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developmental defects (autistic) or intrinsic brain abnor-
malities including cerebellar hypoplasia, pontine hypo-
plasia and hypoplasia of the mesencephalic tectum in one
individual. The Keupp report defined homozygous Wnt1
mutations in three individuals in two arms of a large con-
sanguineous Turkish family. The affected individuals had
short stature, early onset fractures, low bone mineral den-
sity and blue sclerae in some individuals. As noted above,
dental development and hearing were normal. Here, a
large homozygous 1 bp duplication c.859dupC in Wnt
was located in a large homozygous region in 12q13. The
parents were heterozygous for the mutation. This muta-
tion was predicted to lead to a frameshift and early ter-
mination of the C-terminal part of the protein leading
to a truncation of the C-terminal domain of the protein.
Expanding this information to other patients known not
to harbor recessive gene mutations led to the definition of
four additional mutations involving other consanguine-
ous families affected with OI.
The Keupp report included two individuals from a
four generation family with dominantly inherited osteo-
porosis and fractures in whom Wnt1 mutations were
also observed. This mutation was a heterozygous 703>T
variant changing arginine to tryptophan at position 235.
Interestingly, one father with the heterozygous c.858dupC
mutation, age 42 years, had early onset osteoporosis.
An important expansion of the association of Wnt1
with skeletal disease was reported by Laine et. al., who
identified a heterozygous missense mutation in WNT1,
[c.652 T→G (p.Cys218Gly)] in ten family members with
dominantly inherited, early-onset osteoporosis.
19
These
investigators also identified a homozygous nonsense
mutation (c.884C→A, p.Ser295) in a separate family with
two siblings affected by clinically severe recessive osteo-
genesis imperfecta.
In vitro
studies in C57MG cells with
the mutant WNT1 proteins showed significantly reduced
capacity to activate canonical WNT signaling compared
to wild-type WNT1.
References
[10]
[11]
[12]
[13]
[14]
SUMMARY
[15]
Interesting observations arise from these reports. These
phenotypes are recessively inherited. The Wnt1 mutations
are expressed as clinical phenotypes that vary in severity
ranging from moderate to progressively deforming dis-
ease similar to Sillence type III. Of interest is the observa-
tion that Wnt1 mutations are associated with so-called
“early onset osteoporosis.” At this time we cannot esti-
mate the prevalence of these mutations in the osteopo-
rotic/OI population. The expression of these genes with a
moderate to severe OI phenotype expands the numbers of
genes that should be examined as a diagnosis is sought.
[16]
[17]
[18]
[19]
