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Saudi Arabia and the southern Israeli Bedouin popula-
tion. Abu-Rabia points out that the ancestors of most
of the Bedouins in southern Israel had migrated from
the Arabian Peninsula around 700 AC probably carry-
ing the founder mutation. The Bedouin had three main
reasons for migration: searching for grass and water for
themselves and their livestock, avoiding blood revenge
and the expansion of Islam in the 7th century. 7,8
Shaheen et  al. identified a homozygous truncating
mutation in the TMEM38B gene in 27 affected members of
two simple and 11 multiplex families from Saudi Arabia.
In the initial evaluation of these individuals, analysis for
COL1A1 and COL1A2 genes were negative. Subsequent
additional analysis for autosomal recessive genes in this
cohort surfaced mutations involving SERPINF1, CRTAP,
LEPRE1 and FKBP10 in individual families. Two fami-
lies had evidence of gonadal mosaicism for COL1A1 and
COL1A2. In three families a novel locus was identified
by SNP analysis involving 9q31.1-31-3. Exome sequenc-
ing identified complete loss of exon 4 of TMEM38B which
predicted early truncation of the protein. 6
The phenotype in these families included: generalized
osteopenia, thin calvarial cortex with thickening of the
occiput, normal shape and height of vertebrae, and bow-
ing of the upper and lower extremities.
Volodarsky et  al. reported autosomal recessive OI in
three unrelated Israeli Bedouin families. Homozygous
21 kb deletion led to an early stop codon which caused
deletion of exon 4 leading to the synthesis of a truncated
protein. This led to loss of one-third of the intracellular
cation receptor domain as well as two of four transmem-
brane domains. A four-fold decrease in RNA levels of the
residual transcript was found. 8
These individuals presented with a clinical phenotype
consistent with Sillence type IV OI, that is, moderately
severe disease. The phenotype in these three families
included: fractures present in infancy, Wormian bones,
thin ribs, normal vertebral height but bowing of the
femurs and tibias.
The relationship of mutations affecting the TRIC-B
channel and its subsidiary pathways to defective osteo-
blast function remains to be defined. Also, the mechanism
underlying the expression of this particular phenotype
(e.g., moderately severe OI-like bone disease) also
remains to be explained.
collagen synthetic pathway. Mutations in osterix/Sp7,
which have been reported in Egyptian children with
types III/IV OI, are discussed in Chapter 18. 11
The Wnt family includes 19 secreted glycoproteins
which act as signaling molecules that regulate multi-
ple processes affecting cellular development and tissue
homeostasis in the adult. 12 In addition to activating por-
tions of the β-catenin pathway, Wnt proteins participate
in other metabolic pathways. Proteins of the Wnt family
function as signals in cell-to-cell communication and as
morphogens in a variety of tissues. 13 The secretion of Wnt
proteins is in turn regulated by the seven member trans-
membrane protein Wntless. In the absence of Wntless,
Wnt proteins are sequestered in the secretory pathway of
Wnt-producing cells and fail to reach the plasma mem-
brane, resulting in Wnt loss-of-function phenotypes. 14
Wnt1 interacts with frizzled (Frz) receptors on osteoblasts
which leads to stabilization of β-catenin and subsequent
transcriptional regulation of osteoblast differentiation
and function. Wnt1 also interacts with the LRP5 core-
ceptor leading to the phosphorylation and stabilization
of B-catenin permitting its interaction with downstream
elements. 15
Three recent reports have defined inactivating muta-
tions in the WNT1 gene in association with recessive
inheritance and with variable expression of the OI phe-
notype. Although the majority of reported cases express
a moderately severe and recessively inherited OI pheno-
type, both mild OI phenotypes and dominant inheritance
have been reported with WNT1 mutations.
In February, 2013, Fatiminiya et  al. reported WNT1
mutations in four children from three families. 16 These
involved a missense mutation in two siblings from one
consanguineous family, a homozygous frameshift muta-
tion in a child from a second family and a compound
heterozygous mutation (frameshift and missense muta-
tions) in a child from the third family. The phenotype
was that of moderately severe OI with short stature, mul-
tiple long bone fractures during infancy and multiple
vertebral compression fractures.
Shortly thereafter, several mutations in the Wnt1 gene
were reported by two groups, Pyott et  al. and Keupp
et al. 17,18
Pyott reported four families in which recessive inheri-
tance was associated with the expression of severe, pro-
gressive OI, typical of Sillence type III disease in seven
children. Multiple fractures including vertebral frac-
tures were reported for each of the affected children.
Dentinogenesis imperfecta was not observed, hearing
was apparently intact in younger individuals, scoliosis
was present, and there were long bone deformities due
to fractures and bowing. There was variable expression
of blue sclerae; both blue and white scleral hues were
observed in these affected individuals. Notable in this
group of patients was the associated occurrence of either
W NT1 MUTATIONS AND O I
The Wnt LRP5/β-catenin signaling pathway plays an
essential role in the regulation of osteoblast progenitor
proliferation, osteoblast differentiation and survival. 9,10
Osterix, a component of the Wnt pathway, is an osteo-
blast-specific transcription factor which is essential for
normal bone formation. Osterix/Sp7 is not in the type I
 
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