scholarly journals Atomic structure of the autosomal recessive hypercholesterolemia phosphotyrosine-binding domain in complex with the LDL-receptor tail

2012 ◽  
Vol 109 (18) ◽  
pp. 6916-6921 ◽  
Author(s):  
H. Dvir ◽  
M. Shah ◽  
E. Girardi ◽  
L. Guo ◽  
M. G. Farquhar ◽  
...  
Keyword(s):  
Atomic Structure ◽  
Autosomal Recessive ◽  
Ldl Receptor ◽  
Binding Domain ◽  
Autosomal Recessive Hypercholesterolemia ◽  
Phosphotyrosine Binding Domain

Abstract 1921: Clinical Impact of Heterozygous Carrier of Autosomal Recessive Hypercholesterolemia on Asymptomatic Hyperlipidemic Patients: Evidence From Familial Gene Analysis

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hayato Tada ◽  
Masa-aki Kawashiri ◽  
Tohru Noguchi ◽  
Chiaki Nakanishi ◽  
Masayuki Tsuchida ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Genetic Defect ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Serum Triglyceride ◽  
Adaptor Protein ◽  
Receptor Internalization ◽  
Single Mutation ◽  
Heterozygous Carrier ◽  
Autosomal Recessive Hypercholesterolemia

Autosomal recessive hypercholesterolemia (ARH) is an extremely rare genetic defect, and is recognized only around 50 cases in all over the world. The genetic cause of ARH is mutation in an adaptor protein involved in low-density lipoprotein (LDL) receptor internalization, which results in marked elevation of serum LDL cholesterol (LDL-C) and premature atherosclerosis. Therefore, few data exist regarding the clinical significance about the heterozygous carrier of ARH. We recently identified the second ARH patient (Ins C 599 ) in Japan and his some relatives who have the same single mutation (heterozygous). We identified 11 heterozygous ARH carriers (male=5, mean age=48.2) and 7 non-carriers (male=3, mean age=53.3) in the same family. In addition, we screened the same mutations in unrelated consecutive 500 hyperlipidemic patients (male=32, mean age=49.4) with mean LDL-C of 225.2±6.1mg/dl using PCR to determine its frequency and examined their clinical features. We identified an unrelated heterozygous ARH carrier and a non-carrier in the same family among unrelated to the original family. Serum LDL-C levels of heterozygous ARH carriers (mean=153.8±35.8mg/dl) were significantly higher than those of non-carriers (mean=108.2±41.4mg/dl, p<0.05). Serum triglyceride (151.9±110.7mg/dl vs 140.4±48.8mg/dl) and high-density lipoprotein cholesterol (57.4±11.0mg/dl vs 54.0±11.9mg/dl) levels were not different between them. Interestingly, heterozygous ARH carriers didn’t show any xanthomas including Achilles tendon (6.4±1.1mm vs 5.7±1.1mm) in contrast to FH, which is frequently associated with typical xanthoma. These results demonstrate that heterozygous ARH (Ins C 599 ) carriers show higher LDL-C levels compared with non-carrier family member without tendon xanthomas observed in FH. We suggest that heterozygous ARH (Ins C 599 ) carrier may explain a part of primary hypercholesterolemia.

scholarly journals Restoration of LDL receptor function in cells from patients with autosomal recessive hypercholesterolemia by retroviral expression of ARH1

2002 ◽  
Vol 110 (11) ◽  
pp. 1695-1702 ◽  
Author(s):  
Emily R. Eden ◽  
Dilipkumar D. Patel ◽  
Xi-Ming Sun ◽  
Jemima J. Burden ◽  
Michael Themis ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Ldl Receptor ◽  
Receptor Function ◽  
Autosomal Recessive Hypercholesterolemia ◽  
In Cells

Homozygous autosomal recessive hypercholesterolaemia in a South Asian child presenting with multiple cutaneous xanthomata

