 42
In BS loss of PLOD2 (LH2) leads to under-
hydroxylation of lysine residues within the telopep-
tide of type I collagen producing aberrant crosslink-
ing. Indistinguishable phenotypic overlap between BS
patients harboring PLOD2 or FKBP10 mutations begged
the question of whether abnormal crosslinking of the
telopeptide lysines contributed to the underlying biol-
ogy due to FKBP10 mutations. Two important papers
showed that it did. In Schwarze et  al. 24 the authors
showed that bone derived from an affected individual
had decreased amounts of mature crosslinks in the
telopeptide, but not the helix. Barnes et  al. 39 also dem-
onstrated that secreted collagen from an affected indi-
vidual also had under-hydroxylated telopeptide lysines.
However, the mechanism by which this occurs is not
understood. Clearly, mutations in FKBP lead to both
OI and BS by a contribution of diminished telopep-
tide crosslinking. Yet how FKBP65 influences LH2 is
FKBP1 0 AND BRUCK SYNDROM E (BS)
After the identification of FKBP10 as an OI gene,
Shaheen et  al. reported two brothers with Bruck syn-
drome who mapped to chromosome 17q21 and identified
homozygosity for mutations in FKBP10 . 19 This suggested
that perhaps the original mapping data that localized
BS1 to chromosome 17p12 was incorrect. Subsequently
numerous reports have demonstrated that mutations
in FKBP10 produce Bruck syndrome. One of the origi-
nally described Bruck syndrome patients was shown to
have mutations in FKBP10 as well as a BS1 patient from
the original mapping paper. 20,24 Clinically and radio-
graphically, patients with Bruck syndrome due to muta-
tions in either FKBP10 or PLOD2 are indistinguishable.
Interestingly, patients reported on by Schwarze et  al. 24
that had normal or increased cortical width and normal
bone density suggested that low bone mass was not the
only factor contributing to the fractures. Further compli-
cating the phenotypic diversity is the report by Barnes
 
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