In the present study, we delineated a 29-day-old female baby with incidentally found severe hyperlipidemia originated from a novel and homozygous GPIHBP1 duplication variant, who was successfully managed by low-fat diet combined with pharmacological therapy.
As is known that elevated plasma triglyceride may, as an independent risk factor, lead to cardiovascular diseases (CVDs). LPL plays a critical role in lipid metabolism and energy balancing by hydrolyzing the triglyceride in blood circulation. Although it is parenchymal cells that synthesize and secret LPL, it somehow acts on the luminal capillary endothelium, so the mechanism of LPL migrating into the luminal capillary has long been among the list of relevant research [18]. According to previous studies, hyperlipidemia is very likely to be triggered by gene variants which consequently cause LPL dysfunction [19–21]. It has been known that multiple factors can interact with LPL, positively or negatively, thus exerting an influence on TG lipolysis. Among them is a recently identified factor GPIHBP1, which is considered indispensible in transportation of LPL to the luminal capillary endothelium as well as in the establishment of the platform for TG hydrolysis [22]. Currently, a large amount of evidence supports that GPIHBP1 functions in triglyceride-rich lipoprotein (TRL) metabolism of human in unique and diverse ways [23–25]. Recent studies have shown that LPL mislocalization as a result of GPIHBP1 deficiency may cause severe hyperlipidemia [13, 26]. Therefore, the importance of GPIHBP1 in lipolysis is being recognized more widely with more relevant research published.
It was reported that Ioka et al. first identified GPIHBP1 as a protein with an HDL binding capability [15]. Nevertheless, disputes about its HDL-binding ability has been existed ever since until its function in lipolysis became unumbiguous due to the finding of significantly elevated plasma triglyceride levels in GPIHBP1 knockout mice [27]. Moreover, GPIHBP1 was proved to be able to bind not only LPL, but also chylomicrons, and the activity of LPL after heparin processing was compromised in knockout mice. Thereafter, looking into its mechanism of how to handle triglycerides has always been one of the highlights of such studies. It has already been known that LPL migrating into luminal capillary is a prerequisite to perform its triglyceride-hydrolyzing function in lipoproteins, and GPIHBP1 is exactly the very carrier responsible for translocating LPL to capillary lumen after binding it in the subendothelial space. Without the presence of GPIHBP1, LPL will be trapped in the intercelullar space, with no possibility to hydrolyze triglycerides in circulating chylomicrons and VLDLs [28, 29].
The human GPIHBP1 gene consists of 4 exons which encode a 184 amino acid protein. An acidic domain being able to bind LPL and chylomicrons is located in the N-terminus of GPIHBP1. Its C-terminus is encoded by exons 3 and 4, including a cysteine-rich lymphocyte antigen 6 (Ly6) motif as well as a carboxylterminal hydrophobic sequence involved in the addition of a GPI anchor [30]. A bunch of residues in the domain of C-terminus, such as Ser107, Thr124, and Leu135 also play a critical role in LPL binding and its transportation from subendothelial space to luminal capillary [31]. Therefore, deleting exons 3 and 4 will produce a crippled protein characterized by the absence of a domain indispensible for LPL binding and translocation as well as for anchoring LPL to the cell surface. This makes sense of the phenotype in cases with severe hyperlipidemia and also explains the lack of circulating LPL and LPL activity in heparin-processed plasma. Since the initial description of hyperlipidemia resulting from the variant of GPIHBP1 in 2007 [32], only about 50 cases have been reported worldwide [26, 33, 34]. Meanwhile, the genotypic spectrum based on HGMD has recorded 47 various pathogenic variants in GPIHBP1 that can result in severe hyperlipidemia, with most of them (33/47) identified as missense variants. Tendency of these variants towards any ethnicity or racial groups was not observed. Therefore, thorough analysis on these disease-causing variants probably linking to developmental malfunction and phenotypic changes is essential to pathogenesis clarifying and clinical treatment.
The patient in our study predominantly manifested fever, vomiting and convulsion, with unexpected discovery of severe hyperlipidemia and molecular genetic tests revealing the etiology. With the WES method, we found a novel homozygous variant, c.45_48dupGCGG(Pro17Alafs*22), in exons 1 of GPIHBP1, which, absent in all of the 100 healthy control samples, was inherited from both of her parents.
The c.45_48dupGCGG duplication variant in exon 1 may lead to the substitution of the remaining 168 C-terminal amino acid residues with 21 mutant ones, at a highly conserved position of this protein. Based on the clinical presentations, serum lipid level and bioinformatics study, an inference stood out from the potential pathogeneses that the disease of the proband was very likely to be attributed to the homozygous duplication variant, which, certainly, needs to be further verified by functional experiments in the future. Fortunately, these unexpected findings, together with timely and proper treatment, have resulted in a good prognosis observed in this patient. Furthermore, this orphan case gave us a lively lesson, and deepened our knowledge of this disease.