2020 ◽  
pp. 000456322096175
Author(s):  
V Thadchanamoorthy ◽  
Kavinda Dayasiri ◽  
S I Majitha ◽  
Amanda J Hooper ◽  
John R Burnett
Keyword(s):  
Autosomal Recessive ◽  
Ldl Receptor ◽  
Good Effect ◽  
Atherosclerotic Cardiovascular Disease ◽  
Sequencing Analysis ◽  
Loss Of Function ◽  
Cutaneous Lesions ◽  
Increased Risk ◽  
Autosomal Recessive Hypercholesterolemia ◽  
Coa Reductase

Autosomal recessive hypercholesterolemia (ARH; OMIM #603813) is an extremely rare disorder of lipid metabolism caused by loss-of-function variants in the LDL receptor adapter protein 1 ( LDLRAP1) gene, which is characterized by severe hypercholesterolaemia and an increased risk of premature atherosclerotic cardiovascular disease. We report the case of an 11-year-old girl who presented with multiple painless yellowish papules around her elbows and knees of two-year duration. She had been reviewed by several general practitioners, with some of the papules having been excised, but without a specific diagnosis being made. The child was referred to a paediatric service for further evaluation and treatment of the cutaneous lesions, which appeared xanthomatous in nature. A lipid profile showed severe hypercholesterolaemia. Next generation sequencing analysis of a monogenic hypercholesterolaemia gene panel revealed homozygosity for a pathogenic frameshift mutation, c.71dupG, p.Gly25Argfs*9 in LDLRAP1. Her parents and brother, who were asymptomatic, were screened and found to be heterozygous carriers of the LDLRAP1 variant. There was no known consanguinity in the family. She was commenced on the HMG-CoA reductase inhibitor, atorvastatin, to good effect, with a ∼76% reduction in LDL-cholesterol at a dose of 50 mg per day. At six-month follow-up, there had been no obvious regression of the xanthomata, but importantly, no enlargement of, or the development of new papular lesions, have occurred. In summary, we report a child who presented with multiple cutaneous xanthomata and was confirmed to have ARH by the presence of a homozygous novel pathogenic frameshift variant in LDLRAP1.

scholarly journals ARH directs megalin to the endocytic recycling compartment to regulate its proteolysis and gene expression

2013 ◽  
Vol 202 (1) ◽  
pp. 113-127 ◽  
Author(s):  
Mehul Shah ◽  
Oscar Y. Baterina ◽  
Vanessa Taupin ◽  
Marilyn G. Farquhar
Keyword(s):  
Gene Expression ◽  
Transcriptional Repression ◽  
Autosomal Recessive ◽  
Ldl Receptor ◽  
Endocytic Recycling ◽  
Regulated Intramembrane Proteolysis ◽  
Early Endosomes ◽  
Recycling Pathway ◽  
Autosomal Recessive Hypercholesterolemia ◽  
Receptor Family

Receptors internalized by endocytosis can return to the plasma membrane (PM) directly from early endosomes (EE; fast recycling) or they can traffic from EE to the endocytic recycling compartment (ERC) and recycle from there (slow recycling). How receptors are sorted for trafficking along these two pathways remains unclear. Here we show that autosomal recessive hypercholesterolemia (ARH) is required for trafficking of megalin, a member of the LDL receptor family, from EE to the ERC by coupling it to dynein; in the absence of ARH, megalin returns directly to the PM from EE via the connecdenn2/Rab35 fast recycling pathway. Binding of ARH to the endocytic adaptor AP-2 prevents fast recycling of megalin. ARH-mediated trafficking of megalin to the ERC is necessary for γ-secretase mediated cleavage of megalin and release of a tail fragment that mediates transcriptional repression. These results identify a novel mechanism for sorting receptors for trafficking to the ERC and link ERC trafficking to regulated intramembrane proteolysis (RIP) and expression of megalin.

scholarly journals A Single Common Portal for Clathrin-mediated Endocytosis of Distinct Cargo Governed by Cargo-selective Adaptors

