Whole‐Exome Sequencing Reveals <i>GPIHBP1</i> Mutations in Infantile Colitis With Severe Hypertriglyceridemia

Gonzaga‐Jauregui, Claudia; Mir, Sabina; Penney, Samantha; Jhangiani, Shalini N.; Midgen, Craig; Finegold, Milton J.; Wang, Min; Bacino, Carlos A.; Gibbs, Richard A.; Lupski, James R.; Kellermayer, Richárd; Hanchard, Neil A.

doi:10.1097/mpg.0000000000000363

Cited by 20 publications

(13 citation statements)

References 43 publications

(60 reference statements)

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“…A S107C mutation, which introduces an unpaired cysteine into the LU domain, also causes chylomicronemia (Figure 2B) [52]. Q115P and T111P mutations, which introduce a proline adjacent to a conserved cysteine, have also been observed in chylomicronemia patients (Figure 2B) [53, 54]. Chylomicronemia has also been reported in association with a T80K mutation [56], which prevents N-linked glycosylation and would be expected to reduce trafficking of GPIHBP1 to the plasma membrane [22].…”

Section: Gpihbp1 Mutations Cause Chylomicronemiamentioning

confidence: 99%

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GPIHBP1 and Plasma Triglyceride Metabolism

Fong

Young

Beigneux

et al. 2016

Trends in Endocrinology & Metabolism

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GPIHBP1, a GPI-anchored protein in capillary endothelial cells, is crucial for the lipolytic processing of triglyceride-rich lipoproteins (TRLs). GPIHBP1 shuttles lipoprotein lipase (LPL) to its site of action in the capillary lumen and is essential for the margination of TRLs along capillaries—so that lipolytic processing can proceed. GPIHBP1 also reduces the unfolding of LPL’s catalytic domain, thereby stabilizing LPL catalytic activity. Many different GPIHBP1 mutations have been identified in patients with severe hypertriglyceridemia (chylomicronemia), the majority of which interfere with folding of the protein and abolish its capacity to bind and transport LPL. The discovery of GPIHBP1 has substantially revised our understanding of intravascular triglyceride metabolism but has also raised many new questions for future research.

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Section: Gpihbp1 Mutations Cause Chylomicronemiamentioning

confidence: 99%

“…The plasma triglyceride levels in “GPIHBP1 homozygotes” are often >2,000 mg/dl (similar to levels in LPL-deficient patients), although some have had triglyceride levels less than 1000 mg/dl [46–54]. Many patients have had a history of pancreatitis.…”

Section: Gpihbp1 Mutations Cause Chylomicronemiamentioning

confidence: 99%

GPIHBP1 and Plasma Triglyceride Metabolism

Fong

Young

Beigneux

et al. 2016

Trends in Endocrinology & Metabolism

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“…Fab′ fragments were prepared with immobilized papain and Fc fragments removed with Protein LU domain is primarily responsible for high-affinity binding of LPL, while the acidic domain augments the interaction and promotes an initial interaction complex between LPL and GPIHBP1 (6,11). A variety of missense mutations in GPIHBP1's LU domain have been identified in patients with chylomicronemia (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22), and all of those abolish the ability of GPIHBP1 to bind LPL (6). Most of these mutations interfere with the formation of disulfide bonds in the LU domain, leading to disulfide-linked dimers and multimers (23).…”

Section: Monoclonal Antibodiesmentioning

confidence: 99%

An LPL–specific monoclonal antibody, 88B8, that abolishes the binding of LPL to GPIHBP1

