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

Maurizio Averna, Vincenza Valenti, Rossella Spina, Angelo Baldassare Cefalu', James P. Pirruccello, Namrata Gupta, Sekar Kathiresan, Patrizia Tarugi, Stacey Gabriel, Davide Noto

Risultato della ricerca: Article

37 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)2021-2025
Numero di pagine5
RivistaArteriosclerosis, Thrombosis, and Vascular Biology
Volume33
Stato di pubblicazionePublished - 2013

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Exome
Fatty Liver
Liver Neoplasms
Mutation
Cholesterol
Fibrosis
Exons
Hypobetalipoproteinemias
Inheritance Patterns
Nonsense Codon
Liver Cirrhosis
LDL Cholesterol
Nucleotides
Carcinoma
Liver
Genes

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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A Novel APOB Mutation Identified by Exome Sequencing Cosegregates With Steatosis, Liver Cancer, and Hypocholesterolemia. / Averna, Maurizio; Valenti, Vincenza; Spina, Rossella; Cefalu', Angelo Baldassare; Pirruccello, James P.; Gupta, Namrata; Kathiresan, Sekar; Tarugi, Patrizia; Gabriel, Stacey; Noto, Davide.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 33, 2013, pag. 2021-2025.

Risultato della ricerca: Article

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title = "A Novel APOB Mutation Identified by Exome Sequencing Cosegregates With Steatosis, Liver Cancer, and Hypocholesterolemia.",
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.",
author = "Maurizio Averna and Vincenza Valenti and Rossella Spina and Cefalu', {Angelo Baldassare} and Pirruccello, {James P.} and Namrata Gupta and Sekar Kathiresan and Patrizia Tarugi and Stacey Gabriel and Davide Noto",
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T1 - A Novel APOB Mutation Identified by Exome Sequencing Cosegregates With Steatosis, Liver Cancer, and Hypocholesterolemia.

AU - Averna, Maurizio

AU - Valenti, Vincenza

AU - Spina, Rossella

AU - Cefalu', Angelo Baldassare

AU - Pirruccello, James P.

AU - Gupta, Namrata

AU - Kathiresan, Sekar

AU - Tarugi, Patrizia

AU - Gabriel, Stacey

AU - Noto, Davide

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

UR - http://hdl.handle.net/10447/77662

M3 - Article

VL - 33

SP - 2021

EP - 2025

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

SN - 1079-5642

ER -