A Novel APOB Mutation Identified by Exome Sequencing Cosegregates With Steatosis, Liver Cancer, and Hypocholesterolemia

Abstract

Objective In familial hypobetalipoproteinemia (FHBL), 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 (LDL) 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 four more subjects died of either hepatocarcinoma or carcinoma on cirrhosis. To identify the causal mutation in this family, we performed exome sequencing in two 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 due 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 non-carriers 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.

A “systems medicine” approach to the study of non-alcoholic fatty liver disease

“…Therefore, both PNPLA3-I148M and TM6SF2E167K may be useful in identifying NAFLD patients at a higher risk of hepatic than cardiovascular complications and the PNPLA3-based categorisation of NAFLD may have therapeutic implications. Preliminary data suggest that I148M-homozygous subjects might benefit from weight loss after a short-term low-carbohydrate diet [68,78]; however, disease progression is modulated by multiple environmental and genetic factors [48,[79][80][81][82]. Thus, PNPLA3 I148M and TM6SF2 variants plus/minus a family history for cirrhosis and/or HCC and ethnicity can be used to stratify patients at risk in clinical practice ( Table 2).…”

Nem alkoholos zsírmáj és hepatocellularis carcinoma – 2016

“…További NAFLD-t (és HCC-t) érintő génmutációk: az apolipoprotein-B gén (Apo-B) "loss-of function" variánsa csökkent VLDL-szekrécióhoz és steatosishoz vezet [9,25], míg a telomerázreduktáz gén (TERT) mutánsai a sejtöregedésben jelentősek [9,26]. Két praemalignus biomarker, a keraten multigén család tagja (KRT23) és az aldolázreduktáz (AKR1B10) gén upregulációja a steatosisból való korai NASH-és HCC-progresszióban ját-szik szerepet [27].…”

Exome Sequencing in Suspected Monogenic Dyslipidemias

“…However, this mutation occurs at a highly conserved position within the highly conserved LDLR-binding domain of ApoB where other missense mutations causing ADH have been identified. A threonine for alanine substitution at this position is computationally predicted to be damaging. § This mutation has been previously identified as causing ADH in other families 5 . || A report detailing this mutation has been previously published 23 . # To our knowledge this mutation has not been previously identified as causing familial hypobetalipoproteinemia (FHBL) however this is expected type of causal mutation for FHBL, inducing a premature truncation of ApoB. ** To our knowledge this mutation has not been previously identified as causing Tangier disease. However, this mutation is in the second conserved nucleotide-binding domain (ATP binding cassette) within the Walker A/P-loop of ABCA1 .…”