2006 ◽  
Vol 17 (10) ◽  
pp. 4300-4317 ◽  
Author(s):  
Peter A. Keyel ◽  
Sanjay K. Mishra ◽  
Robyn Roth ◽  
John E. Heuser ◽  
Simon C. Watkins ◽  
...  
Keyword(s):  
Rna Interference ◽  
Cell Surface ◽  
Gene Silencing ◽  
Ldl Receptor ◽  
Binding Domain ◽  
Recent Proposal ◽  
Ldl Receptors ◽  
General Existence ◽  
Bud Site ◽  
Phosphotyrosine Binding Domain

Sorting of transmembrane cargo into clathrin-coated vesicles requires endocytic adaptors, yet RNA interference (RNAi)-mediated gene silencing of the AP-2 adaptor complex only disrupts internalization of a subset of clathrin-dependent cargo. This suggests alternate clathrin-associated sorting proteins participate in cargo capture at the cell surface, and a provocative recent proposal is that discrete endocytic cargo are sorted into compositionally and functionally distinct clathrin coats. We show here that the FXNPXY-type internalization signal within cytosolic domain of the LDL receptor is recognized redundantly by two phosphotyrosine-binding domain proteins, Dab2 and ARH; diminishing both proteins by RNAi leads to conspicuous LDL receptor accumulation at the cell surface. AP-2–dependent uptake of transferrin ensues relatively normally in the absence of Dab2 and ARH, clearly revealing delegation of sorting operations at the bud site. AP-2, Dab2, ARH, transferrin, and LDL receptors are all present within the vast majority of clathrin structures at the surface, challenging the general existence of specialized clathrin coats for segregated internalization of constitutively internalized cargo. However, Dab2 expression is exceptionally low in hepatocytes, likely accounting for the pathological hypercholesterolemia that accompanies ARH loss.

scholarly journals Serine Phosphorylation Proximal to Its Phosphotyrosine Binding Domain Inhibits Insulin Receptor Substrate 1 Function and Promotes Insulin Resistance

2004 ◽  
Vol 24 (21) ◽  
pp. 9668-9681 ◽  
Author(s):  
Yan-Fang Liu ◽  
Avia Herschkovitz ◽  
Sigalit Boura-Halfon ◽  
Denise Ronen ◽  
Keren Paz ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Insulin Treatment ◽  
Binding Domain ◽  
Serine Phosphorylation ◽  
Insulin Receptor Substrate ◽  
Control Mechanisms ◽  
Insulin Receptor Substrate 1 ◽  
Phosphotyrosine Binding Domain

ABSTRACT Ser/Thr phosphorylation of insulin receptor substrate (IRS) proteins negatively modulates insulin signaling. Therefore, the identification of serine sites whose phosphorylation inhibit IRS protein functions is of physiological importance. Here we mutated seven Ser sites located proximal to the phosphotyrosine binding domain of insulin receptor substrate 1 (IRS-1) (S265, S302, S325, S336, S358, S407, and S408) into Ala. When overexpressed in rat hepatoma Fao or CHO cells, the mutated IRS-1 protein in which the seven Ser sites were mutated to Ala (IRS-17A), unlike wild-type IRS-1 (IRS-1WT), maintained its Tyr-phosphorylated active conformation after prolonged insulin treatment or when the cells were challenged with inducers of insulin resistance prior to acute insulin treatment. This was due to the ability of IRS-17A to remain complexed with the insulin receptor (IR), unlike IRS-1WT, which underwent Ser phosphorylation, resulting in its dissociation from IR. Studies of truncated forms of IRS-1 revealed that the region between amino acids 365 to 430 is a main insulin-stimulated Ser phosphorylation domain. Indeed, IRS-1 mutated only at S408, which undergoes phosphorylation in vivo, partially maintained the properties of IRS-17A and conferred protection against selected inducers of insulin resistance. These findings suggest that S408 and additional Ser sites among the seven mutated Ser sites are targets for IRS-1 kinases that play a key negative regulatory role in IRS-1 function and insulin action. These sites presumably serve as points of convergence, where physiological feedback control mechanisms, which are triggered by insulin-stimulated IRS kinases, overlap with IRS kinases triggered by inducers of insulin resistance to terminate insulin signaling.

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