Clinical, molecular and functional characterization of two novel mutations associated to compound heterozygous FHBL

Valenti V; Garlaschelli K; Cefalù Ab; Grigore L; Spina R; Uboldi P; Noto D; Norata Gd; Ghiglioni D; Fiocchi L; Terracciano L; Zoja A; Catapano Al; Averna M

Risultato della ricerca: Paper

Abstract

Introduction. Primary hypobetalipoproteinemia (pHBL) is a monogenic heterogeneous condition characterized by total cholesterol (TC) and/or LDL cholesterol (LDL-C) levels below the 5th percentile of the reference population. Heterozygous APOB gene mutations are responsible for the majority of the dominant pHBL causing the familial hypobetalipoproteinemia (FHBL). The clinical phenotype of heterozygous FHBL is usually mild. The homozygous or compound heterozygous APOB mutations are in some cases responsible for a more severe biochemical and clinical phenotype, similar to the abetalipoproteinemia (ABL) due to homozygous mutations in the MTP gene, characterized by intestinal malabsorption, pigmentary retinal degeneration, ataxic neuropathy, and almost undetectable levels of LDL-C and APOB. methods and Results. In this report we describe the clinical and molecular characterization of a child with severe hypolipidemia and a clinical phenotype suggesting the clinical diagnosis of ABL. Parents serum total cholesterol (TC) and LDL cholesterol (LDLC) levels however were below the 5th percentile thus suggesting that the proband could have been homozygous or compound heterozygous FHBL. Western blot analysis showed the presence of two truncated forms of apoB protein of different molecular weight in the serum of the proband; a single truncated form was then observed in the mother on in the father. The direct sequence the apoB gene in the proband allowed to identify two novel mutations: a) a mutation of the donor splice site of intron 23 of the APOB gene (c.3824+1G>C) and b) a mutation of the acceptor site of intron 23 of of the ApoB gene (c.3825-1G>A). The parents were heterozygous carriers. Splicing mechanisms of both mutations were further characterized by minigene assay in vitro. Conclusion. In this report we have characterized at the clinical and molecular level a rare case of compound heterozygous FHBL which carries two novel splicing mutations of the APOB gene affecting the splicing machinery.
Lingua originaleEnglish
Stato di pubblicazionePublished - 2012

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Hypobetalipoproteinemias
Mutation
Apolipoproteins B
Abetalipoproteinemia
LDL Cholesterol
Genes
Cholesterol
Phenotype
Retinal Degeneration
RNA Splice Sites
Serum
Fathers
Introns
Familial Hypobetalipoproteinemia
Parents
Western Blotting
Mothers

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Valenti V; Garlaschelli K; Cefalù Ab; Grigore L; Spina R; Uboldi P; Noto D; Norata Gd; Ghiglioni D; Fiocchi L; Terracciano L; Zoja A; Catapano Al; Averna M (2012). Clinical, molecular and functional characterization of two novel mutations associated to compound heterozygous FHBL.

Clinical, molecular and functional characterization of two novel mutations associated to compound heterozygous FHBL. / Valenti V; Garlaschelli K; Cefalù Ab; Grigore L; Spina R; Uboldi P; Noto D; Norata Gd; Ghiglioni D; Fiocchi L; Terracciano L; Zoja A; Catapano Al; Averna M.

2012.

Risultato della ricerca: Paper

Valenti V; Garlaschelli K; Cefalù Ab; Grigore L; Spina R; Uboldi P; Noto D; Norata Gd; Ghiglioni D; Fiocchi L; Terracciano L; Zoja A; Catapano Al; Averna M 2012, 'Clinical, molecular and functional characterization of two novel mutations associated to compound heterozygous FHBL'.
Valenti V; Garlaschelli K; Cefalù Ab; Grigore L; Spina R; Uboldi P; Noto D; Norata Gd; Ghiglioni D; Fiocchi L; Terracciano L; Zoja A; Catapano Al; Averna M. Clinical, molecular and functional characterization of two novel mutations associated to compound heterozygous FHBL. 2012.
Valenti V; Garlaschelli K; Cefalù Ab; Grigore L; Spina R; Uboldi P; Noto D; Norata Gd; Ghiglioni D; Fiocchi L; Terracciano L; Zoja A; Catapano Al; Averna M. / Clinical, molecular and functional characterization of two novel mutations associated to compound heterozygous FHBL.
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title = "Clinical, molecular and functional characterization of two novel mutations associated to compound heterozygous FHBL",
abstract = "Introduction. Primary hypobetalipoproteinemia (pHBL) is a monogenic heterogeneous condition characterized by total cholesterol (TC) and/or LDL cholesterol (LDL-C) levels below the 5th percentile of the reference population. Heterozygous APOB gene mutations are responsible for the majority of the dominant pHBL causing the familial hypobetalipoproteinemia (FHBL). The clinical phenotype of heterozygous FHBL is usually mild. The homozygous or compound heterozygous APOB mutations are in some cases responsible for a more severe biochemical and clinical phenotype, similar to the abetalipoproteinemia (ABL) due to homozygous mutations in the MTP gene, characterized by intestinal malabsorption, pigmentary retinal degeneration, ataxic neuropathy, and almost undetectable levels of LDL-C and APOB. methods and Results. In this report we describe the clinical and molecular characterization of a child with severe hypolipidemia and a clinical phenotype suggesting the clinical diagnosis of ABL. Parents serum total cholesterol (TC) and LDL cholesterol (LDLC) levels however were below the 5th percentile thus suggesting that the proband could have been homozygous or compound heterozygous FHBL. Western blot analysis showed the presence of two truncated forms of apoB protein of different molecular weight in the serum of the proband; a single truncated form was then observed in the mother on in the father. The direct sequence the apoB gene in the proband allowed to identify two novel mutations: a) a mutation of the donor splice site of intron 23 of the APOB gene (c.3824+1G>C) and b) a mutation of the acceptor site of intron 23 of of the ApoB gene (c.3825-1G>A). The parents were heterozygous carriers. Splicing mechanisms of both mutations were further characterized by minigene assay in vitro. Conclusion. In this report we have characterized at the clinical and molecular level a rare case of compound heterozygous FHBL which carries two novel splicing mutations of the APOB gene affecting the splicing machinery.",
author = "{Valenti V; Garlaschelli K; Cefal{\`u} Ab; Grigore L; Spina R; Uboldi P; Noto D; Norata Gd; Ghiglioni D; Fiocchi L; Terracciano L; Zoja A; Catapano Al; Averna M} and Maurizio Averna and Cefalu', {Angelo Baldassare} and Vincenza Valenti and Rossella Spina and Davide Noto",
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TY - CONF

