Wilson disease: Novel mutations in theATP7B gene and clinical correlation in Brazilian patients

Deguti, Marta Mitiko; Genschel, Janine; Cançado, Eduardo Luiz Rachid; Barbosa, Egberto Reis; Bochow, Bettina; Mucenic, Marcos; Porta, Gilda; Lochs, Herbert; Carrilho, Flair José; Schmidt, Hartmut

doi:10.1002/humu.9227

Cited by 104 publications

(74 citation statements)

References 17 publications

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“…The second most frequent mutation was the c.2123T>C at exon 8, with an allelic frequency of 14.1%. The c.3207C>A substitution at exon 14 was absent in the studied population 10 . These results differ dramatically from the ones reported here.…”

Section: Discussionmentioning

confidence: 74%

“…The study of Deguti et al 10 , References that the c.3402delC at exon 15 was the most common mutation, with an allelic frequency of 30.8%. The second most frequent mutation was the c.2123T>C at exon 8, with an allelic frequency of 14.1%.…”

Section: Discussionmentioning

confidence: 96%

“…Its frequency is higher in Poland and eastern Germany and decreases to the west and to the south, with an allelic frequency ranging between 30 and 70% (9). The c.3402delC is the most common mutation described for the Brazilian population, with an allelic frequency of 30.8% 10 . Data of WD patients' continental origin and their ATP7B identified mutations are described in table 2.…”

Section: Mutation Analysismentioning

confidence: 98%

“…Deguti et al 10 evaluated the ATP7B genotype of 60 WD patients from different Brazilian regions, showing that the c.3402delC and the c.2123T>C were the most common, representing nearly 50% of all the mutations in the country.…”

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confidence: 99%

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Wilson's disease in Southern Brazil: genotype-phenotype correlation and description of two novel mutations in ATP7B gene

Raskin

Muzzillo

et al. 2013

Arq. Neuro-Psiquiatr.

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OBJECTIVE: Wilson's disease (WD) is an inborn error of metabolism caused by abnormalities of the copper-transporting protein encoding gene ATP7B. In this study, we examined ATP7B for mutations in a group of patients living in southern Brazil. METHODS: 36 WD subjects were studied and classified according to their clinical and epidemiological data. In 23 subjects the ATP7B gene was analyzed. RESULTS: Fourteen distinct mutations were detected in at least one of the alleles. The c.3207C>A substitution at exon 14 was the most common mutation (allelic frequency=37.1%) followed by the c.3402delC at exon 15 (allelic frequency=11.4%). The mutations c.2018-2030del13 at exon 7 and c.4093InsT at exon 20 are being reported for the first time. CONCLUSION: The c.3207C>A substitution at exon 14, was the most common mutation, with an allelic frequency of 37.1%. This mutation is the most common mutation described in Europe.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 96%

Section: Mutation Analysismentioning

confidence: 98%

mentioning

confidence: 99%

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Wilson's disease in Southern Brazil: genotype-phenotype correlation and description of two novel mutations in ATP7B gene

Raskin

Muzzillo

et al. 2013

Arq. Neuro-Psiquiatr.

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“…This line of investigation is up to nowadays one of the most traditional of the Neurologic Clinic (HC-FMUSP) and for the last 20 years, has counted with an effective participation of researchers from the Gastroenterology department [32][33][34] .…”

Section: Discussionmentioning

confidence: 99%

Wilson's Disease: a case report and a historical review

Barbosa

Machado

Cançado

et al. 2009

Arq. Neuro-Psiquiatr.

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-The purpose of this report is to present a short review of the history of Wilson's disease and to describe the first diagnosed case at the Neurologic Clinic of Hospital das Clínicas of São Paulo University Medical School. The topics of the historical review are the first contributions of authors along the second half of the XIX century, the seminal monograph of Samuel Alexander Kinnier Wilson (1912), the landmarks in the investigation of mechanisms of the disease and the introduction of the first effective treatment by John Walshe (1956). The first case studied in our Clinic, in 1946, was a 20 year-old male whose main neurological manifestations were postural tremor ("wing beat") and dysarthria and could be characterized as WestphalStrümpell form of the disease. Along the discussion of this case difficulties to establish the diagnosis and to treat the patient at that time are highlighted. We conclude with a brief history of the development of researches on Wilson's disease in our Clinic, with an honor to the pioneer contributions of Horacio Martins Canelas.Key WordS: Wilson's disease, historical review, copper metabolism. Doença de Wilson: relato de caso e revisão históricaResumo -Neste artigo inicialmente é feito um retrospecto dos principais marcos na história dos conhecimentos sobre a doença de Wilson, desde as primeiras descrições de casos no século XIX, passando pela magnífica monografia de Samuel Alexander Kinnier Wilson, m 1912, pelas descobertas sobre a causa da doença e chegando à era do tratamento efetivo da moléstia inaugurada por Walshe em 1956. A seguir, relata-se o primeiro caso de doença de Wilson estudado na Clínica Neurológica do HC-FMUSP. o paciente admitido na Clínica Neurológica em 1946, aos 20 anos de idade, apresentava a variante da doença em que predominavam tremor postural e disartria, conhecida como forma de Westphal-Strümpell. Na discussão, são ressaltadas as dificuldades da época para a confirmação do diagnóstico e para o tratamento; além de se realizar um breve histórico do estudo da doença na Clínica Neurológica, com o devido realce para a figura de Horácio Martins Canelas, pela sua participação pioneira nas pesquisas sobre a doença de Wilson em nosso meio.PAlAvrAS-CHAve: doença de Wilson, revisão histórica, metabolismo do cobre.

