Low Syndrome Research Articles

The Importance of Vaccinating Children and Pregnant Women against Influenza Virus Infection.

Influenza virus infection is responsible for significant morbidity and mortality in the pediatric and pregnant women populations, with deaths frequently caused by severe influenza-associated lower respiratory tract infection and acute respiratory distress syndrome (ARDS). An appropriate immune response requires controlling the viral infection through activation of antiviral defenses, which involves cells of the lung and immune system. High levels of viral infection or high levels of inflammation in the lower airways can contribute to ARDS. Pregnant women and young children, especially those born prematurely, may develop serious complications if infected with influenza virus. Vaccination against influenza virus will lead to lower infection rates and fewer complications, even if the vaccine is poorly matched to circulating viral strains. Maternal vaccination offers infants protection via antibody transmission through the placenta and breast milk. Despite the health benefits of the influenza vaccine, vaccination rates around the world remain well below targets. Trust in the use of vaccines among the public must be restored in order to increase vaccination rates and decrease the public health burden of influenza.

The prolonged sub-tenon block for long vitreoretinal surgery

The purpose of this study was to compare efficiency and safety of the prolonged Sub-Tenon block in comparison with IV 100 mg tramadol for long vitreoretinal surgery ander general anesthesia. 74 patients were undergoing microinvasive vitrectomy. For the prolonged Sub-Tenon block 1% solution of lidocaine at the speed of 2 ml/hour was used. The value of block of oculovisceral reflexes, HR and MAP, the need for muscle relaxants, time of awakening and time of removal of a laryngeal mask, postoperative pain and analgesia requirements, and postoperative nausea and vomiting were recorded. In prolonged Sub-Tenon block group there was more effective blocking of oculocardiac and oculovasomotor reflexes, a smaller average dose of muscle relaxants, shorter awakening time and removal of a laryngeal mask, and also lower pain syndrome in the first 24 hours after surgery. Postoperative nausea and vomiting also was in Sub-Tenon block group considerably less frequent than in tramadol group. Use of the prolonged Sub-Tenon block with the general anesthesia is an effective and safe technique for vitreoretinal surgery.

Major lower extremity amputation: a contemporary analysis from an academic tertiary referral centre in a developing community

BackgroundWe aimed to explore the surgical outcomes of major lower extremity amputation (MLEA) and influencing factors at an academic tertiary referral centre in north Jordan, optimistically providing a platform for future health care policies and initiatives to improve the outcomes of MLEA in Jordan.MethodsClinical records of patients who had undergone MLEA between January 2012 and December 2017 were identified and retrospectively reviewed. International Classification of Diseases codes were used to identify the study cohort from a prospectively maintained computerised database. We included adult patients of both genders who underwent amputations for ischemic lower limb (acute and chronic) and diabetic foot syndrome (DFS). We excluded patients for whom MLEA surgery was performed for other indications (trauma and tumors). Outcomes of interest included patient demographics and comorbidities, type of amputation and indications, length of hospital stay (LOS), the need for revision surgery (ipsilateral conversion to a higher level of amputation), and cumulative mortality rate at 1 year. The impact of the operating surgeon’s specialty (vascular vs. non-vascular surgeon) on outcomes was evaluated.ResultsThe study cohort comprised 140 patients who underwent MLEA (110 below-knee amputations [BKA] and 30 above-knee amputations [AKA]; ratio: 3:1; 86 men; 54 women; mean age, 62.9 ± 1.1 years). Comorbidities included diabetes, hypertension, dyslipidaemia, ischaemic heart disease, congestive heart failure, chronic kidney disease, stroke, and Buerger disease. The only associated comorbidity was chronic kidney disease, which was more prevalent among BKA patients (p = 0.047). Indications for MLEA included DFS, and lower limb ischaemia. Acute limb ischaemia was more likely to be an indication for AKA (p = 0.006). LOS was considerably longer for AKA (p = 0.035). The cumulative mortality rate at 1 year was 30.7%. Revision surgery rates and LOS improved significantly with increased rate of vascular surgeon-led MLEA.ConclusionsIn developing countries, the adverse impact of MLEA is increased because of limited resources and increased prevalence of diabetes-related foot complications. Vascular surgeon-led MLEA is associated with decreased revision rates, LOS and possibly improved outcomes, particularly when it is performed for vascular insufficiency. It is important to formulate national health care policies to improve patient outcomes in these countries.

