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unfolded collagen chains, perhaps increasing their ther-
mostability. Ishikawa
17
also tested for a chaperone effect
of FKBP65 on type I procollagen using several different
assays and showed a concentration-dependent effect on
fibril formation, establishing it as a type I collagen chap-
erone. It is a highly abundant protein in the ER and thus
could form multiprotein complexes with other proteins
involved in protein synthesis, particularly type I collagen
and elastin. However, to date no other specific partners
for FKBP65 have been identified.
region there were numerous genes including FKBP10
(65). Among these families, all affected individuals were
homozygous for an in-frame deletion in the
FKBP10
gene
(c.321_353del), predicted to result in deletion of 11 amino
acids (p.Met107_Leu117del). The phenotype for these
affected individuals is consistent with a severe progres-
sive form of OI. The patients presented with early onset
postnatal fractures, recurrent fractures, short stature and
progressive kyphoscoliosis. Radiographic abnormalities
include Wormian bones, severe osteoporosis, diaphy-
seal thinning and bending, fractures, wedge vertebrae,
scoliosis, gracile fibulae, acetabular protrusion and
radiography similar to severe progressing deforming OI
(
Figures 15.2 and 15.3
). Unlike individuals with severe
OI due to mutations in the genes that encode type I col-
lagen, these individuals have normal scelera, hearing
and dentition. In the Alanay et al. paper
18
another family
originating from Mexico was delineated with homozy-
gosity for a null mutation in
FKBP10.
These three siblings
presented in young childhood with recurrent fractures
and then progressive kyphoscoliosis. These affected indi-
viduals had limited mobility as adults.
Soon after the description of autosomal recessive
non-perinatal lethal OI due to mutations in
FKBP10
,
Shaheen et al. identified homozygosity for an 8 bp inser-
tion mutation in the
FKBP10
gene that had phenotypic
features consistent with Bruck syndrome, an autosomal
FKBP10
(GENE) AND OI
Employing five families with an autosomal recessive
form of OI originating from the north coast of Turkey,
Alanay et al.
18
localized an OI disease gene to a less than
one megabase region on chromosome 17q21. Previous
biochemical analysis on the affected patients showed
normal collagen electrophoresis. In each of these five
families, OI co-segregated with epidermolysis bullosa,
a rare autosomal recessive disorder of the skin. In these
five families, homozygosity for a nonsense mutation
in
Keratin 14
(
KRT14
) was identified. This suggested
that the gene producing OI was in linkage equilibrium
with
KRT14
and resided within the 1 Mb homozygous
region identified on chromosome 17q21. Within this
FIGURE 15.2
Radiographs from an affected individual with homozygosity for an
FKBP10
mutation: (A) Upper extremity showing bending,
bowing and thin cortex of the radius and ulna. (B) Humerus showing bowing, osteopenia and thin cortex. (C) Humerus showing more fractures
with healing and enlarged proximal metaphyses with irregularity.