Allan

Larsson

et al. 2016

Journal of Lipid Research

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For more than 50 years, it has been known that LPL, a triglyceride hydrolase secreted by myocytes and adipocytes, is crucial for the intravascular processing of triglyceriderich lipoproteins (TRLs) (1-3). For most of that time, it was assumed that LPL was attached to the heparan-sulfate proteoglycans along the lumen of blood vessels (4), but how LPL reached the lumen of blood vessels was a stubborn mystery. Within the past few years, that mystery has been solved (5, 6). Glycosylphosphatidylinositol-anchored high density lipoprotein binding protein 1 (GPIHBP1), a GPI-anchored protein of capillary endothelial cells, picks up freshly secreted LPL within the interstitial spaces and shuttles it across endothelial cells to the capillary lumen (7,8). In the absence of GPIHBP1, LPL remains in the interstitial spaces and never reaches the capillary lumen, resulting in an accumulation of plasma TRLs and extremely high plasma triglyceride levels ("chylomicronemia") (8). Recent studies showed that GPIHBP1 (and GPIHBP1-bound LPL) are also crucial for the margination of TRLs along the capillary lumen, allowing triglyceride hydrolysis to proceed (9).GPIHBP1 has two main structural features-an aminoterminal acidic domain and a cysteine-rich three-fingered "LU domain" (7, 10). Recent studies have shown that the Abstract LPL contains two principal domains: an aminoterminal catalytic domain (residues 1-297) and a carboxylterminal domain (residues 298-448) that is important for binding lipids and binding glycosylphosphatidylinositolanchored high density lipoprotein binding protein 1 (GPIHBP1) (an endothelial cell protein that shuttles LPL to the capillary lumen). The LPL sequences required for GPIHBP1 binding have not been examined in detail, but one study suggested that sequences near LPL's carboxyl terminus (residues 403-438) were crucial. Here, we tested the ability of LPLspecific monoclonal antibodies (mAbs) to block the binding of LPL to GPIHBP1. One antibody, 88B8, abolished LPL binding to GPIHBP1. Consistent with those results, antibody 88B8 could not bind to GPIHBP1-bound LPL on cultured cells. Antibody 88B8 bound poorly to LPL proteins with amino acid substitutions that interfered with GPIHBP1 binding (e.g., C418Y, E421K). However, the sequences near LPL's carboxyl terminus (residues 403-438) were not sufficient for 88B8 binding; upstream sequences (residues 298-400) were also required. Additional studies showed that these same sequences are required for LPL binding to GPI-HBP1. In conclusion, we identified an LPL mAb that binds to LPL's GPIHBP1-binding domain. The binding of both antibody 88B8 and GPIHBP1 to LPL depends on large segments of LPL's carboxyl-terminal domain.

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“…The technique of next-generation sequencing with WES has been of pivotal value in molecular diagnosis of a wide spectrum of Mendelian traits, thus improving the therapeutics and counseling of the affected individuals (Hanchard et al 2013; Gonzaga-Jauregui et al 2014). WES is also useful in known monogenetic conditions, particularly those with significant locus heterogeneity, to identify lesser-recognized genes or in the detection of a novel gene.…”

Section: Introductionmentioning

confidence: 99%

Whole-exome sequencing reveals an inherited R566X mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of Liddle syndrome

Polfus

Boerwinkle

Gibbs

et al. 2016

Cold Spring Harb Mol Case Stud

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To comprehensively evaluate a European–American child with severe hypertension, whole-exome sequencing (WES) was performed on the child and parents, which identified causal variation of the proband's early-onset disease. The proband's hypertension was resistant to treatment, requiring a multiple drug regimen including amiloride, spironolactone, and hydrochlorothiazide. We suspected a monogenic form of hypertension because of the persistent hypokalemia with low plasma levels of renin and aldosterone. To address this, we focused on rare functional variants and indels, and performed gene-based tests incorporating linkage scores and allele frequency and filtered on deleterious functional mutations. Drawing upon clinical presentation, 27 genes were selected evidenced to cause monogenic hypertension and matched to the gene-based results. This resulted in the identification of a stop-gain mutation in an epithelial sodium channel (ENaC), SCNN1B, an established Liddle syndrome gene, shared by the child and her father. Interestingly, the father also harbored a missense mutation (p.Trp552Arg) in the α-subunit of the ENaC trimer, SCNN1A, possibly pointing to pseudohypoaldosteronism type I. This case is unique in that we present the early-onset disease and treatment response caused by a canonical stop-gain mutation (p.Arg566*) as well as ENaC digenic hits in the father, emphasizing the utility of WES informing precision medicine.

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Whole‐Exome Sequencing Reveals GPIHBP1 Mutations in Infantile Colitis With Severe Hypertriglyceridemia

Cited by 20 publications

References 43 publications

GPIHBP1 and Plasma Triglyceride Metabolism

GPIHBP1 and Plasma Triglyceride Metabolism

An LPL–specific monoclonal antibody, 88B8, that abolishes the binding of LPL to GPIHBP1

Whole-exome sequencing reveals an inherited R566X mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of Liddle syndrome

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