Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients.
Wilson disease (WD) is a rare inherited autosomal recessive disorder caused by a defect in a metal transporting P-type ATPase, resulting in copper overload in various tissues and cells. The aim was to assess both the phenotype in Brazilian WD patients and the corresponding ATP7B genotype. Sixty subjects belonging to 46 pedigrees diagnosed as WD were included in this study. Direct sequencing of all 21 exons within ATP7B and their flanking introns was performed. Demographic, clinical, laboratory and histopathological data at the time of diagnosis were obtained. We identified twenty-five mutations, twelve of them reported for the first time. The c.3402delC mutation had the highest allelic frequency (30.8%), followed by the c.2123T>C (p.L708P) (16.7%). Exons 8 and 15 were the site of 62.5% of the mutations. The common European mutation c.3207C>A (p.H1069Q) was not present at all. Phenotype varied greatly among individuals with the same ATP7B genotype. Our data confirm the heterogeneity of ATP7B genotype in Brazilian WD patients. The mutational spectrum is compatible with the Brazilian history of Mediterranean immigration; however, new mutations, and different frequencies and phenotype associated with the previously known mutations characterize this population. Exons 8 and 15 should be preferentially screened in WD cases from Brazil. Phenotype variation among subjects with the same ATP7B genotype suggests that modifying factors play an additional role in the pathogenesis of WD.
Deguti
Marta M
MM
Department of Gastroenterology, Sao Paulo University School of Medicine, Sao Paulo, Brazil.
Genschel
Janine
J
Cancado
Eduardo L R
EL
Barbosa
Egberto R
ER
Bochow
Bettina
B
Mucenic
Marcos
M
Porta
Gilda
G
Lochs
Herbert
H
Carrilho
Flair J
FJ
Schmidt
Hartmut H-J
HH
D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000483:Alleles; D001938:Brazil; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D000073840:Copper-Transporting ATPases; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006527:Hepatolenticular Degeneration / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D009154:Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012326:RNA Splicing
D027682:Cation Transport Proteins; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases