{'fraction_non_alphanumeric': 0.024308466051969825, 'fraction_numerical': 0.0044705224923162895, 'mean_word_length': 5.568807339449541, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Broadening the implications of gene discovery

In the mid-1980s the enthusiastic rationale for identifying the gene somehow responsible for any given monogenic disease was, first, to facilitate accurate diagnosis and, second, to cure the disease. When gene analysis was extremely labor-intensive and gene replacement therapy proved difficult or even perilous to patients, such motivation seemed like pure hype. Yet unquestionably, for clinically pleomorphic diseases like cystic fibrosis (CF) and Wilson disease (WD) genotype determination promoted accurate diagnosis. Fast-forward to 2012: inclusive analysis of the large ATP7B gene associated with WD is realistic and almost routine. Some CF patients can effectively be cured with a drug, ivacaftor, which permits the modestly abnormal CF transmembrane conductance regulator protein of G551D homozygotes to function adequately within the cell membrane. This treatment would not have been possible without identifying the gene first, yet it is very different from gene replacement or gene editing. However, there was another rationale for this gene discovery research—though much less glamorous. Identifying the gene was expected to energize research into relevant physiology and help elucidate the pathophysiology of the disease. For WD, this was certainly the case. Complementing research already under way with various bacteria and yeasts, within a few years of identifying the human gene ATP7B, key features of the structure of its gene product, ATP7B, the Wilson adenosine triphosphatase (ATPase), were worked out and copper-responsive intracellular movement of this protein was reported. Understanding the role of metals such as copper and zinc, and more recently platinum and manganese, in hepatocellular function acquired new interest. The Wilson ATPase is a metal-transporting P1-type ATPase. The paradoxical clinical features of WD (hepatic copper overload but low serum copper) became explicable when it was apparent that the Wilson ATPase has two functions within the hepatocyte. When ambient hepatocellular copper concentrations are relatively low, it participates in the incorporation of copper into apoceruloplasmin. When the Wilson ATPase is dysfunctional, copper is not made available for incorporation and apoceruloplasmin devoid of copper is produced. Serum copper is consequently measured as subnormal. When bioavailable hepatocellular copper concentrations are high, the Wilson ATPase expedites biliary excretion of copper. Failure at this function leads to toxic accumulation of copper in the hepatocyte. Evidently the Wilson ATPase has at least one other function. It serves as a copper sensor within the hepatocyte. Persisting questions include the following: What regulates Wilson ATPase function? Given multiple mechanisms, how does copper actually get excreted into bile? Answers to such questions may reveal new opportunities for therapeutic intervention, if a therapy could compensate for, or potentiate, an imperfect Wilson ATPase. Much is known about selected disease-causing mutations among the hundreds of gene alterations thus far identified in ATP7B. Some result in such severe disruption of Wilson ATPase structure that effectively no protein is produced, a situation resembling the knockout mouse. Other mutations result in misfolded proteins that get hung up in the endoplasmic reticulum. Still Abbreviations: ATPase, adenosine triphosphatase; CF, cystic fibrosis; FXR, farnesoid X receptor; JNK, c-Jun N-terminal kinase; LXR, liver X receptor; RXR, retinoid X receptor; WD, Wilson disease.