Inscrutable Genes

• "In most cases, the molecular consequences of disease, or trait-associated variants for human physiology, are not understood." from: Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex diseases. Nature 2009;461:747–53.

The 1960s was a wonderful decade for the field of molecular genetics. Hundreds of inherited metabolic diseases were being studied. Most of these diseases could be characterized by a simple inherited mutation in a disease-causing gene. Back then, we thought we understood genetic diseases. Here’s how it all might have worked, if life were simple: one mutation! one gene ! one protein ! one disease. This lovely genetic parable, from a bygone generation, seldom applies in the era of Precision Medicine. The purpose of this section is to explain some of the complexities of modern genetics and to lay out the job of the Precision Medicine scientist who must dissect the pathways that lead from gene to disease.

In Precision Medicine and the Reinvention of Human Disease, two of the most confuding aspects of modern disease genetics are discussed: that a single disease may result from one of many distinct molecular defects; and that a single gene may produce many different diseases. These two countervailing phenomena tell us something very important about disease development. The first is that different pathways may converge to the same disease, and that any single gene may perturb a biological system (i.e., a living organism) in different ways. Some of that discussion is excerpted here.

There are numerous examples wherein mutations in one gene may result in more than one disease [2]. In some cases, each of the diseases caused by the altered gene is fundamentally similar (e.g., spherocytosis and elliptocytosis, caused by mutations in the alpha-spectrin gene; Usher syndrome type IIIA and retinitis pigmentosa-61 caused by mutations in the CLRN1 gene). In other case, diseases caused by the same gene may have no obvious relation to one another. For example, the APOE gene encodes apolipoprotein E, which is involved in the synthesis of lipoproteins. One common allele of the APOE locus, e4, increases the risk of Alzheimer disease and of heart disease, two disorders of no obvious clinical similarities [3,4].

Let’s look at a few other examples where mutations in a single gene play causal roles in the development of diverse diseases. For example, different mutations of the same gene, desmoplakin, cause the following diseases [2]:

• Arrhythmogenic right ventricular dysplasia 8

• Dilated cardiomyopathy with woolly hair and keratoderma

• Lethal acantholytic epidermolysis bullosa

• Keratosis palmoplantaris striata II

• Skin fragility-woolly hair syndrome

How is it possible that errors in the gene coding for desmoplakin, a constituent protein found in intercellular junctions, could account for such apparently unrelated diseases as arrhythmogenic right ventricular dysplasia and lethal acantholytic epidermolysis bullosa? It happens that we know that specialized desmosomes in cardiac cells (i.e., intercalated discs) tightly couple myocytes so that they can function as a coordinated group. Desmosomes are also required to adhese skin epidermal cells to one another and to the underlying basement membrane. In the case of desmoplakin mutations, it is relatively easy to see the pathogenetic relationship among these diseases.

In other sets of diseases that result from an error in one specific gene, the pathogenetic relationship may not be so easily discerned. Some cases of Charcot-Marie-Tooth axonal neuropathy, lipodystrophy, Emery-Dreyfus muscular dystrophy, and premature aging syndromes are all caused by mutation in the LMNA (Lamin A/C) gene. Stickler syndrome type III, Fibrochondrogenesis-2, and a form of nonsyndromic hearing loss are all caused by mutations in the COL11A2 gene. In these cases, how can variations in a single gene cause many different diseases?

Let’s look at just a few of the possibilities:

• One gene can control the synthesis of more than one protein [6].

• A single protein may have multiple functions. For example, nuclear lamina (lamin a/c) has several biological roles: controlling nuclear shape, influencing transcription, and organizing heterochromatin. Mutations in the LMNA gene cause more than 10 different clinical syndromes, including neuromuscular and cardiac disorders, premature aging disorders, and lipodystrophy. Likewise, the polyfunctional TP53 gene has been linked to 11 clinically distinguishable cancer-related disorders [7].

• A single protein with a single function may have different biological effects based on the cell type in which the protein is expressed, the stage of development in which the protein is expressed, and the cellular milieu (e.g., concentrations of substrate or protein inhibitors) for a given cell type, at a particular moment in time.

• Diseases develop through a sequence of biological events occurring over time. A mutation may exert a different biological effect based on where and when, in the sequence of pathogenetic events, it is expressed.

more to follow

- Jules Berman

key words: precision medicine, genetics, multi-step, pathogenesis, genetic heterogeneity, jules j berman Ph.D. M.D.