A loss-of-function variant in OSBPL1A predisposes to low plasma HDL cholesterol levels and impaired cholesterol efflux capacity

Motazacker, Mahdi M.; Pirhonen, Juho; Capelleveen, Julian C. van; Weber-Boyvat, Marion; Kuivenhoven, Jan Albert; Shah, Saundarya; Hovingh, G. Kees; Metso, Jari; Li, Shiqian; Ikonen, Elina; Jauhiainen, Matti; Dallinga‐Thie, Geesje M.; Olkkonen, Vesa M.

doi:10.1016/j.atherosclerosis.2016.04.005

Cited by 27 publications

(15 citation statements)

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“…Dyslipidaemia can predispose individuals to cardiovascular disease, hepatic disease and metabolic syndrome(102). Genetic analyses of patients with dyslipidaemia have indicated a role for the OSBP/OSBPL/ORP family in lipoprotein metabolism and this suggestion has been supported by functional studies in both mouse models and cell culture studies(103).Individuals who possess a heterozygous loss-of-function mutation in ORP1L have extremely low plasma levels of HDL cholesterol and apolipoprotein A1 (apoA-1)(103). In vitro assays demonstrated that fibroblasts carrying the loss of function mutation had significantly reduced cholesterol efflux to lipid free apoA1, but not to mature HDL particles, which suggests a defect in the ATP binding cassette transporter A1 (ABCA1) efflux pathway.…”

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confidence: 99%

WITHDRAWN: The Fundamental And Pathological Importance Of Oxysterol Binding Protein And Its Related Proteins

et al. 2018

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confidence: 99%

WITHDRAWN: The Fundamental And Pathological Importance Of Oxysterol Binding Protein And Its Related Proteins

et al. 2018

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“…In addition, other OMIM genes included in the deletions have also been shown to be associated with specific phenotypes. Heterozygous loss of function variants of OSBPL1A are associated with low plasma high density lipoprotein cholesterol levels and impaired cholesterol efflux capacity (Motazacker et al, ), therefore our patient 1 may benefit from a lipid profile screening. Of note, there is a hemizygosity of ZNF24 in patient 2, which is associated with seizures and tremors (Cody et al, ), but these features are not seen in our patient.…”

Section: Discussionmentioning

confidence: 93%

Clinical delineation of 18q11‐q12 microdeletion: Intellectual disability, speech and behavioral disorders, and conotruncal heart defects

Rojnueangnit

Charalsawadi

Thammachote

et al. 2019

Molec Gen & Gen Med

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Background Since the establishment of chromosomal microarrays in clinical practice, many new microdeletion/microduplication syndromes have been identified, including 18q11.2 microdeletion. Chromosome 18q deletion syndrome is commonly classified into distal deletion and a much rarer proximal interstitial deletion spanning the 18q11.2‐q21.1 region. Methods We report two new patients and review 27 additional cases in DECIPHER/ClinGen databases and four cases from the literature, with more proximal 18q deletions involving 18q11‐q12 (band 1 only; 17.2–43.5 Mb position) deletion. Results Common presentations of 18q11‐q12 deletions include developmental delay/intellectual disability (DD/ID) (82%); speech delay/autism/attention deficit and hyperactivity/other behavioral problems (30%); conotruncal heart defects (15%); and subtle/non‐specific facial dysmorphism. The deletion in four out of five cases with cardiac defect was distal to GATA6, suggesting an alternative mechanism other than haploinsufficiency of GATA6 as an underlying cause of cardiac malformations. Precocious puberty with advanced skeletal age was first observed in one patient, suggesting a unique and expanded phenotype of proximal 18q deletion. When comparing genotype–phenotype correlations from the present study with previous reports, the critical regions for selected phenotypes of 18q11‐q12 deletion syndrome could be narrowed down as follows: 38.8–43.5 Mb for moderate to severe DD/ID, 19.6–24.4 Mb and 26.9–28.6 Mb for conotruncal heart defect. Conclusion The detailed clinical delineation of the proximal 18q deletions identified in this study should contribute to better understanding of the genotype–phenotype correlations and better long‐term care of patients with this rare syndrome.

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“…The gene Osbpl9 ( oxysterol binding protein-like 9 ) belongs to the oxysterol-binding protein family, which has been implicated in the function of, e.g., endoplasmic reticulum (ER) junctions, non-vesicular transport of lipids, integration of sterol and sphingomyelin metabolism, sterol transport, regulation of neutral lipid metabolism, and regulation of signaling cascades ( Olkkonen et al, 2006 ). Familial loss-of-function variants of OSBPL1 in humans predisposed to impaired reverse cholesterol transport and low plasma high-density lipoprotein (HDL) levels ( Motazacker et al, 2016 ). Studies on OSBPL10 suggested a suppressive function on hepatic lipogenesis and very low density lipoprotein (VLDL) production ( Perttilä et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Potential Type 2 Diabetes Genes Mediating β-Cell Loss and Hyperglycemia Using Positional Cloning

et al. 2020

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Type 2 diabetes (T2D) is a complex metabolic disease regulated by an interaction of genetic predisposition and environmental factors. To understand the genetic contribution in the development of diabetes, mice varying in their disease susceptibility were crossed with the obese and diabetes-prone New Zealand obese (NZO) mouse. Subsequent whole-genome sequence scans revealed one major quantitative trait loci (QTL), Nidd/DBA on chromosome 4, linked to elevated blood glucose and reduced plasma insulin and low levels of pancreatic insulin. Phenotypical characterization of congenic mice carrying 13.6 Mbp of the critical fragment of DBA mice displayed severe hyperglycemia and impaired glucose clearance at week 10, decreased glucose response in week 13, and loss of β-cells and pancreatic insulin in week 16. To identify the responsible gene variant(s), further congenic mice were generated and phenotyped, which resulted in a fragment of 3.3 Mbp that was sufficient to induce hyperglycemia. By combining transcriptome analysis and haplotype mapping, the number of putative responsible variant(s) was narrowed from initial 284 to 18 genes, including gene models and non-coding RNAs. Consideration of haplotype blocks reduced the number of candidate genes to four ( Kti12 , Osbpl9 , Ttc39a , and Calr4 ) as potential T2D candidates as they display a differential expression in pancreatic islets and/or sequence variation. In conclusion, the integration of comparative analysis of multiple inbred populations such as haplotype mapping, transcriptomics, and sequence data substantially improved the mapping resolution of the diabetes QTL Nidd/DBA . Future studies are necessary to understand the exact role of the different candidates in β-cell function and their contribution in maintaining glycemic control.

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A loss-of-function variant in OSBPL1A predisposes to low plasma HDL cholesterol levels and impaired cholesterol efflux capacity

Cited by 27 publications

References 43 publications

WITHDRAWN: The Fundamental And Pathological Importance Of Oxysterol Binding Protein And Its Related Proteins

WITHDRAWN: The Fundamental And Pathological Importance Of Oxysterol Binding Protein And Its Related Proteins

Clinical delineation of 18q11‐q12 microdeletion: Intellectual disability, speech and behavioral disorders, and conotruncal heart defects

Identification of Novel Potential Type 2 Diabetes Genes Mediating β-Cell Loss and Hyperglycemia Using Positional Cloning

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