212
A. Fainsod et al.
CHARGE syndrome has a somewhat complex connection to RA signaling
(Sanlaville and Verloes 2007; Petrelli et al. 2019). The common malformations
in CHARGE include; coloboma, heart defects, atresia choanae (choanal atresia),
growth retardation, genital abnormalities, and ear abnormalities, which give it its
name. CHARGE syndrome is caused by heterozygous mutation in the chd7 (Chromodomain Helicase DNA Binding Protein 7) gene (Vissers et al. 2004). The protein
encoded by this gene affects transcriptional function and regulates gene expression
by changing nucleosome accessibility (Feng et al. 2017). chd7
−/− mice have forebrain neurogenesis defects that can be reduced by supplementation with all-trans
RA. Those mice also have inner ear malformations which can be rescued by citral, a
RA biosynthesis inhibitor (Micucci et al. 2014; Yao et al. 2018). It is clear then that in
some of the regions affected in CHARGE syndrome, there is a cooperation and cross
regulation between CHD7 and RA signaling, including regulation of the aldh1A3
gene (Micucci et al. 2014; Yao et al. 2018). In agreement, the CHARGE clinical features, including craniofacial malformations, overlap with VAD syndrome (Maden
2001), RA embryopathy (Lammer et al. 1985), and FASD phenotypes (Popova et al.
2016).
PAGOD syndrome is a very rare disease whose etiology is unknown. The characterization of this syndrome includes multiple congenital anomalies including cardiovascular defects, pulmonary artery, lung hypoplasia, diaphragmatic defects, cardiac
defects, omphalocele and various genital anomalies (Kennerknecht et al. 1993). Many
of the birth defects observed on PAGOD syndrome are similar to the developmental
anomalies observed in VAD animal models (Macayran et al. 2002; Gavrilova et al.
2009). Beyond the similarity in the malformations observed, it has been reported that
an infant with PAGOD syndrome also has low levels of plasma vitamin A, while the
maternal plasma vitamin A levels are normal (Gavrilova et al. 2009). These observations suggest that reduced vitamin A may play a role in the development of PAGOD
syndrome in a similar fashion to FAS.
Congenital Zika virus infection has extensive overlap with FAS. It causes microcephaly, craniofacial malformations, IUGR, brain and eye abnormalities, all reminiscent of those seen in babies with FAS (Moore et al. 2017). Recently, sequences
with repetitive RA Response Elements (RARE) (consensus elements) were identified
in the Zika virus genome. It was proposed that these viral RARE sequences could
bind RXR-RAR heterodimers normally required for normal RA-dependent gene
regulation during embryogenesis. This reduced RA gene regulatory activity would
induce malformations characteristic of reduced RA signaling (Kumar et al. 2016;
Audouze et al. 2018). Zika virus strains that induce microcephaly and craniofacial
malformations are characterized by more RARE elements in their genome (Kumar
et al. 2016). These RARE enriched viral strains would be more susceptible to teratogenic reduction in RA signaling. While both Congenital Zika and FASD syndromes
have different mechanisms causing craniofacial malformations and microcephaly,
the underlying etiology in both cases might stem from reduced RA signaling.
A. Fainsod et al.
CHARGE syndrome has a somewhat complex connection to RA signaling
(Sanlaville and Verloes 2007; Petrelli et al. 2019). The common malformations
in CHARGE include; coloboma, heart defects, atresia choanae (choanal atresia),
growth retardation, genital abnormalities, and ear abnormalities, which give it its
name. CHARGE syndrome is caused by heterozygous mutation in the chd7 (Chromodomain Helicase DNA Binding Protein 7) gene (Vissers et al. 2004). The protein
encoded by this gene affects transcriptional function and regulates gene expression
by changing nucleosome accessibility (Feng et al. 2017). chd7
−/− mice have forebrain neurogenesis defects that can be reduced by supplementation with all-trans
RA. Those mice also have inner ear malformations which can be rescued by citral, a
RA biosynthesis inhibitor (Micucci et al. 2014; Yao et al. 2018). It is clear then that in
some of the regions affected in CHARGE syndrome, there is a cooperation and cross
regulation between CHD7 and RA signaling, including regulation of the aldh1A3
gene (Micucci et al. 2014; Yao et al. 2018). In agreement, the CHARGE clinical features, including craniofacial malformations, overlap with VAD syndrome (Maden
2001), RA embryopathy (Lammer et al. 1985), and FASD phenotypes (Popova et al.
2016).
PAGOD syndrome is a very rare disease whose etiology is unknown. The characterization of this syndrome includes multiple congenital anomalies including cardiovascular defects, pulmonary artery, lung hypoplasia, diaphragmatic defects, cardiac
defects, omphalocele and various genital anomalies (Kennerknecht et al. 1993). Many
of the birth defects observed on PAGOD syndrome are similar to the developmental
anomalies observed in VAD animal models (Macayran et al. 2002; Gavrilova et al.
2009). Beyond the similarity in the malformations observed, it has been reported that
an infant with PAGOD syndrome also has low levels of plasma vitamin A, while the
maternal plasma vitamin A levels are normal (Gavrilova et al. 2009). These observations suggest that reduced vitamin A may play a role in the development of PAGOD
syndrome in a similar fashion to FAS.
Congenital Zika virus infection has extensive overlap with FAS. It causes microcephaly, craniofacial malformations, IUGR, brain and eye abnormalities, all reminiscent of those seen in babies with FAS (Moore et al. 2017). Recently, sequences
with repetitive RA Response Elements (RARE) (consensus elements) were identified
in the Zika virus genome. It was proposed that these viral RARE sequences could
bind RXR-RAR heterodimers normally required for normal RA-dependent gene
regulation during embryogenesis. This reduced RA gene regulatory activity would
induce malformations characteristic of reduced RA signaling (Kumar et al. 2016;
Audouze et al. 2018). Zika virus strains that induce microcephaly and craniofacial
malformations are characterized by more RARE elements in their genome (Kumar
et al. 2016). These RARE enriched viral strains would be more susceptible to teratogenic reduction in RA signaling. While both Congenital Zika and FASD syndromes
have different mechanisms causing craniofacial malformations and microcephaly,
the underlying etiology in both cases might stem from reduced RA signaling.