Myelomeningocele exomes with PCP genes disrupted
Closure of the developing neural tube occurs via a process of convergent
extension that is orchestrated by the PCP pathway (Nikolopoulou et al.,
2017). Any disruption of PCP has the potential to prevent proper neural
tube closure. When WNT ligand binds only the cell surface receptor
Frizzled (FZD), then DVL is recruited and the PCP branch of WNT
signaling is initiated (Fig 4). Our results reproduce and expand the
findings of several current human NTD studies that show damaging
variants in PCP genes play a role in the development of NTDs (Juriloff
& Harris, 2012).
DVL2 , a human homolog of the Dishevelled gene family, associated
with myelomeningocele in the EA population. Dvl2 is a Dvl family protein
essential in the PCP pathway (Henderson et al., 2018). Specifically,
Dvl2 is required for endocytosis of the activated Wnt receptor, Frizzled
(Yu et al., 2007). Frog knockouts for the DVL2 homologXdsh lack convergent extension and consequently display open
neural tubes (Wallingford & Harland, 2002). Similarly, mouse knockouts
for Dvl2 display a spina bifida phenotype (Hamblet et al., 2002).
Also, DVL2 is differentially expressed in the caudal neural tube
during neural tube closure (Krupp et al., 2012). Therefore, loss of
correct DVL2 function in some EA population subjects may cause
myelomeningocele by preventing convergent extension during neural tube
closure through disruption of PCP signaling.
PRICKLE2 on chromosome 3 associated with myelomeningocele in the
MA population. PRICKLE2 is one of the two vertebrate homologs of
the fruit fly’s Prickle (Katoh & Katoh, 2003). As summarized in
Y. Yang & Mlodzik, 2015, Prickle and Vangl help establish
PCP by directly antagonizing the formation of the
Frizzled/FZD-Disheveled/DVL complex (Y. Yang & Mlodzik, 2015). Because
this polarity is required for convergent extension, loss ofPRICKLE2 may prevent proper convergent extension and thus failure
of the neural tube to close. Another human myelomeningocele association
study revealed more potential single-nucleotide polymorphism
associations in PRICKLE2 than any other gene among three of the
four ethnicities evaluated; however, similar to our own findings, the
study failed to establish any strong associations to myelomeningocele in
PCP genes (Wen et al., 2010). Similarly, a targeted sequencing study of
ninety human cranial NTD cases reported a discovery of likely damaging
rare variants in PRICKLE2 as well (Ishida et al., 2018).
CDH2 , which codes for a cadherin cell adhesion protein,
associated with myelomeningocele in the MA population. Other cadherin
genes such as CELSR1 are expressed diversely in the developing
neural tube (Paulson, Prasad, Thuringer, & Manzerra, 2014). Also,
mutations in cell adhesion protein genes such as Celsr1 ,EphrinA5 , and EphA7 cause NTD phenotypes in mice (Curtin
et al., 2003; Holmberg, Clarke, & Frisen, 2000). Moreover, CDH2itself is already implicated in the cause of NTDs because homozygous
mouse knockouts for the homolog Cdh2 displayed a wavy neural tube
phenotype (Radice et al., 1997).
The gene FUZ on chromosome 19, whose mouse homolog Fuz is
a PCP effector protein required for ciliogenesis by transporting DVL to
the cilium (Dai et al., 2011; Gray et al., 2009; Heydeck et al., 2009),
is also associated with myelomeningocele in the MA population. Five of
the eight MA subjects with qualifying variants in FUZ possessed
the variant NC_000019.9:g.50315872C>T p.(Ser78Asn), a
variant which was 21 times more frequent in the MA cases than the
matched gnomAD exome controls. Murdoch and Copp reviewed the complex
relationship between cilia and NTDs (Murdoch & Copp, 2010). Similar to
the cilia proteins associated with exencephaly, perhaps FUZ’s transport
of DVL to the cilium can also influence neural tube closure in
myelomeningocele subjects. Indeed, mice with homozygous loss ofFuz expression display NTD phenotypes such as exencephaly before
dying in utero (Gray et al., 2009; Heydeck et al., 2009). Also,
multiple human myelomeningocele subjects possessed nonsynonymous
mutations in FUZ that were not found in control subjects, and
these human variants revealed impaired cilia formation when tested in
mouse cell lines (Seo et al., 2011).