Neurofibromatosis type-I (NF-1), also referred to as von Recklinghausen's disease is a developmental disorder caused by germline mutations of NF1 genes encoding inneurofibromin, a gene that is involved in the RAS pathway (RASopathy). NF-1 exhibits several clinical features such as multiple café-au-lait spots, Lisch nodules, optic glioma etc. The definition of Rasopathy is that there are several resembling diseases in which Ras signal is constitutively activated. RASopathy is composed of Legius syndrome, Noonan syndrome, Costello syndrome etc. For instance, Legius syndrome in which SPRED1 gene has a loss-of-functional mutation, thereby the negative regulation of Ras signaling pathway is no longer works. However, Legius syndrome shows multiple café-au-lait spots much the same as NF1, but also exhibits the different clinical features as compared with NF1 such as macrocephaly and ADHD (mild mental disorder). I have always wondered what is responsible for the genotype-phenotype decorrelation. Considering the case of RASopathy, in which hyperactivated Ras signal in the germline level shows different phenotypes, the correlation of signal activation disorder and the clinical symptoms is not always correlated. I would be appreciated if you give me some opinion on what makes the signal-phenotype decorrelation.
The decorrelation between genotype and phenotype is a classical issue in genetics. The chain of events that goes from the presence of the gene into the genome (the genotype) , then to gene expression (transcription, translation and related events), and finally to the multiple interactions of the produced protein with many other components of intracellular pathways that determine the phenotype is often complex and diverse. This is called epistasis i, genetics. Thus, the phenotype, that is the signs or characteristics determined by this chain of events, can vary according to the nature of interactions taking place in different contexts, at different time points (development, living conditions, and even stochastic conditions..), different places (organs, cell types...etc). In short, the large number of interactions that goes frpm gene expression to the existence of of a given "type" described by several characters (a disease and its symptoms, in the case you described) accounts for this phenotypic variability. In principle, each of the factors capable of interaction with the gene product you are considering, can sligtly vary from one individual to another, and can lead to variable phenotype. Environmental challenge or threat, can also promote significant variation in the outcome of gebe expression. As a matter of fact, the nature of the interactions often selected by millions years of evolution, are able to buffer a large part of the possible variations, a process recognized as "canalization" by Waddington (1953). In addition, the multiple interactions of the mutated gene product of interest with other factors, either intrinsic or extrinsic (environmental for example) may also provide compensation to the mutation and lead to less severe disease in some individual. This is called variable penetrance. There are important reviews on such a topic, which could be helpful for you, and there nice accounts in textbooks such as "Genes" from B. Lewin. For example: Cooper DN et al, 2013, Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease. Hum. Genet., 132:1077-130. Glazier et al. (2002) Finding genes that underlie complex traits. Science, 298: 2345-9.
I am greatly appreciated for your kind comment. As you have explained, the concept of Waddington's epigenetic landscape is critical to understand the reversible differentiation with higher plasticity. Temporal and tissue-dependent characteristics of gene expression pattern seems to make the decorrelation between genotype/ signal abnormality and phenotype/ clinical symptoms.
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