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A. Fainsod et al.
and ethnicity, leaving genetic differences between dizygotic twins as the main distinguishing variable. The results of these studies showed that dizygotic twins exhibited
differences in the severity of alcohol-induced defects, whereas monozygotic twins
exhibited the same degree of severity (Christoffel and Salafsky 1975; Harris et al.
1993; Streissguth and Dehaene 1993; Riikonen 1994). These studies and others came
to prove a clear genetic contribution to FASD outcome.
Follow up studies focused on polymorphisms in the genes encoding enzymes
needed for alcohol clearance (McCarver et al. 1997; McCarver 2001; Viljoen et al.
2001; Stoler et al. 2002; Arfsten et al. 2004; Das et al. 2004; Jacobson et al. 2006;
Green and Stoler 2007; Hurley and Edenberg 2012). These studies identified FASD
protective alleles and also risk increasing alleles (Green and Stoler 2007). Interestingly, most alleles functioned from the maternal genome, supporting her important
role in alcohol elimination. Several examples have been described where RA network genes affect the severity of disease (Krivospitskaya et al. 2012; Fransén et al.
2013; Nilsson et al. 2016). Future studies should explore the potential effects of
different isozymes and genetic polymorphisms of enzymes participating in vitamin
A metabolism. Modifying the metabolic efficiency of some of these enzymes might
protect or, alternatively, become risk factors in the presence of ethanol.
RA signaling relies on nutrition and environment, to provide precursors for its
biosynthesis. Nutrition might be balanced, but also can be either poor or very enriched
in retinoids or carotenoids which can shift this signaling pathway out of balance.
This real-time response to changing environmental conditions is termed robustness.
Robustness relies on cross-regulatory genetic circuitry and on the enzymatic efficiency of the components. The regulatory elements, together with the enzymes themselves can exhibit sequence polymorphisms that can alter robustness. Many of the
components of the RA metabolic and signaling network are regulated by RA levels.
Therefore, the effect of an environmental disturbance, such as ethanol, will depend
upon the robustness efficiency of the network, which in turn depends upon the polymorphisms of the individual components. This robustness efficiency can affect the
severity of FASD. Our understanding of the RA network robustness is minimal at
best and requires extensive analysis (Sosnik et al. 2016). Better knowledge of RA
robustness will allow better understanding of the etiology of FASD and will help in
the identification of central components in this regulation. In the future, better understanding of the genetic changes in the RA network and ethanol clearance will direct
efforts to design molecular genetic approaches for diagnosis of alcohol-exposed pregnancies, monitoring of the extent of damage, and treatments that improve the quality
of life.
References
Abel EL (1997) Was the fetal alcohol syndrome recognized in the ancient Near East? Alcohol
Alcohol 32:3–7 Xenopus
A. Fainsod et al.
and ethnicity, leaving genetic differences between dizygotic twins as the main distinguishing variable. The results of these studies showed that dizygotic twins exhibited
differences in the severity of alcohol-induced defects, whereas monozygotic twins
exhibited the same degree of severity (Christoffel and Salafsky 1975; Harris et al.
1993; Streissguth and Dehaene 1993; Riikonen 1994). These studies and others came
to prove a clear genetic contribution to FASD outcome.
Follow up studies focused on polymorphisms in the genes encoding enzymes
needed for alcohol clearance (McCarver et al. 1997; McCarver 2001; Viljoen et al.
2001; Stoler et al. 2002; Arfsten et al. 2004; Das et al. 2004; Jacobson et al. 2006;
Green and Stoler 2007; Hurley and Edenberg 2012). These studies identified FASD
protective alleles and also risk increasing alleles (Green and Stoler 2007). Interestingly, most alleles functioned from the maternal genome, supporting her important
role in alcohol elimination. Several examples have been described where RA network genes affect the severity of disease (Krivospitskaya et al. 2012; Fransén et al.
2013; Nilsson et al. 2016). Future studies should explore the potential effects of
different isozymes and genetic polymorphisms of enzymes participating in vitamin
A metabolism. Modifying the metabolic efficiency of some of these enzymes might
protect or, alternatively, become risk factors in the presence of ethanol.
RA signaling relies on nutrition and environment, to provide precursors for its
biosynthesis. Nutrition might be balanced, but also can be either poor or very enriched
in retinoids or carotenoids which can shift this signaling pathway out of balance.
This real-time response to changing environmental conditions is termed robustness.
Robustness relies on cross-regulatory genetic circuitry and on the enzymatic efficiency of the components. The regulatory elements, together with the enzymes themselves can exhibit sequence polymorphisms that can alter robustness. Many of the
components of the RA metabolic and signaling network are regulated by RA levels.
Therefore, the effect of an environmental disturbance, such as ethanol, will depend
upon the robustness efficiency of the network, which in turn depends upon the polymorphisms of the individual components. This robustness efficiency can affect the
severity of FASD. Our understanding of the RA network robustness is minimal at
best and requires extensive analysis (Sosnik et al. 2016). Better knowledge of RA
robustness will allow better understanding of the etiology of FASD and will help in
the identification of central components in this regulation. In the future, better understanding of the genetic changes in the RA network and ethanol clearance will direct
efforts to design molecular genetic approaches for diagnosis of alcohol-exposed pregnancies, monitoring of the extent of damage, and treatments that improve the quality
of life.
References
Abel EL (1997) Was the fetal alcohol syndrome recognized in the ancient Near East? Alcohol
Alcohol 32:3–7 Xenopus