Limits...
The role of noise and positive feedback in the onset of autosomal dominant diseases.

Bosl WJ, Li R - BMC Syst Biol (2010)

Bottom Line: Autosomal dominant (AD) diseases result when a single mutant or non-functioning gene is present on an autosomal chromosome.These diseases often do not emerge at birth.Model pathways for two autosomal dominant diseases, AD polycystic kidney disease and mature onset diabetes of youth (MODY) were simulated and the results are compared to known disease characteristics.

View Article: PubMed Central - HTML - PubMed

Affiliation: Harvard Medical School, Boston, MA 02115, USA. william.bosl@childrens.harvard.edu

ABSTRACT

Background: Autosomal dominant (AD) diseases result when a single mutant or non-functioning gene is present on an autosomal chromosome. These diseases often do not emerge at birth. There are presently two prevailing theories explaining the expression of AD diseases. One explanation originates from the Knudson two-hit theory of hereditary cancers, where loss of heterozygosity or occurrence of somatic mutations impairs the function of the wild-type copy. While these somatic second hits may be sufficient for stable disease states, it is often difficult to determine if their occurrence necessarily marks the initiation of disease progression. A more direct consequence of a heterozygous genetic background is haploinsufficiency, referring to a lack of sufficient gene function due to reduced wild-type gene copy number; however, haploinsufficiency can involve a variety of additional mechanisms, such as noise in gene expression or protein levels, injury and second hit mutations in other genes. In this study, we explore the possible contribution to the onset of autosomal dominant diseases from intrinsic factors, such as those determined by the structure of the molecular networks governing normal cellular physiology.

Results: First, simple models of single gene insufficiency using the positive feedback loops that may be derived from a three-component network were studied by computer simulation using Bionet software. The network structure is shown to affect the dynamics considerably; some networks are relatively stable even when large stochastic variations in are present, while others exhibit switch-like dynamics. In the latter cases, once the network switches over to the disease state it remains in that state permanently. Model pathways for two autosomal dominant diseases, AD polycystic kidney disease and mature onset diabetes of youth (MODY) were simulated and the results are compared to known disease characteristics.

Conclusions: By identifying the intrinsic mechanisms involved in the onset of AD diseases, it may be possible to better assess risk factors as well as lead to potential new drug targets. To illustrate the applicability of this study of pathway dynamics, we simulated the primary pathways involved in two autosomal dominant diseases, Polycystic Kidney Disease (PKD) and mature onset diabetes of youth (MODY). Simulations demonstrate that some of the primary disease characteristics are consistent with the positive feedback-stochastic variation theory presented here. This has implications for new drug targets to control these diseases by blocking the positive feedback loop in the relevant pathways.

Show MeSH

Related in: MedlinePlus

Key pathway involved in MODY diabetes. The pathway components highlighted in red illustrate that the basic network structure is of type 1.c, with a subnet of type 1.c embedded in a larger network of the same type. The disease type that results from haploinsufficiency of each gene is shown in parentheses.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2902440&req=5

Figure 7: Key pathway involved in MODY diabetes. The pathway components highlighted in red illustrate that the basic network structure is of type 1.c, with a subnet of type 1.c embedded in a larger network of the same type. The disease type that results from haploinsufficiency of each gene is shown in parentheses.

Mentions: The key pathway involved in MODY onset is shown in Figure 7. This pathway contains a network structure of type 1c, but the dynamics are complicated by another embedded sub-network of type 1c and extra feedback loops. As seen in Figure 2, networks of type 1c are more sensitive to deficiencies in X than in Y (Figure 3). The implication is that an upstream component will have a more significant impact on the network dynamics when a deficiency in production exists.


The role of noise and positive feedback in the onset of autosomal dominant diseases.

Bosl WJ, Li R - BMC Syst Biol (2010)

Key pathway involved in MODY diabetes. The pathway components highlighted in red illustrate that the basic network structure is of type 1.c, with a subnet of type 1.c embedded in a larger network of the same type. The disease type that results from haploinsufficiency of each gene is shown in parentheses.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2902440&req=5

Figure 7: Key pathway involved in MODY diabetes. The pathway components highlighted in red illustrate that the basic network structure is of type 1.c, with a subnet of type 1.c embedded in a larger network of the same type. The disease type that results from haploinsufficiency of each gene is shown in parentheses.
Mentions: The key pathway involved in MODY onset is shown in Figure 7. This pathway contains a network structure of type 1c, but the dynamics are complicated by another embedded sub-network of type 1c and extra feedback loops. As seen in Figure 2, networks of type 1c are more sensitive to deficiencies in X than in Y (Figure 3). The implication is that an upstream component will have a more significant impact on the network dynamics when a deficiency in production exists.

Bottom Line: Autosomal dominant (AD) diseases result when a single mutant or non-functioning gene is present on an autosomal chromosome.These diseases often do not emerge at birth.Model pathways for two autosomal dominant diseases, AD polycystic kidney disease and mature onset diabetes of youth (MODY) were simulated and the results are compared to known disease characteristics.

View Article: PubMed Central - HTML - PubMed

Affiliation: Harvard Medical School, Boston, MA 02115, USA. william.bosl@childrens.harvard.edu

ABSTRACT

Background: Autosomal dominant (AD) diseases result when a single mutant or non-functioning gene is present on an autosomal chromosome. These diseases often do not emerge at birth. There are presently two prevailing theories explaining the expression of AD diseases. One explanation originates from the Knudson two-hit theory of hereditary cancers, where loss of heterozygosity or occurrence of somatic mutations impairs the function of the wild-type copy. While these somatic second hits may be sufficient for stable disease states, it is often difficult to determine if their occurrence necessarily marks the initiation of disease progression. A more direct consequence of a heterozygous genetic background is haploinsufficiency, referring to a lack of sufficient gene function due to reduced wild-type gene copy number; however, haploinsufficiency can involve a variety of additional mechanisms, such as noise in gene expression or protein levels, injury and second hit mutations in other genes. In this study, we explore the possible contribution to the onset of autosomal dominant diseases from intrinsic factors, such as those determined by the structure of the molecular networks governing normal cellular physiology.

Results: First, simple models of single gene insufficiency using the positive feedback loops that may be derived from a three-component network were studied by computer simulation using Bionet software. The network structure is shown to affect the dynamics considerably; some networks are relatively stable even when large stochastic variations in are present, while others exhibit switch-like dynamics. In the latter cases, once the network switches over to the disease state it remains in that state permanently. Model pathways for two autosomal dominant diseases, AD polycystic kidney disease and mature onset diabetes of youth (MODY) were simulated and the results are compared to known disease characteristics.

Conclusions: By identifying the intrinsic mechanisms involved in the onset of AD diseases, it may be possible to better assess risk factors as well as lead to potential new drug targets. To illustrate the applicability of this study of pathway dynamics, we simulated the primary pathways involved in two autosomal dominant diseases, Polycystic Kidney Disease (PKD) and mature onset diabetes of youth (MODY). Simulations demonstrate that some of the primary disease characteristics are consistent with the positive feedback-stochastic variation theory presented here. This has implications for new drug targets to control these diseases by blocking the positive feedback loop in the relevant pathways.

Show MeSH
Related in: MedlinePlus