Biomedical Engineering Reference
In-Depth Information
Importantly,
VANGL1
mutations have been identified in a cohort of 144
patients with sporadic (M328T) and familial (V239I, R274Q) NTDs (spina
bifida), including a
de novo
mutation (V239I) in a familial setting (
Kibar et al.,
2007
). Independently, mutations in human
VANGL2
(S84F, R353C,
F437S) were recently identified in stillborn fetuses with anencephaly and
holoprosencephaly (
Lei et al., 2010
). Functional studies in model organisms
have established that VANGL1 variants V239I and M328T and VANGL2
variant F347S are functionally inactive (
Kibar et al., 2007; Lei et al., 2010;
Reynolds et al., 2010
). These findings confirm that mutations in
VANGL1
and
VANGL2
cause NTDs in human and mice. Screening of a larger cohort
of 673 nonsyndromic sporadic cases of NTDs (cranial, open and closed spinal
dysraphisms) in patients of various ethnic origins identified additional
independent patient-specific
VANGL1
(S83L, F153S, R181Q, L202F,
R274Q, and A404S) (
Kibar et al., 2009
)and
VANGL2
(S88F, R135W,
R177H, V178I, L242V, T247M, R270H, and R482H) (
Kibar et al., 2011
)
mutations. In these studies, putative pathogenic mutations were identified
on the basis of (a) absence of the variant in ethnically matched controls, (b)
evolutionary conservation of the residue affected, and (c) nonconservative
nature of the variant. Of notable interest are Arginine at positions R181 and
R274 (VANGL1 numbering) which were found independently mutated to
Histidine (H-VANGL2
R177H
) or Glutamine (Q-VANGL1
R181Q
)forR181
and mutated to H (VANGL2
R270H
)orQ(VANGL1
R274Q
)forR274in
unrelated patients, suggesting a critical role for these two invariant Arginine
residues in the function of Vangl proteins. As of today, a total of 22 naturally
occurring VANGL protein variants associated with clinical cases of NTDs in
humans have been discovered (
Fig. 10.3
).
2. VANGL PROTEINS, PLANAR CELL POLARITY, AND
TISSUE PATTERNING
Vangl proteins are highly conserved in evolution with relatives found
in flies (
Vangl/Stbm
), fish (
trilobite/Vangl2
), and frogs (
Xstbm
)(
Darken et al.,
2002; Jessen et al., 2002; Taylor, Abramova, Charlton, & Adler, 1998; Wolff
& Rubin, 1998
). The study of these relatives in model organisms has shed
considerable light on the function and molecular mechanism of action of
mammalian Vangl proteins during development. In flies, mutations in the
Vang
(
Van Gogh
)
/Stbm
(
Strabismus
) gene were initially identified as
impairing the planar polarization of several epithelial structures (
Gubb &
Garcia-Bellido, 1982
). In flies, the PCP axis of polarity is visible in the
