Isabel De Castro-Orós1, Fernando Civeira2, María Jesús Pueyo3, Rocío Mateo-Gallego2, Alfonso Bolado-Carrancio4, Itziar Lamíquiz-Moneo2, Luis Álvarez-Sala5, Fernando Fabiani6, Montserrat Cofán7, Ana Cenarro2, José Carlos Rodríguez-Rey4, Emilio Ros7, Miguel Pocoví3. 1. Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain; Dpto. Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain. Electronic address: isadco@gmail.com. 2. Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain. 3. Dpto. Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain. 4. Dpto. Biología Molecular. Facultad de Medicina, Universidad de Cantabria and Instituto de Formación e Investigación Marqués de Valdecilla (IFIMAV), Santander, Cantabria, Spain. 5. Lipid Unit, Medicina Interna, Hospital Universitario Gregorio Marañón, RIC, Instituto de Salud Carlos III (ISCIII), Instituto de Investigación Sanitaria Gregorio Marañón and Dpto. Medicina, Facultad de Medicina, Universidad Complutense, Madrid, Spain. 6. Departamento de Bioquímica Clínica, Hospital Universitario Virgen Macarena, Universidad de Sevilla, Sevilla, Spain. 7. Servei d'Endocrinologia i Nutrició, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Hospital Clínic, Barcelona and Ciber Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.
Abstract
BACKGROUND: Most primary severe hypertriglyceridemias (HTGs) are diagnosed in adults, but their molecular foundations have not been completely elucidated. OBJECTIVE: We aimed to identify rare dysfunctional mutations in genes encoding regulators of lipoprotein lipase (LPL) function in patients with familial and non-familial primary HTG. METHODS: We sequenced promoters, exons, and exon-intron boundaries of LPL, APOA5, LMF1, and GPIHBP1 in 118 patients with severe primary HTG (triglycerides >500 mg/dL) and 53 normolipidemic controls. Variant functionality was analyzed using predictive software and functional assays for mutations in regulatory regions. RESULTS: We identified 29 rare variants, 10 of which had not been previously described: c.(-16A>G), c.(1018+2G>A), and p.(His80Arg) in LPL; p.(Arg143Alafs*57) in APOA5; p.(Val140Ile), p.(Leu235Ile), p.(Lys520*), and p.(Leu552Arg) in LMF1; and c.(-83G>A) and c.(-192A>G) in GPIHBP1. The c.(1018+2G>A) variant led to deletion of exon 6 in LPL cDNA, whereas the c.(-16A>G) analysis showed differences in the affinity for nuclear proteins. Overall, 20 (17.0%) of the patients carried at least one allele with a rare pathogenic variant in LPL, APOA5, LMF1, or GPIHBP1. The presence of a rare pathogenic variant was not associated with lipid values, family history of HTG, clinical diagnosis, or previous pancreatitis. CONCLUSIONS: Less than one in five subjects with triglycerides >500 mg/dL and no major secondary cause for HTG may carry a rare pathogenic mutation in LPL, APOA5, LMF1, or GPIHBP1. The presence of a rare pathogenic variant is not associated with a differential phenotype.
BACKGROUND: Most primary severe hypertriglyceridemias (HTGs) are diagnosed in adults, but their molecular foundations have not been completely elucidated. OBJECTIVE: We aimed to identify rare dysfunctional mutations in genes encoding regulators of lipoprotein lipase (LPL) function in patients with familial and non-familial primary HTG. METHODS: We sequenced promoters, exons, and exon-intron boundaries of LPL, APOA5, LMF1, and GPIHBP1 in 118 patients with severe primary HTG (triglycerides >500 mg/dL) and 53 normolipidemic controls. Variant functionality was analyzed using predictive software and functional assays for mutations in regulatory regions. RESULTS: We identified 29 rare variants, 10 of which had not been previously described: c.(-16A>G), c.(1018+2G>A), and p.(His80Arg) in LPL; p.(Arg143Alafs*57) in APOA5; p.(Val140Ile), p.(Leu235Ile), p.(Lys520*), and p.(Leu552Arg) in LMF1; and c.(-83G>A) and c.(-192A>G) in GPIHBP1. The c.(1018+2G>A) variant led to deletion of exon 6 in LPL cDNA, whereas the c.(-16A>G) analysis showed differences in the affinity for nuclear proteins. Overall, 20 (17.0%) of the patients carried at least one allele with a rare pathogenic variant in LPL, APOA5, LMF1, or GPIHBP1. The presence of a rare pathogenic variant was not associated with lipid values, family history of HTG, clinical diagnosis, or previous pancreatitis. CONCLUSIONS: Less than one in five subjects with triglycerides >500 mg/dL and no major secondary cause for HTG may carry a rare pathogenic mutation in LPL, APOA5, LMF1, or GPIHBP1. The presence of a rare pathogenic variant is not associated with a differential phenotype.
Authors: Xuchen Hu; Geesje M Dallinga-Thie; G Kees Hovingh; Sandy Y Chang; Norma P Sandoval; Tiffany Ly P Dang; Isamu Fukamachi; Kazuya Miyashita; Katsuyuki Nakajima; Masami Murakami; Loren G Fong; Michael Ploug; Stephen G Young; Anne P Beigneux Journal: J Clin Lipidol Date: 2017-06-13 Impact factor: 4.766
Authors: Miklós Péterfy; Candy Bedoya; Carola Giacobbe; Carmen Pagano; Marco Gentile; Paolo Rubba; Giuliana Fortunato; Maria Donata Di Taranto Journal: J Clin Lipidol Date: 2018-07-25 Impact factor: 4.766