Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency

Rute Rodrigues; Marta Artieda; Diego Tejedor; Antonio Martínez; Pavlina Konstantinova; Harald Petry; Christian Meyer; Deyanira Corzo; Claus Sundgreen; Hans U Klor; Ioanna Gouni-Berthold; Sabine Westphal; Elisabeth Steinhagen-Thiessen; Ulrich Julius; Karl Winkler; Erik Stroes; Anja Vogt; Phillip Hardt; Heinrich Prophet; Britta Otte; Børge Nordestgaard; Samir S Deeb; John D. Brunzell

doi:10.1016/j.jacl.2015.12.015

Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency

Rute Rodrigues, Marta Artieda, Diego Tejedor, Antonio Martínez, Pavlina Konstantinova, Harald Petry, Christian Meyer, Deyanira Corzo, Claus Sundgreen, Hans U Klor, Ioanna Gouni-Berthold, Sabine Westphal, Elisabeth Steinhagen-Thiessen, Ulrich Julius, Karl Winkler, Erik Stroes, Anja Vogt, Phillip Hardt, Heinrich Prophet, Britta OtteBørge Nordestgaard, Samir S Deeb, John D. Brunzell

Department of Clinical Medicine

23 Citations (Scopus)

Abstract

BACKGROUND: Lipoprotein lipase (LPL) deficiency is a serious lipid disorder of severe hypertriglyceridemia (SHTG) with chylomicronemia. A large number of variants in the LPL gene have been reported but their influence on LPL activity and SHTG has not been completely analyzed. Gaining insight into the deleterious effect of the mutations is clinically essential.

METHODS: We used gene sequencing followed by in-vivo/in-vitro and in-silico tools for classification. We classified 125 rare LPL mutations in 33 subjects thought to have LPL deficiency and in 314 subjects selected for very SHTG.

RESULTS: Of the 33 patients thought to have LPL deficiency, only 13 were homozygous or compound heterozygous for deleterious mutations in the LPL gene. Among the 314 very SHTG patients, 3 were compound heterozygous for pathogenic mutants. In a third group of 51,467 subjects, from a general population, carriers of common variants, Asp9Asn and Asn291Ser, were associated with mild increase in triglyceride levels (11%-35%).

CONCLUSION: In total, 39% of patients clinically diagnosed as LPL deficient had 2 deleterious variants. Three patients selected for very SHTG had LPL deficiency. The deleterious mutations associated with LPL deficiency will assist in the diagnosis and selection of patients as candidates for the presently approved LPL gene therapy.

Original language	English
Journal	Journal of Clinical Lipidology
Volume	10
Issue number	2
Pages (from-to)	394-409
Number of pages	16
ISSN	1933-2874
DOIs	https://doi.org/10.1016/j.jacl.2015.12.015
Publication status	Published - 1 Mar 2016

Keywords

Humans
Hyperlipoproteinemia Type I
Hypertriglyceridemia
Lipoprotein Lipase
Mutation
Oligonucleotide Array Sequence Analysis
Triglycerides
Journal Article
Research Support, Non-U.S. Gov't

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10.1016/j.jacl.2015.12.015

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Rodrigues, R., Artieda, M., Tejedor, D., Martínez, A., Konstantinova, P., Petry, H., Meyer, C., Corzo, D., Sundgreen, C., Klor, H. U., Gouni-Berthold, I., Westphal, S., Steinhagen-Thiessen, E., Julius, U., Winkler, K., Stroes, E., Vogt, A., Hardt, P., Prophet, H., ... Brunzell, J. D. (2016). Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency. Journal of Clinical Lipidology, 10(2), 394-409. https://doi.org/10.1016/j.jacl.2015.12.015

Rodrigues, R, Artieda, M, Tejedor, D, Martínez, A, Konstantinova, P, Petry, H, Meyer, C, Corzo, D, Sundgreen, C, Klor, HU, Gouni-Berthold, I, Westphal, S, Steinhagen-Thiessen, E, Julius, U, Winkler, K, Stroes, E, Vogt, A, Hardt, P, Prophet, H, Otte, B, Nordestgaard, B, Deeb, SS & Brunzell, JD 2016, 'Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency', Journal of Clinical Lipidology, vol. 10, no. 2, pp. 394-409. https://doi.org/10.1016/j.jacl.2015.12.015

@article{2d768fe295d24358895261a66d2e9bfb,

title = "Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency",

abstract = "BACKGROUND: Lipoprotein lipase (LPL) deficiency is a serious lipid disorder of severe hypertriglyceridemia (SHTG) with chylomicronemia. A large number of variants in the LPL gene have been reported but their influence on LPL activity and SHTG has not been completely analyzed. Gaining insight into the deleterious effect of the mutations is clinically essential.METHODS: We used gene sequencing followed by in-vivo/in-vitro and in-silico tools for classification. We classified 125 rare LPL mutations in 33 subjects thought to have LPL deficiency and in 314 subjects selected for very SHTG.RESULTS: Of the 33 patients thought to have LPL deficiency, only 13 were homozygous or compound heterozygous for deleterious mutations in the LPL gene. Among the 314 very SHTG patients, 3 were compound heterozygous for pathogenic mutants. In a third group of 51,467 subjects, from a general population, carriers of common variants, Asp9Asn and Asn291Ser, were associated with mild increase in triglyceride levels (11%-35%).CONCLUSION: In total, 39% of patients clinically diagnosed as LPL deficient had 2 deleterious variants. Three patients selected for very SHTG had LPL deficiency. The deleterious mutations associated with LPL deficiency will assist in the diagnosis and selection of patients as candidates for the presently approved LPL gene therapy.",