Lowe syndrome identified in the offspring of an oocyte donor who was an unknown carrier of a de novo mutation: a case report and review of the literature

BackgroundOculocerebrorenal syndrome of Lowe is an X-linked disorder with very low prevalence in the general population. The OCRL gene encodes the protein phosphatidylinositol 4,5-bisphosphate-5-phosphatase, a lipid phosphatase, located in the trans-Golgi network. Point mutations in the OCRL gene cause Lowe syndrome and Dent disease, which are characterized as a multisystemic disorder. The symptoms of Lowe syndrome are expressed primarily as dysfunction of the eyes, kidneys, and the central nervous system.Case presentationThis report describes a case of a 31-year-old Georgian woman with a de novo pathogenic mutation causing oculocerebrorenal syndrome of Lowe, who was a volunteer in an oocyte donation program for in vitro fertilization purposes, and the outcome of the treatments of this particular donor’s oocyte receivers, describing the implications of the mutation for the children born as a result of the treatments. It raises important medical and ethical issues about the necessity of genetic testing of oocyte donors and the possibility of rare genetic disorders being inherited by the offspring of donors.ConclusionThis particular case indicates the legal, medical, and emotional risks of utilizing donor oocytes from phenotypically healthy women, whose genetic constitution is unknown in terms of being silent carriers of rare diseases. In addition, all the necessary actions were followed; the further examinations that are required are mentioned. The donor and the offspring should be further tested. The remaining cryopreserved embryos should be destroyed or preimplantation genetic testing should be performed before they are utilized. Finally, all the people involved, the treated couples and the donor, alongside her family, should follow genetic and psychological counselling.

Acute compartment syndrome of the lower leg causing cardiac arrest after resection of the right external iliac vein for autologous graft: a case report

BackgroundThe right external iliac vein (REIV) is often used for portal vein reconstruction in patients undergoing pancreatoduodenectomy with portal-superior mesenteric vein resection. We report a case of cardiac arrest caused by acute lower leg compartment syndrome as a result of REIV resection.Case presentationA 53-year-old man underwent pancreatoduodenectomy with portal vein resection. Hyperkalemia progressed during surgery due to intestinal reperfusion injury, which caused recurrent ventricular arrhythmia required for cardio-pulmonary resuscitation. The surgery was discontinued after resuscitation, and portal vein reconstruction using the REIV was performed 2 days post-operatively. Acute compartment syndrome was diagnosed immediately following the surgery. Hyperkalemia progressed, causing pulseless ventricular tachycardia. Emergent fasciotomy was performed, but right leg dysfunction persisted after discharge.ConclusionREIV resection can cause lower-extremity acute compartment syndrome. The status, including intracompartmental pressure, of the lower extremity should be carefully observed after REIV resection during and after surgery.

Phospholipase C-related catalytically inactive protein regulates cytokinesis by protecting phosphatidylinositol 4,5-bisphosphate from metabolism in the cleavage furrow

Cytokinesis is initiated by the formation and ingression of the cleavage furrow. Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] accumulation followed by RhoA translocation to the cleavage furrow are prerequisites for cytokinesis progression. Here, we investigated whether phospholipase C (PLC)-related catalytically inactive protein (PRIP), a metabolic modulator of PI(4,5)P2, regulates PI(4,5)P2-mediated cytokinesis. We found that PRIP localised to the cleavage furrow during cytokinesis. Moreover, HeLa cells with silenced PRIP displayed abnormal cytokinesis. Importantly, PI(4,5)P2 accumulation at the cleavage furrow, as well as the localisation of RhoA and phospho-myosin II regulatory light chain to the cleavage furrow, were reduced in PRIP-silenced cells. The overexpression of oculocerebrorenal syndrome of Lowe-1 (OCRL1), a phosphatidylinositol-5-phosphatase, in cells decreased PI(4,5)P2 levels during early cytokinesis and resulted in cytokinesis abnormalities. However, these abnormal cytokinesis phenotypes were ameliorated by the co-expression of PRIP but not by co-expression of a PI(4,5)P2-unbound PRIP mutant. Collectively, our results indicate that PRIP is a component at the cleavage furrow that maintains PI(4,5)P2 metabolism and regulates RhoA-dependent progression of cytokinesis. Thus, we propose that PRIP regulates phosphoinositide metabolism correctively and mediates normal cytokinesis progression.

Selective fasciotomy for acute traumatic lower leg compartment syndrome: is it feasible?

