A NOVEL APOB MUTATION IDENTIFIED BY EXOME SEQUENCING COSEGREGATES WITH STEATOSIS, LIVER CANCER AND HYPOCHOLESTEROLEMIA

Cefalù Ab; Pirruccello, Jp; Noto, D; Gabriel, S; Gupta, N; Tarugi, P; Kathiresan, S

Risultato della ricerca: Paper

37 Citazioni (Scopus)

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 identi- ed in each sample. After variant ltering, 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 identi ed and this variant was con rmed 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 signi cant 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.
Lingua originaleEnglish
Stato di pubblicazionePublished - 2013

Fingerprint

Exome
Apolipoproteins B
Fatty Liver
Mutation
Cholesterol
Liver Cirrhosis
Exons
Hypobetalipoproteinemias
LDL Cholesterol
Fibrosis
Nucleotides
Carcinoma
Liver
Genes

Cita questo

Cefalù Ab; Pirruccello, Jp; Noto, D; Gabriel, S; Gupta, N; Tarugi, P; Kathiresan, S (2013). A NOVEL APOB MUTATION IDENTIFIED BY EXOME SEQUENCING COSEGREGATES WITH STEATOSIS, LIVER CANCER AND HYPOCHOLESTEROLEMIA.

A NOVEL APOB MUTATION IDENTIFIED BY EXOME SEQUENCING COSEGREGATES WITH STEATOSIS, LIVER CANCER AND HYPOCHOLESTEROLEMIA. / Cefalù Ab; Pirruccello, Jp; Noto, D; Gabriel, S; Gupta, N; Tarugi, P; Kathiresan, S.

2013.

Risultato della ricerca: Paper

Cefalù Ab; Pirruccello, Jp; Noto, D; Gabriel, S; Gupta, N; Tarugi, P; Kathiresan, S 2013, 'A NOVEL APOB MUTATION IDENTIFIED BY EXOME SEQUENCING COSEGREGATES WITH STEATOSIS, LIVER CANCER AND HYPOCHOLESTEROLEMIA'.
Cefalù Ab; Pirruccello, Jp; Noto, D; Gabriel, S; Gupta, N; Tarugi, P; Kathiresan, S. A NOVEL APOB MUTATION IDENTIFIED BY EXOME SEQUENCING COSEGREGATES WITH STEATOSIS, LIVER CANCER AND HYPOCHOLESTEROLEMIA. 2013.
Cefalù Ab; Pirruccello, Jp; Noto, D; Gabriel, S; Gupta, N; Tarugi, P; Kathiresan, S. / A NOVEL APOB MUTATION IDENTIFIED BY EXOME SEQUENCING COSEGREGATES WITH STEATOSIS, LIVER CANCER AND HYPOCHOLESTEROLEMIA.
@conference{b91b07f28a6a456ab9d2b816e2c10527,
title = "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 identi- ed in each sample. After variant ltering, 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 identi ed and this variant was con rmed 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 signi cant 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.",
author = "{Cefal{\`u} Ab; Pirruccello, Jp; Noto, D; Gabriel, S; Gupta, N; Tarugi, P; Kathiresan, S} and Maurizio Averna and Cefalu', {Angelo Baldassare} and Vincenza Valenti and Francesca Fayer and Rossella Spina and Altieri, {Grazia Ida} and Ornella Palesano",
year = "2013",
language = "English",

}

TY - CONF

T1 - A NOVEL APOB MUTATION IDENTIFIED BY EXOME SEQUENCING COSEGREGATES WITH STEATOSIS, LIVER CANCER AND HYPOCHOLESTEROLEMIA

AU - Cefalù Ab; Pirruccello, Jp; Noto, D; Gabriel, S; Gupta, N; Tarugi, P; Kathiresan, S

AU - Averna, Maurizio

AU - Cefalu', Angelo Baldassare

AU - Valenti, Vincenza

AU - Fayer, Francesca

AU - Spina, Rossella

AU - Altieri, Grazia Ida

AU - Palesano, Ornella

PY - 2013

Y1 - 2013

N2 - 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 identi- ed in each sample. After variant ltering, 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 identi ed and this variant was con rmed 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 signi cant 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.

AB - 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 identi- ed in each sample. After variant ltering, 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 identi ed and this variant was con rmed 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 signi cant 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.

UR - http://hdl.handle.net/10447/104768

M3 - Paper

ER -