Myelomeningocele exomes with WNT trafficking genes disrupted
Disrupting the process of WNT synthesis or secretion has the potential
to directly and indirectly inhibit one or more of the three downstream
WNT signaling pathways. WNT ligands are expressed, processed, and
secreted into extracellular space before finding their target cell
membrane, where they can bind several cell surface receptors (Angers &
Moon, 2009) (Fig 3).
In the Hispanic mutational burden comparison, the X chromosome genePORCN associated with risk for myelomeningocele. PORCN is
necessary for the post-translational modification of the WNT3A ligand.PORCN belongs to an evolutionarily conserved gene family termed
“Porcupine,” whose members code for Wnt processing proteins across
species (Caricasole, Ferraro, Rimland, & Terstappen, 2002; Tanaka,
Okabayashi, Asashima, Perrimon, & Kadowaki, 2000). In humans, the PORCN
protein catalyzes O-palmitoylation of WNT3A’s Ser209 residue, allowing
WNT3A to leave the endoplasmic reticulum (Gao & Hannoush, 2014; Takada
et al., 2006) with the help of Wntless/WLS (Coombs et al., 2010).
Therefore, the likely deleterious variants found in PORCN in our
MA myelomeningocele population may prevent WNT3A from leaving the
endoplasmic reticulum, ultimately downregulating all WNT signaling
pathways in the target cell because less WNT3A would be secreted.
Previously, PORCN ’s potential role in the development of NTDs has
been suggested in a mouse study where heterozygous constitutive
inactivation of its homolog Porcn caused open neural tubesin utero (W. Liu et al., 2012). Myelomeningocele has been
documented in a person with focal dermal hypoplasia (FDH), a rare
congenital disorder associated with mutations in PORCN (Peters,
Perrier, & Haber, 2014). Furthermore, PORCN is differentially
expressed in the caudal human neural tube during closure (Krupp et al.,
2012). Three myelomeningocele subjects (two females and one male)
carried the three RDVs NC_000023.10:g.48371088G>A
p.(Gly223Ser), NC_000023.10:g.48371104G>A p.(Arg228His),
and NC_000023.10:g.48374165C>G p.(Ala336Gly), all in
highly conserved functional regions of PORCN (Rios-Esteves,
Haugen, & Resh, 2014). The male who carries
NC_000023.10:g.48371088G>A may constitute a homozygote
loss of PORCN function. Although a p.(Arg228Cys) has been described as
benign in FDH subjects, the NC_000023.10:g.48371104G>A
p.(Arg228His) variant we report is different because it is predicted to
be damaging by multiple functional analysis algorithms (Leoyklang,
Suphapeetiporn, Wananukul, & Shotelersuk, 2008). The
NC_000023.10:g.48374165C>G p.(Ala336Gly) variant is
located within one of the transmembrane domains of PORCN that forms the
substrate transportation pore to provide substrate for acylation of WNT
in the ER lumen. The NC_000023.10:g.48374165C>G
p.(Ala336Gly) variant is located in between several FDH variants that
cause amino acid substitutions such as p.(Leu331Arg), p.(Ser337Arg) and
p.(Ala338Pro) (Fokkema et al., 2011).
The carboxypeptidase E (CPE) gene on chromosome 4, which may
affect binding of WNT3A to the target cell’s receptor, associated with
myelomeningocele in the MA population. The peptide encoded by
full-length CPE interacts with WNT3A and its receptor Frizzled
(FZD) to decrease WNT/β-catenin signaling in a proteasome-dependent
manner in human cells (Skalka, Caspi, Caspi, Loh, & Rosin-Arbesfeld,
2013). Disruption of this protein’s function, therefore, may upregulate
the WNT/β-catenin pathway.