The standard treatment for an acute compartment syndrome (ACS) of the lower leg is a four compartment fasciotomy. It can be performed through either one lateral or a lateral and medial incision. Selective fasciotomy, only opening the compartments with elevated pressure, is a less invasive procedure. The aim of this study was to describe a procedure of selective fasciotomy after pressure measurement and to determine its feasibility in a retrospective cohort study. All patients with an ACS of the lower leg due to a proximal or tibia shaft fracture (AO 41 or 42) who received either a four compartment fasciotomy or a selective fasciotomy after pressure measurement between 2006 and 2016 were included. Every compartment with an intracompartment pressure of more than 30mmHg was opened. The primary outcome was any missed compartment syndrome after selective fasciotomy. Secondary outcomes were reoperations for completing four compartment fasciotomy and persistent sensomotoric deficits. Fifty-one patients with a mean age of 43years (6-76) were included. Of these, 41 (80%) had a selective fasciotomy. There was no missed compartment syndrome. One patient had a reoperation 8h after primary selective fasciotomy due to ACS of the superficial and deep flexor compartment. The anterior compartment had to be released in all patients. In 67%, the release of 2 compartments was sufficient. Six patients had postoperative sensomotoric deficits at discharge with full recovery during follow-up. Selective fasciotomy is feasible and seems to be safe. Future comparative studies will have to focus on possible benefits of this less invasive treatment.

A mutation in the filamin c gene causes myofibrillar myopathy with lower motor neuron syndrome: a case report

BackgroundMyofibrillar myopathies (MFMs) are a genetically heterogeneous group of muscle disorders. Mutations in the filamin C gene (FLNC) have previously been identified in patients with MFM. The phenotypes of FLNC-related MFM are heterogeneous.Case presentationThe patient was a 37-year-old male who first experienced weakness in the distal muscles of his hand, which eventually spread to the lower limbs and proximal muscles. Serum creatine kinase levels were moderately elevated. Obvious neuropathic changes in the electromyographic exam and edema changes in lower distal limb magnetic resonance imaging were observed. Histopathological examination revealed the presence of abnormal protein aggregates and angular atrophy in some muscle fibers. Ultrastructural analysis showed inordinate myofibrillar structures and dissolved myofilaments. DNA sequencing analysis detected a heterozygous missense mutation (c.7123G > A, p.V2375I) in the immunoglobulin (Ig)-like domain 21 of FLNC.ConclusionsFLNC mutation c.7123G > A, p.V2375I in the immunoglobulin (Ig)-like domain 21 can be associated with distal myopathy with typical MFM features and lower motor neuron syndrome. Although electromyographic examination of our patient showed obvious neuropathic changes, MFM could not be excluded. Therefore, genetic testing is necessary to make an accurate diagnosis.

MON-328 Oculocerebrorenal syndrome: novel pathogenic OCRL1 mutations and genotype-phenotype analysis

Oculocerebrorenal syndrome of Lowe is a rare X-linked disorder characterized by congenital cataract, mental retardation and proximal tubulopathy. The mutation of OCRL1 gene localized at chromosome Xq26.1, encoding an inositol polyphosphate 5-phosphatase, is responsible for the phenotypic characteristics of this syndrome.

Lowe syndrome-linked endocytic adaptors direct membrane cycling kinetics with OCRL in Dictyostelium discoideum.

Mutations of the inositol 5-phosphatase OCRL cause Lowe syndrome (LS), characterized by congenital cataract, low IQ, and defective kidney proximal tubule resorption. A key subset of LS mutants abolishes OCRL’s interactions with endocytic adaptors containing F&H peptide motifs. Converging unbiased methods examining human peptides and the unicellular phagocytic organism Dictyostelium discoideum reveal that, like OCRL, the Dictyostelium OCRL orthologue Dd5P4 binds two proteins closely related to the F&H proteins APPL1 and Ses1/2 (also referred to as IPIP27A/B). In addition, a novel conserved F&H interactor was identified, GxcU (in Dictyostelium) and the Cdc42-GEF FGD1-related F-actin binding protein (Frabin) (in human cells). Examining these proteins in D. discoideum, we find that, like OCRL, Dd5P4 acts at well-conserved and physically distinct endocytic stations. Dd5P4 functions in coordination with F&H proteins to control membrane deformation at multiple stages of endocytosis and suppresses GxcU-mediated activity during fluid-phase micropinocytosis. We also reveal that OCRL/Dd5P4 acts at the contractile vacuole, an exocytic osmoregulatory organelle. We propose F&H peptide-containing proteins may be key modifiers of LS phenotypes.

The clinical efficacy of Shi-style lumbar manipulations for symptomatic degenerative lumbar spondylolisthesis: protocol for a randomized, blinded, controlled trial

BackgroundSymptomatic degenerative lumbar spondylolisthesis (DLS) presents spinal problems in daily life. Shi-style lumbar manipulation (SLM), as an alternative treatment for DLS, is popular in China. SLM is based on the channels and collaterals theory of the traditional Chinese medicine, in which the symptoms are believed to result from channel blockage and joint displacement. However, there is no solid evidence to show the effect of the SLM on the management of symptomatic DLS.Methods/designWe conduct a prospective randomized, blinded, controlled trial to compare the effectiveness of SLM with mechanical lumbar traction and explore whether it could be a potential therapy for symptomatic DLS. A total of 60 patients with symptomatic DLS will be enrolled and treated with the SLM or mechanical lumbar traction for 2 weeks. VAS score and SF-36 questionnaire were assessed at baseline and at 2, 4, 12, and 24 weeks. Any signs of acute adverse reactions, such as lower limb paralysis or syndrome of cauda equina, will be recorded at each visit during treatment.DiscussionAlthough the SLM has been used in China for many years to treat symptomatic DLS, there is a lack of consensus about its effectiveness. This trial will provide convincing evidence about the effect of SLM on symptomatic DLS.Trial registrationRegistered on 6 January 2019; the trial number is ChiCTR1900020519.

Extracorporeal Shockwave Therapy in Lower Limb Sports Injuries

To outline current evidence on the use of ESWT for the treatment of lower limb sports injuries. There is growing evidence to support the use of extracorporeal shockwave therapy (ESWT) for a variety of musculoskeletal conditions in the general population. However, research focused on the use of ESWT specifically for lower extremity injuries in the athletic population is more limited. Athletes represent a subgroup of patients that may benefit from ESWT. Compared with injections or surgical interventions, athletes undergoing ESWT often are able to continue sports participation with fewer limitations in activity during treatment. The review identifies considerable variability in study design and treatment protocols that affect the overall quality of evidence. Sports participation was allowed in most studies. One case of plantar fascia tear was identified during ESWT treatment; this injury was self-limited. Most studies report pain-relieving and/or functional benefit with the use of ESWT for common lower extremity tendinopathies, plantar fasciitis, and medial tibial stress syndrome. This review highlights the need for further investigations on optimal methods of ESWT use in athletes given the high prevalence of lower extremity injuries and favorable safety profile for treatment.

Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction.

PIK3C2A is a class II member of the phosphoinositide 3-kinase (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and the phosphorylation of PI(4)P into PI(3,4)P2. At the cellular level, PIK3C2A is critical for the formation of cilia and for receptor mediated endocytosis, among other biological functions. We identified homozygous loss-of-function mutations in PIK3C2A in children from three independent consanguineous families with short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities, neurological manifestations, among other findings. Cellular studies of patient-derived fibroblasts found that they lacked PIK3C2A protein, had impaired cilia formation and function, and demonstrated reduced proliferative capacity. Collectively, the genetic and molecular data implicate mutations in PIK3C2A in a new Mendelian disorder of PI metabolism, thereby shedding light on the critical role of a class II PI3K in growth, vision, skeletal formation and neurological development. In particular, the considerable phenotypic overlap, yet distinct features, between this syndrome and Lowe’s syndrome, which is caused by mutations in the PI-5-phosphatase OCRL, highlight the key role of PI metabolizing enzymes in specific developmental processes and demonstrate the unique non-redundant functions of each enzyme. This discovery expands what is known about disorders of PI metabolism and helps unravel the role of PIK3C2A and class II PI3Ks in health and disease.

EFFICACY OF SILODOSIN VS TAMSULOSIN IN PATIENTS WITH BENIGN PROSTATIC HYPERPLASIA: A DOUBLE-BLIND RANDOMIZED CLINICAL TRIAL

