Homozygosity for a gross partial gene deletion of the C‐terminal end of ATP7B in a Wilson patient with hepatic and no neurological manifestations

Abstract

We identified a partial gene deletion of ATP7B in a patient with Wilson disease with hepatic onset. The deletion covered exon 20 including major parts of the flanking introns. The breakpoints were identified and the size of the deletion determined to be 2144 bp. The deletion is predicted to lead to a mutated protein product containing 45 aberrant amino acids after transmembrane domain 7, and lacking the transmembrane domain 8 as well as the entire C-terminal cytoplasmic tail. This is the first time a partial gene deletion has been demonstrated in ATP7B. The patient presented at age 10 with hepatic manifestations, including severe jaundice, hepato-splenomegaly, ascites, and spider naevi. The liver biopsy showed fibrosis and early signs of cirrhosis. There was a Kayser-Fleischer ring but no neurological manifestations. All symptoms disappeared with penicillamine therapy. This suggests that the C-terminal cytoplasmatic tail of ATP7B, is not essential for its neurological function. Large deletions in ATP7B may be an overlooked cause of Wilson disease. Patients that are homozygotes for deletions may be valuable for the understanding of the function of various regions of the ATP7B protein.

Clinical presentation and mutations in Danish patients with Wilson disease

“…Approximately 70% of the mutations were located in exons 8, 14, 17, 18, and 20. In patient WD9, a homozygous deletion of exon 21-22 (c.4022-?_4398+?del) was observed as described previously, 14 and a deletion of exon 5-6 (c.1708-?_1946+?del) in the heterozygous form was found in patient WD44. Thus, partial deletions of the ATP7B gene were observed in 4% of the alleles (3/70).…”

Partial USH2A deletions contribute to Usher syndrome in Denmark

“…However, by sequencing exon 12 and exon 19 in the two patients, we found a function-affecting variant c.2023C4T, p. 33 Great care must therefore be exercised, especially when MLPA results indicate the deletion of a single exon.…”

Genotype–phenotype correlation of the Wilson diseaseATP7B gene

“…We read with great interest the paper of Moller et al [2005] showing a delection in ATP7B gene of a Wilson disease (WD) patient with hepatic onset. We recently discovered a new missense homozygous mutation (T1288R) of the ATP7B gene in a patient affected by WD showing liver cirrhosis and Coombspositive hemolytic anemia [Leggio et al, 2006].…”