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The His1069Gln mutation in the ATP7B gene in Russian patients with Wilson disease
  1. Department of Neurogenetics, Institute of Neurology, Russian Academy of Medical Sciences, Volokolamskoye Shosse 80, Moscow 123367, Russia

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    Editor—Wilson disease (WD), or hepatolenticular degeneration, is an autosomal recessive disorder of copper transport characterised by toxic accumulation of copper in a number of organs, principally the liver, brain, and kidney.1 An effective treatment strategy in patients with WD is based on removal of excess copper by chelating agents or zinc salts.

    The gene for WD, originally assigned to chromosome 13 by linkage studies,2 was recently cloned and encodes a putative copper transporting P type ATPase (ATP7B).3 4 To date, more than 50 disease specific mutations have been identified in a number of WD patients from different countries.5 6 Some of these mutations were reported to be frequent in specific populations, which may help to introduce rapid diagnostic procedures based on direct DNA analysis into routine clinical practice. One of the most common mutations, His1069Gln, accounts for 22-31% of the WD chromosomes in European and American populations,4 5 with the highest frequency of 73% found in a Polish series of WD patients.7 Here we present our results of molecular screening for the above mutation in a large number of Russian patients with WD.

    We examined 40 unrelated WD patients of Slavonic ethnic origin from the European part of Russia. They represented an unselected series of patients admitted to our clinic between 1995 and 1997 and not included in the previously reported small series of Russian patients with WD studied by molecular genetic analysis.6 The diagnosis of WD was established by the detection of Kayser-Fleischer rings and low copper and caeruloplasmin levels in serum. Peripheral blood was collected with informed consent and genomic DNA was extracted by standard procedures. Exon 14 of the ATP7B gene was amplified by polymerase chain reaction (PCR).5 Mutation screening was performed using single strand conformation polymorphism (SSCP) analysis as described elsewhere,8 followed by direct sequencing of the presumed mutated samples. Mutated sequences were confirmed on both identical and complementary strands.

    On SSCP analysis, no abnormally migrating bands were found in 14 WD patients compared to control chromosomes. Two different abnormal SSCP patterns were detected in 26 patients. Direct nucleotide sequence analysis showed that one pattern, observed in 13 WD patients, corresponded to a homozygous C→A mutation resulting in the His1069Gln change; another abnormal SSCP pattern, found in 13 patients, corresponded to the same mutation in the heterozygous state. No other sequence alterations were identified in exon 14 of the ATP7B gene in our cohort, so we can conclude that the His1069Gln mutation represents 48.7% of the WD chromosomes in a large set of Slavonic families from the European part of Russia. Our findings are strikingly similar to those reported in a Polish series of patients with WD,7which is not unexpected in view of the very close ethnic and geographical origin of these two populations. Further molecular analysis, in particular studies of disease associated haplotypes, will help to answer the question as to whether the high frequency of the His1069Gln mutation in Russia results from a founder effect or whether it is caused by a mutation hot spot.

    Our results have important clinical implications. In total, the above major mutation in either the homozygous or the heterozygous state was detected in 26 out of 40 of our WD patients (65% of the patients studied). These findings, therefore, allow accurate molecular diagnosis in a majority of WD patients in the Slavonic population of Russia. At present in our clinic, direct DNA testing for the presence of this major mutation is an essential part of the diagnostic algorithm in patients with a suspected diagnosis of WD.

    The His1069Gln change occurs within the highly conserved phosphorylation domain of the protein and is predicted to reduce (but not eliminate) the transport of copper ions across the membrane. Thomaset al 5 observed later onset of the disease in WD patients carrying this mutation compared with non-carriers. In contrast, Shah et al 6 showed lower copper stimulated ATPase activity and, therefore, more severe protein alteration in a patient homozygous for His1069Gln compared with WD patients with other mutations. It is of interest that our patients homozygous for His1069Gln had more severe hepatic symptoms, than heterozygous patients and those lacking the His1069Gln mutation, while ages of onset did not differ significantly between homozygous and heterozygous patients. This may suggest a more benign nature of other, as yet unidentified, ATP7B mutations in our cohort of Russian WD patients, a possibility which deserves further study.


    This study was supported by a grant from the Russian Fund for Basic Research (No 96-04-49837).