Objective: Benign prostatic hyperplasia (BPH) is a nonmalignant enlargement of the prostate associated with aging. BPH can cause lower urinary tract syndrome (LUTS). Medical therapy for patients with moderate and severe LUTS symptoms comprises a-1 adrenergic receptor antagonists. This study aimed to determine whether there are differences in the international prostate symptom score (IPSS) and maximal flow rate (Qmax) of patients with BPH receiving either silodosin or tamsulosin over 12 w.
 Methods: This study was a double-blind randomized clinical trial. Subjects were 50 men aged ³ 50 y diagnosed with BPH with an IPSS ³ 8 at the Gatot Soebroto Indonesian Army Hospital. The participants received either silodosin or tamsulosin. Their IPSS and Qmax were assessed at the initial assessment and after 4, 8, and 12 w of treatment.
 Results: The initial median IPSS was 15 in the tamsulosin group and 17 in the silodosin group (P = 0.808). After 12 w of therapy, the median IPSS decreased to 9 in the tamsulosin group and 10 in the silodosin group (P = 0.186). The initial median Qmax was 10.1 ml/s in the tamsulosin group and 10.9 ml/s in the silodosin group (P = 0.290). After 12 w of therapy, the median Qmax increased to 12.1 ml/s in the tamsulosin group and 11.9 ml/s in the silodosin group (P = 0.969). Although the differences between groups were not significant, the initial and 12-week IPSS and Qmax values differed significantly within each group.
 Conclusion: There were no significant between-group differences in the IPSS or Qmax after 12 w of therapy. However, both silodosin and tamsulosin produced significant differences between initial and 12-week assessments of IPSS and Qmax.

BM-MNCs for Lower Extremity Compartment Syndrome Injury

BM-MNCs for Lower Extremity Compartment Syndrome Injury

Guanine nucleotide exchange factors activate Rab8a for Toll-like receptor signalling

ABSTRACT Macrophages are important immune sentinels that detect and clear pathogens and initiate inflammatory responses through the activation of surface receptors, including Toll-like receptors (TLRs). Activated TLRs employ complex cellular trafficking and signalling pathways to initiate transcription for inflammatory cytokine programs. We have previously shown that Rab8a is activated by multiple TLRs and regulates downstream Akt/mTOR signalling by recruiting the effector PI3Kγ, but the guanine nucleotide exchange factors (GEF) canonically required for Rab8a activation in TLR pathways is not known. Using GST affinity pull-downs and mass spectrometry analysis, we identified a Rab8 specific GEF, GRAB, as a Rab8a binding partner in LPS-activated macrophages. Co-immunoprecipitation and fluorescence microscopy showed that both GRAB and a structurally similar GEF, Rabin8, undergo LPS-inducible binding to Rab8a and are localised on cell surface ruffles and macropinosomes where they coincide with sites of Rab8a mediated signalling. Rab nucleotide activation assays with CRISPR-Cas9 mediated knock-out (KO) cell lines of GRAB, Rabin8 and double KOs showed that both GEFs contribute to TLR4 induced Rab8a GTP loading, but not membrane recruitment. In addition, measurement of signalling profiles and live cell imaging with the double KOs revealed that either GEF is individually sufficient to mediate PI3Kγ-dependent Akt/mTOR signalling at macropinosomes during TLR4-driven inflammation, suggesting a redundant relationship between these proteins. Thus, both GRAB and Rabin8 are revealed as key positive regulators of Rab8a nucleotide exchange for TLR signalling and inflammatory programs. These GEFs may be useful as potential targets for manipulating inflammation. Abbreviations: TLR: Toll-like Receptor; OCRL: oculocerebrorenal syndrome of Lowe protein; PI3Kγ: phosphoinositol-3-kinase gamma; LPS: lipopolysaccharide; GEF: guanine nucleotide exchange factor; GST: glutathione S-transferases; BMMs: bone marrow derived macrophages; PH: pleckstrin homology; GAP: GTPase activating protein; ABCA1: ATP binding cassette subfamily A member 1; GDI: GDP dissociation inhibitor; LRP1: low density lipoprotein receptor-related protein 1

IPIP27 Coordinates PtdIns(4,5)P2 Homeostasis for Successful Cytokinesis

SummaryDuring cytokinesis, an actomyosin contractile ring drives the separation of the two daughter cells. A key molecule in this process is the inositol lipid PtdIns(4,5)P2, which recruits numerous factors to the equatorial region for contractile ring assembly. Despite the importance of PtdIns(4,5)P2 in cytokinesis, the regulation of this lipid in cell division remains poorly understood. Here, we identify a role for IPIP27 in mediating cellular PtdIns(4,5)P2 homeostasis. IPIP27 scaffolds the inositol phosphatase oculocerebrorenal syndrome of Lowe (OCRL) by coupling it to endocytic BAR domain proteins. Loss of IPIP27 causes accumulation of PtdIns(4,5)P2 on aberrant endomembrane vacuoles, mislocalization of the cytokinetic machinery, and extensive cortical membrane blebbing. This phenotype is observed in Drosophila and human cells and can result in cytokinesis failure. We have therefore identified IPIP27 as a key modulator of cellular PtdIns(4,5)P2 homeostasis required for normal cytokinesis. The results indicate that scaffolding of inositol phosphatase activity is critical for maintaining PtdIns(4,5)P2 homeostasis and highlight a critical role for this process in cell division.

