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Arterioscler Thromb Vasc Biol DOI:10.1161/ATVBAHA.112.301101

A novel APOB mutation identified by exome sequencing cosegregates with steatosis, liver cancer, and hypocholesterolemia.

Publication TypeJournal Article
Year of Publication2013
AuthorsCefalù, AB, Pirruccello, JP, Noto, D, Gabriel, S, Valenti, V, Gupta, N, Spina, R, Tarugi, P, Kathiresan, S, Averna, MR
JournalArterioscler Thromb Vasc Biol
Date Published2013 Aug
KeywordsAdult, Apolipoproteins B, Cholesterol, Codon, Nonsense, Exome, Family Health, Fatty Liver, Female, Humans, Hypobetalipoproteinemias, Liver Neoplasms, Male, Middle Aged, Pedigree, Young Adult

OBJECTIVE: In familial hypobetalipoproteinemia, fatty liver is a characteristic feature, and there are several reports of associated cirrhosis and hepatocarcinoma. We investigated a large kindred in which low-density lipoprotein cholesterol, fatty liver, and hepatocarcinoma displayed an autosomal dominant pattern of inheritance.

APPROACH AND RESULTS: The proband was a 25-year-old female with low plasma cholesterol and hepatic steatosis. Low plasma levels of total cholesterol and fatty liver were observed in 10 more family members; 1 member was affected by liver cirrhosis, and 4 more subjects died of either hepatocarcinoma or carcinoma on cirrhosis. To identify the causal mutation in this family, we performed exome sequencing in 2 participants with hypocholesterolemia and fatty liver. Approximately 22 400 single nucleotide variants were identified in each sample. After variant filtering, 300 novel shared variants remained. A nonsense variant, p.K2240X, attributable to an A>T mutation in exon 26 of APOB (c.6718A>T) was identified, and this variant was confirmed by Sanger sequencing. The gentotypic analysis of 16 family members in total showed that this mutation segregated with the low cholesterol trait. In addition, genotyping of the PNPLA3 p.I148M did not show significant frequency differences between carriers and noncarriers of the c.6718A>T APOB gene mutation.

CONCLUSIONS: We used exome sequencing to discover a novel nonsense mutation in exon 26 of APOB (p.K2240X) responsible for low cholesterol and fatty liver in a large kindred. This mutation may also be responsible for cirrhosis and liver cancer in this family.


Alternate JournalArterioscler. Thromb. Vasc. Biol.
PubMed ID23723369
PubMed Central IDPMC3870266
Grant ListR01 HL107816 / HL / NHLBI NIH HHS / United States
R01 HL-107816 / HL / NHLBI NIH HHS / United States