Editing Wilson's disease (section)

==Genetics==
[[Image:autorecessive.svg|thumb|Wilson's disease has an autosomal recessive pattern of inheritance.]]

{{main|ATP7B}}

The Wilson's disease gene (''ATP7B'') is on [[chromosome 13]] (13q14.3) and is expressed primarily in the liver, [[kidney]], and [[placenta]]. The gene codes for a [[P-ATPase|P-type]] (cation transport enzyme) [[ATPase]] that transports copper into [[bile]] and incorporates it into [[ceruloplasmin]].<ref name=Ala/> Most people who have Wilson's disease – 60% – are [[homozygous]] for ''ATP7B'' mutations (two abnormal copies), and 30% of them have only one abnormal copy.<ref name=Merle2007/> In up to 7% of cases, people with Wilson's disease have no detectable mutations.<ref name=Stattermayer/>

Although more than 500 mutations of ''ATP7B'' have been described,<ref name=Stattermayer>{{Cite journal |last1=Stattermayer |first1=Albert |last2=Zoller |first2=Heinz M. |last3=Weiss |first3=Karl Heinz |last4=Szalay |first4=Ferenc |last5=Bruha |first5=Radan |last6=Houwen |first6=Roderick |last7=Stauber |first7=Rudolf E. |last8=Steindl-Munda |first8=Petra E. |last9=Hofer |first9=Harald |last10=Stremmel |first10=Wolfgang |last11=Ferenci |first11=Peter |date=October 2014 |title=Patients with Wilson disease without detectable ATP7B mutations: 464 |url=https://journals.lww.com/hep/citation/2014/10001/patients_with_wilson_disease_without_detectable.464.aspx |journal=Hepatology |language=en-US |volume=60 |pages=427A |issn=0270-9139}}</ref> a very small number of those cause most cases of Wilson's disease; which mutation an individual will have tends to be specific to the population they are part of. For instance, in Western populations, the H1069Q mutation (replacement of a [[histidine]] by a [[glutamine]] at position 1069 in the protein) is present in 37%–63% of cases, while in China this mutation is very uncommon; R778L ([[arginine]] to [[leucine]] at 778) is found more often there. Relatively little is known about the relative impact of the various mutations, although the H1069Q mutation seems to predict later onset and predominantly neurological problems, according to some studies.<ref name=Ala/><ref name=deBie2007>{{cite journal |vauthors=de Bie P, Muller P, Wijmenga C, Klomp LW |title=Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes |journal=J. Med. Genet. |volume=44 |issue=11 |pages=673–88 |date=November 2007 |pmid=17717039 |pmc=2752173 |doi=10.1136/jmg.2007.052746 }}</ref> A comprehensive clinically annotated resource, WilsonGen, provides a clinical classification for the variants as per the recent ACMG & AMP guidelines.<ref>{{Cite journal|last1=Kumar|first1=Mukesh|last2=Gaharwar|first2=Utkarsh|last3=Paul|first3=Sangita|last4=Poojary|first4=Mukta|last5=Pandhare|first5=Kavita|last6=Scaria|first6=Vinod|last7=Bk|first7=Binukumar|date=2020-06-03|title=WilsonGen a comprehensive clinically annotated genomic variant resource for Wilson's Disease|journal=Scientific Reports|language=en|volume=10|issue=1|page=9037|doi=10.1038/s41598-020-66099-2|pmid=32493955|pmc=7270127|bibcode=2020NatSR..10.9037K|issn=2045-2322}}</ref>

A normal variation in the ''[[PRNP]]'' gene can modify the course of the disease by delaying the age of onset and affecting the type of symptoms that develop. This gene produces [[prion protein]], which is active in the brain and other tissues and also appears to be involved in transporting copper.<ref>{{cite journal |vauthors=Grubenbecher S, Stüve O, Hefter H, Korth C |title=Prion protein gene codon 129 modulates clinical course of neurological Wilson disease |journal=NeuroReport |volume=17 |issue=5 |pages=549–52 |year=2006 |pmid=16543824 |doi=10.1097/01.wnr.0000209006.48105.90|s2cid=37186426 }}</ref> A role for the ''[[Apolipoprotein E|ApoE]]'' gene was initially suspected, but could not be confirmed.<ref name=deBie2007/>

The condition is inherited in an autosomal recessive pattern. To inherit it, both of the parents of an individual must carry an affected gene. Most people with Wilson's disease have no family history of the condition.<ref name=deBie2007/> People with only one abnormal gene are called carriers (heterozygotes) and may have mild, but medically insignificant, abnormalities of copper metabolism.<ref name=Roberts2003/>

There are several hereditary diseases that cause copper overload in the liver; Wilson's disease is the most common of them. All can cause [[cirrhosis]] at a young age. The other copper overload diseases are [[Indian childhood cirrhosis]] (ICC), endemic Tyrolean infantile cirrhosis, and idiopathic copper toxicosis. These three, unlike Wilson's disease, are not related to ''ATP7B'' mutations; for example, ICC has been linked to mutations in the ''[[Keratin 8|KRT8]]'' and the ''[[Keratin 18|KRT18]]'' genes.<ref name=deBie2007/>