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Molecular Genetics of Wilson Disease

Roberts

2013

Encyclopedia of Life Sciences

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Wilson disease is an autosomal‐recessive genetic disorder of hepatocellular copper disposition. It is rare but has a worldwide distribution. It is clinically diverse. Disease patterns include various kinds of liver disease; neurological movement disorders and psychiatric disease including psychosis, and less commonly recurrent haemolytic anaemia, osseomuscular abnormalities and cardiac dysrhythmias. The classic eye finding, the Kayser–Fleischer ring, has no functional impact. Thus far, only one gene has been identified whose mutations are causal for Wilson disease, ATP7B on chromosome 13q14.3, cloned in 1993. More than 500 mutations have been identified. The encoded protein is a metal‐transporting P‐type adenosine triphosphatase (ATPase), the Wilson ATPase, similar to copper transporters across the phyla. Simple genotypic explanation for the phenotypic diversity does not exist. The important genotype–phenotype correlation is that if the Wilson ATPase is absent or nonfunctional, severe disease (usually hepatic) commonly develops in the first decade of life. Clinically evident Wilson disease is fatal if not treated. The broad age range of diagnoses (3–80+ years) raises the question of incomplete penetrance, an issue along with gene modifiers currently under investigation. The possibility that mutations in other genes may result in Wilson disease has not been entirely eliminated. The contribution of ATP7B to non‐Wilsonian diseases is being determined. Key Concepts: Wilson disease is a rare (30 per million population, on average) autosomal‐recessive disorder of hepatic copper disposition. Wilson disease can present as almost any form of hepatic disease, or as neurological movement disorders, or as psychiatric disease. Genetic diagnosis is definitive; clinical application of genetic findings requires skilled interpretation; success rate for identifying one or both mutations can be highly variable. Most affected individuals are compound heterozygotes. Genetic testing is most efficient for investigating first‐degree relatives, who must be assessed for Wilson disease once a single family member has been diagnosed with Wilson disease. Wilson disease is an example of ‘endogenous hepatotoxicity’ where a normal component of the functioning organism is mishandled and becomes toxic. The mechanism of liver (and likely brain) damage involves oxidative stress with damage to mitochondria; apoptosis is typical. Concepts relating to drug‐induced hepatotoxicity are highly relevant to understanding the mechanism of damage and devising treatments. Metalloproteomics is a research strategy for examining copper disposition in normal and abnormal models/organisms. More than 500 mutations in ATP7B have been identified. These are mainly missense mutations, and less frequently small deletions or insertions, nonsense or splice‐site mutations. In contrast, the homologous gene ATP7A , abnormal in the X‐linked recessive disorder Menkes disease (with copper insufficiency), displays mainly large deletions. Predictably, the phenotypic variation depends on complex factors besides the genotype. The only important genotype–phenotype correlation is that severe disease (usually hepatic) typically develops very early in life if the Wilson ATPase is absent or nonfunctional. A convincing example of this correlation is provided by comparison of the Atp7b ‐knockout mouse and the toxic milk (tx‐j) mouse, which has a point mutation. Few modifying genes have been identified. Candidates include apolipoprotein E, human prion gene and BIRC4/XIAP. Females seem to have more severe Wilson disease. Other disorders of copper disposition exist. These include defects in ceruloplasmin production (aceruloplasminaemia and AT‐1 defect), various congenital glycosylation disorders, Indian childhood cirrhosis and its variants. In the Bedlington terrier, hepatic copper toxicosis is usually related to mutations in the gene for COMMD1. ATP7B may play a secondary role in some forms of Alzheimer disease. The Wilson ATPase plays a direct role in the hepatocellular handling of platinum compounds such as cisplatin.

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Wilson disease: Novel mutations in theATP7B gene and clinical correlation in Brazilian patients

Cited by 104 publications

References 17 publications

Wilson's disease in Southern Brazil: genotype-phenotype correlation and description of two novel mutations in ATP7B gene

Wilson's disease in Southern Brazil: genotype-phenotype correlation and description of two novel mutations in ATP7B gene

Wilson's Disease: a case report and a historical review

Molecular Genetics of Wilson Disease

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