T1 - Clinical, molecular and functional characterization of two novel mutations associated to compound heterozygous FHBL

AU - Valenti V; Garlaschelli K; Cefalù Ab; Grigore L; Spina R; Uboldi P; Noto D; Norata Gd; Ghiglioni D; Fiocchi L; Terracciano L; Zoja A; Catapano Al; Averna M

AU - Averna, Maurizio

AU - Cefalu', Angelo Baldassare

AU - Valenti, Vincenza

AU - Spina, Rossella

AU - Noto, Davide

PY - 2012

Y1 - 2012

N2 - Introduction. Primary hypobetalipoproteinemia (pHBL) is a monogenic heterogeneous condition characterized by total cholesterol (TC) and/or LDL cholesterol (LDL-C) levels below the 5th percentile of the reference population. Heterozygous APOB gene mutations are responsible for the majority of the dominant pHBL causing the familial hypobetalipoproteinemia (FHBL). The clinical phenotype of heterozygous FHBL is usually mild. The homozygous or compound heterozygous APOB mutations are in some cases responsible for a more severe biochemical and clinical phenotype, similar to the abetalipoproteinemia (ABL) due to homozygous mutations in the MTP gene, characterized by intestinal malabsorption, pigmentary retinal degeneration, ataxic neuropathy, and almost undetectable levels of LDL-C and APOB. methods and Results. In this report we describe the clinical and molecular characterization of a child with severe hypolipidemia and a clinical phenotype suggesting the clinical diagnosis of ABL. Parents serum total cholesterol (TC) and LDL cholesterol (LDLC) levels however were below the 5th percentile thus suggesting that the proband could have been homozygous or compound heterozygous FHBL. Western blot analysis showed the presence of two truncated forms of apoB protein of different molecular weight in the serum of the proband; a single truncated form was then observed in the mother on in the father. The direct sequence the apoB gene in the proband allowed to identify two novel mutations: a) a mutation of the donor splice site of intron 23 of the APOB gene (c.3824+1G>C) and b) a mutation of the acceptor site of intron 23 of of the ApoB gene (c.3825-1G>A). The parents were heterozygous carriers. Splicing mechanisms of both mutations were further characterized by minigene assay in vitro. Conclusion. In this report we have characterized at the clinical and molecular level a rare case of compound heterozygous FHBL which carries two novel splicing mutations of the APOB gene affecting the splicing machinery.

AB - Introduction. Primary hypobetalipoproteinemia (pHBL) is a monogenic heterogeneous condition characterized by total cholesterol (TC) and/or LDL cholesterol (LDL-C) levels below the 5th percentile of the reference population. Heterozygous APOB gene mutations are responsible for the majority of the dominant pHBL causing the familial hypobetalipoproteinemia (FHBL). The clinical phenotype of heterozygous FHBL is usually mild. The homozygous or compound heterozygous APOB mutations are in some cases responsible for a more severe biochemical and clinical phenotype, similar to the abetalipoproteinemia (ABL) due to homozygous mutations in the MTP gene, characterized by intestinal malabsorption, pigmentary retinal degeneration, ataxic neuropathy, and almost undetectable levels of LDL-C and APOB. methods and Results. In this report we describe the clinical and molecular characterization of a child with severe hypolipidemia and a clinical phenotype suggesting the clinical diagnosis of ABL. Parents serum total cholesterol (TC) and LDL cholesterol (LDLC) levels however were below the 5th percentile thus suggesting that the proband could have been homozygous or compound heterozygous FHBL. Western blot analysis showed the presence of two truncated forms of apoB protein of different molecular weight in the serum of the proband; a single truncated form was then observed in the mother on in the father. The direct sequence the apoB gene in the proband allowed to identify two novel mutations: a) a mutation of the donor splice site of intron 23 of the APOB gene (c.3824+1G>C) and b) a mutation of the acceptor site of intron 23 of of the ApoB gene (c.3825-1G>A). The parents were heterozygous carriers. Splicing mechanisms of both mutations were further characterized by minigene assay in vitro. Conclusion. In this report we have characterized at the clinical and molecular level a rare case of compound heterozygous FHBL which carries two novel splicing mutations of the APOB gene affecting the splicing machinery.

UR - http://hdl.handle.net/10447/104760

M3 - Paper

ER -