Familial chylomicronemia (type I hyperlipoproteinemia) due to a single missense mutation in the lipoprotein lipase gene.

Ameis, Detlev; Kobayashi, Junji; Davis, Richard C.; Ben-Zeev, Osnat; Malloy, M J; Kane, John P.; Lee, G; Wong, Howard; Havel, R J; Schotz, Michael C.

doi:10.1172/jci115114

Cited by 60 publications

(21 citation statements)

References 44 publications

(29 reference statements)

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“…These effects ofthe mutation at Asp2Os have more similarities to those of the mutations at Arg243 in exon 6 ( Fig. 5) and at Gly'42 in exon 4 (20) rather than to those of the other mutations in exon 5. Therefore, although the dispersion ofthe mutations in exon 5 (Ala'76, Gly'88, IIe'`, Asp2t4) implies the presence of an extensive region necessary for normal LPL function, the amino acid substitutions that occur within the same region can cause different effects on the enzyme.…”

Section: Discussionmentioning

confidence: 75%

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Heterogeneous mutations in the human lipoprotein lipase gene in patients with familial lipoprotein lipase deficiency.

Gotoda

Yamada²,

Kawamura³

et al. 1991

J. Clin. Invest.

113

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The DNA sequences were determined for the lipoprotein lipase (LPL) gene from five unrelated Japanese patients with familial LPL deficiency. The results demonstrated that all five patients are homozygotes for distinct point mutations dispersed throughout the LPL gene. Patient 1 has a G-to-A transition at the first nucleotide of intron 2, which abolishes normal splicing.Patient 2 has a nonsense mutation in exon 3 (Tyr" -> Stop) and patient 3 in exon 8 (Trp"2 --Stop). The latter mutation emphasizes the importance of the carboxy-terminal portion of the enzyme in the expression of LPL activity. Missense mutations were identified in patient 4 (Asp2'-Glu) and patient 5 (Arg'3 His) in the strictly conserved amino acids. Expression study of both mutant genes in COS-1 cells produced inactive enzymes, establishing the functional significance of the two missense mutations. In these patients, postheparin plasma LPL mass was either virtually absent (patients 1 and 2) or significantly decreased (patients 3-5). To detect these mutations more easily, we developed a rapid diagnostic test for each mutation. We also determined the DNA haplotypes for patients and confirmed the occurrence of multiple mutations on the chromosomes with an identical haplotype. These results demonstrate that familial LPL deficiency is a heterogeneous genetic disease caused by a wide variety of gene mutations. (J. Clin. Invest.

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Section: Discussionmentioning

confidence: 75%

“…The human LPL gene has a span of 30 kb and comprises 10 exons that code for a 475-amino acid protein including a 27-amino acid signal peptide. Major rearrangements ofthe LPL gene locus were first reported in a population of Caucasian patients (13,14), and recently several point mutations were also identified in American patients (15)(16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

Heterogeneous mutations in the human lipoprotein lipase gene in patients with familial lipoprotein lipase deficiency.

Gotoda

Yamada²,

Kawamura³

et al. 1991

J. Clin. Invest.

113

View full text Add to dashboard Cite

show abstract

“…Several groups have reported mutations of the LPL gene in patients with primary LPL deficiency. These are gene rearrangements (17,18), missense mutations (19)(20)(21)(22)(23)(24)(25), nonsense mutations (26), addition of several bases (27), and mutation in exon-intron boundary region (22).…”

Section: Introductionmentioning

confidence: 99%

Molecular studies on primary lipoprotein lipase (LPL) deficiency. One base deletion (G916) in exon 5 of LPL gene causes no detectable LPL protein due to the absence of LPL mRNA transcript.

Takagi¹,

Ikeda²,

Tsutsumi³

et al. 1992

J. Clin. Invest.

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We have systematically investigated a genetic defect resulting in a primary lipoprotein lipase (LPL) deficiency in a proband TN and his affected brother SN, both manifesting familial hyperchylomicronemia. Neither LPL activity nor immunoreactive LPL mass was detected in postheparin plasma from the two patients. Immunocytochemical and biosynthetic studies on the proband's monocyte-derived macrophages with rabbit antihuman LPL antiserum revealed that no immunochemically detectable LPL protein was found in either the cells or culture medium, whereas LPL having a molecular mass of 61 kD was detected in normal cells. No detectable LPL mRNA was identified from poly(A)+RNA of the proband's macrophages by Northern blot analysis, and grossly visible LPL gene rearrangement was not observed by Southern blot analysis. Sequence analysis of polymerase chain reaction-amplified LPL gene exons detected one base deletion of G (first position of Ala221) at base 916 in exon 5 which leads to a premature termination by a frameshift. This mutation, designated as LPLAi and resulting in the loss of an Alul restriction enzyme site, was newly identified. We further analyzed the LPL gene from the two patients and their family members by digestion with AluL. Both patients were homozygous for LPLAJt allele, while their spouses did not have this mutation. As genetically expected, their children were all heterozygous for LPLmt.. We conclude that primary LPL deficiency in the proband was caused by a lack of enzyme synthesis due to the absence of LPL mRNA resulting from one base deletion ofG in exon 5, and that heterozygous LPLAi. deficient subjects show almost half value of control LPL mass. (J. Clin. Invest. 1992. 89:581-591.)

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“…In the absence of GPIHBP1, LPL's triglyceride hydrolase domain unfolds, resulting in a rapid decline in catalytic activity (4). GPIHBP1 and LPL are equally important for intravascular lipolysis; a deficiency of either protein markedly impairs intravascular triglyceride hydrolysis and leads to severe hypertriglyceridemia (chylomicronemia) (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). The importance of GPIHBP1 and LPL for plasma triglyceride metabolism in mammals has been underscored by human genetics; specific missense mutations in either protein can abolish LPL-GPIHBP1 interactions, resulting in reduced delivery of LPL to the capillary lumen, impaired TRL processing, and severe hypertriglyceridemia (6,7,(9)(10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Lipoprotein lipase reaches the capillary lumen in chickens despite an apparent absence of GPIHBP1

He¹,

Jung

et al. 2017

JCI Insight

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Familial chylomicronemia (type I hyperlipoproteinemia) due to a single missense mutation in the lipoprotein lipase gene.

Cited by 60 publications

References 44 publications

Heterogeneous mutations in the human lipoprotein lipase gene in patients with familial lipoprotein lipase deficiency.

Heterogeneous mutations in the human lipoprotein lipase gene in patients with familial lipoprotein lipase deficiency.

Molecular studies on primary lipoprotein lipase (LPL) deficiency. One base deletion (G916) in exon 5 of LPL gene causes no detectable LPL protein due to the absence of LPL mRNA transcript.

Lipoprotein lipase reaches the capillary lumen in chickens despite an apparent absence of GPIHBP1

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