Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Case Reports
. 2013 Aug;33(8):2021-5.
doi: 10.1161/ATVBAHA.112.301101. Epub 2013 May 30.

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

Angelo B Cefalù  1 , James P Pirruccello, Davide Noto, Stacey Gabriel, Vincenza Valenti, Namrata Gupta, Rossella Spina, Patrizia Tarugi, Sekar Kathiresan, Maurizio R Averna
Affiliations
Case Reports

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

Angelo B Cefalù et al. Arterioscler Thromb Vasc Biol. 2013 Aug.

Abstract

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.

Keywords: carcinoma, hepatocellular; exome; fatty liver; hypobetalipoproteinemia, familial, 1.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Pedigree of the Family with Familial Hypobetalipoproteinemia. The proband is indicated by an arrow. Half filled symbol: affected subjects carriers of the mutation K2240X of the APOB gene; Empty symbol: unaffected subjects. RHOB: ras homolog gene family, member B precursor; WT: wild-type The ? indicate that the cholesterol phenotype is unknown Subjects marked by an * died of hepatocarcinoma. Subject#: liver cirrhosis
See this image and copyright information in PMC

References

    1. Tarugi P, Averna M, Di Leo E, Cefalù AB, Noto D, Magnolo L, Cattin L, Bertolini S, Calandra S. Molecular diagnosis of hypobetalipoproteinemia: an ENID review. Atherosclerosis. 2007;195:e19–e27. - PubMed
    1. Schonfeld G. Familial hypobetalipoproteinemia: a review. J. Lipid Res. 2003;44:878–883. - PubMed
    1. Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 2005;37:161–165. - PubMed
    1. Fasano T, Cefalù AB, Di Leo E, Noto D, Pollaccia D, Bocchi L, Valenti V, Bonardi R, Guardamagna O, Averna M, Tarugi P. A novel loss of function mutation of PCSK9 gene in white subjects with low-plasma low-density lipoprotein cholesterol. Arterioscler Thromb Vasc Biol. 2007;27:677–681. - PubMed
    1. Miyake Y, Kimura R, Kokubo Y, Okayama A, Tomoike H, Yamamura T, Miyata T. Genetic variants in PCSK9 in the Japanese population: rare genetic variants in PCSK9 might collectively contribute to plasma LDL cholesterol levels in the general population. Atherosclerosis. 2008;196:29–36. - PubMed

Publication types