keywords = "Humans, Hyperlipoproteinemia Type I, Hypertriglyceridemia, Lipoprotein Lipase, Mutation, Oligonucleotide Array Sequence Analysis, Triglycerides, Journal Article, Research Support, Non-U.S. Gov't",

author = "Rute Rodrigues and Marta Artieda and Diego Tejedor and Antonio Mart{\'i}nez and Pavlina Konstantinova and Harald Petry and Christian Meyer and Deyanira Corzo and Claus Sundgreen and Klor, {Hans U} and Ioanna Gouni-Berthold and Sabine Westphal and Elisabeth Steinhagen-Thiessen and Ulrich Julius and Karl Winkler and Erik Stroes and Anja Vogt and Phillip Hardt and Heinrich Prophet and Britta Otte and B{\o}rge Nordestgaard and Deeb, {Samir S} and Brunzell, {John D.}",

year = "2016",

month = mar,

day = "1",

doi = "10.1016/j.jacl.2015.12.015",

language = "English",

volume = "10",

pages = "394--409",

journal = "Journal of Clinical Lipidology",

issn = "1933-2874",

publisher = "Elsevier",

number = "2",

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TY - JOUR

T1 - Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency

AU - Rodrigues, Rute

AU - Artieda, Marta

AU - Tejedor, Diego

AU - Martínez, Antonio

AU - Konstantinova, Pavlina

AU - Petry, Harald

AU - Meyer, Christian

AU - Corzo, Deyanira

AU - Sundgreen, Claus

AU - Klor, Hans U

AU - Gouni-Berthold, Ioanna

AU - Westphal, Sabine

AU - Steinhagen-Thiessen, Elisabeth

AU - Julius, Ulrich

AU - Winkler, Karl

AU - Stroes, Erik

AU - Vogt, Anja

AU - Hardt, Phillip

AU - Prophet, Heinrich

AU - Otte, Britta

AU - Nordestgaard, Børge

AU - Deeb, Samir S

AU - Brunzell, John D.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - BACKGROUND: Lipoprotein lipase (LPL) deficiency is a serious lipid disorder of severe hypertriglyceridemia (SHTG) with chylomicronemia. A large number of variants in the LPL gene have been reported but their influence on LPL activity and SHTG has not been completely analyzed. Gaining insight into the deleterious effect of the mutations is clinically essential.METHODS: We used gene sequencing followed by in-vivo/in-vitro and in-silico tools for classification. We classified 125 rare LPL mutations in 33 subjects thought to have LPL deficiency and in 314 subjects selected for very SHTG.RESULTS: Of the 33 patients thought to have LPL deficiency, only 13 were homozygous or compound heterozygous for deleterious mutations in the LPL gene. Among the 314 very SHTG patients, 3 were compound heterozygous for pathogenic mutants. In a third group of 51,467 subjects, from a general population, carriers of common variants, Asp9Asn and Asn291Ser, were associated with mild increase in triglyceride levels (11%-35%).CONCLUSION: In total, 39% of patients clinically diagnosed as LPL deficient had 2 deleterious variants. Three patients selected for very SHTG had LPL deficiency. The deleterious mutations associated with LPL deficiency will assist in the diagnosis and selection of patients as candidates for the presently approved LPL gene therapy.

AB - BACKGROUND: Lipoprotein lipase (LPL) deficiency is a serious lipid disorder of severe hypertriglyceridemia (SHTG) with chylomicronemia. A large number of variants in the LPL gene have been reported but their influence on LPL activity and SHTG has not been completely analyzed. Gaining insight into the deleterious effect of the mutations is clinically essential.METHODS: We used gene sequencing followed by in-vivo/in-vitro and in-silico tools for classification. We classified 125 rare LPL mutations in 33 subjects thought to have LPL deficiency and in 314 subjects selected for very SHTG.RESULTS: Of the 33 patients thought to have LPL deficiency, only 13 were homozygous or compound heterozygous for deleterious mutations in the LPL gene. Among the 314 very SHTG patients, 3 were compound heterozygous for pathogenic mutants. In a third group of 51,467 subjects, from a general population, carriers of common variants, Asp9Asn and Asn291Ser, were associated with mild increase in triglyceride levels (11%-35%).CONCLUSION: In total, 39% of patients clinically diagnosed as LPL deficient had 2 deleterious variants. Three patients selected for very SHTG had LPL deficiency. The deleterious mutations associated with LPL deficiency will assist in the diagnosis and selection of patients as candidates for the presently approved LPL gene therapy.

KW - Humans

KW - Hyperlipoproteinemia Type I

KW - Hypertriglyceridemia

KW - Lipoprotein Lipase

KW - Mutation

KW - Oligonucleotide Array Sequence Analysis

KW - Triglycerides

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.jacl.2015.12.015

DO - 10.1016/j.jacl.2015.12.015

M3 - Journal article

C2 - 27055971

SN - 1933-2874

VL - 10

SP - 394

EP - 409

JO - Journal of Clinical Lipidology

JF - Journal of Clinical Lipidology

IS - 2

ER -

Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency

Abstract

Keywords

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