The impact of phosphoinositide 5-phosphatases on phosphoinositides in cell function and human disease

Phosphoinositides (PIs) are recognized as major signaling molecules in many different functions of eukaryotic cells. PIs can be dephosphorylated by multiple phosphatase activities at the 5-, 4-, and 3- positions. Human PI 5-phosphatases belong to a family of 10 members. Except for inositol polyphosphate 5-phosphatase A, they all catalyze the dephosphorylation of PI(4,5)P2 and/or PI(3,4,5)P3 at the 5- position. PI 5-phosphatases thus directly control the levels of PI(3,4,5)P3 and participate in the fine-tuning regulatory mechanisms of PI(3,4)P2 and PI(4,5)P2 Second messenger functions have been demonstrated for PI(3,4)P2 in invadopodium maturation and lamellipodia formation. PI 5-phosphatases can use several substrates on isolated enzymes, and it has been challenging to establish their real substrate in vivo. PI(4,5)P2 has multiple functions in signaling, including interacting with scaffold proteins, ion channels, and cytoskeleton proteins. PI 5-phosphatase isoenzymes have been individually implicated in human diseases, such as the oculocerebrorenal syndrome of Lowe, through mechanisms that include lipid control. Oncogenic and tumor-suppressive functions of PI 5-phosphatases have also been reported in different cell contexts. The mechanisms responsible for genetic diseases and for oncogenic or tumor-suppressive functions are not fully understood. The regulation of PI 5-phosphatases is thus crucial in understanding cell functions.

OCRL deficiency impairs endolysosomal function in a humanized mouse model for Lowe syndrome and Dent disease.

Mutations in OCRL encoding the inositol polyphosphate 5-phosphatase OCRL (Lowe oculocerebrorenal syndrome protein) disrupt phosphoinositide homeostasis along the endolysosomal pathway causing dysfunction of the cells lining the kidney proximal tubule (PT). The dysfunction can be isolated (Dent disease 2) or associated with congenital cataracts, central hypotonia and intellectual disability (Lowe syndrome). The mechanistic understanding of Dent disease 2/Lowe syndrome remains scarce due to limitations of animal models of OCRL deficiency. Here, we investigate the role of OCRL in Dent disease 2/Lowe syndrome by using OcrlY/− mice, where the lethal deletion of the paralogue Inpp5b was rescued by human INPP5B insertion, and primary culture of proximal tubule cells (mPTCs) derived from OcrlY/− kidneys. The OcrlY/− mice show muscular defects with dysfunctional locomotricity and present massive urinary losses of low-molecular-weight proteins and albumin, caused by selective impairment of receptor-mediated endocytosis in PT cells. The latter was due to accumulation of phosphatidylinositol 4,5–bisphosphate PI(4,5)P2 in endolysosomes, driving local hyper-polymerization of F-actin and impairing trafficking of the endocytic LRP2 receptor, as evidenced in OcrlY/− mPTCs. The OCRL deficiency was also associated with a disruption of the lysosomal dynamic and proteolytic activity. Partial convergence of disease-pathways and renal phenotypes observed in OcrlY/− and Clcn5Y/− mice suggest shared mechanisms in Dent diseases 1 and 2.These studies substantiate the first mouse model of Lowe syndrome and give insights into the role of OCRL in cellular trafficking of multiligand receptors. These insights open new avenues for therapeutic interventions in Lowe syndrome and Dent disease.

The structure of Legionella effector protein LpnE provides insights into its interaction with Oculocerebrorenal syndrome of Lowe (OCRL) protein

Legionella pneumophila is a freshwater bacterium that replicates in predatory amoeba and alveolar macrophage. The ability of L.pneumophila to thrive in eukaryotic host cells is conferred by the Legionella containing vacuole (LCV). Formation and intracellular trafficking of the LCV are governed by an arsenal of effector proteins, many of which are secreted by the Icm/Dot Type 4 Secretion System. One such effector, known as LpnE (L.pneumophila Entry), has been implicated in facilitating bacterial entry into host cells, LCV trafficking, and substrate translocation. LpnE belongs to a subfamily of tetratricopeptide repeat proteins known as Sel1-like repeats (SLRs). All eight of the predicted SLRs in LpnE are required to promote host cell invasion. Herein, we report that LpnE(1-375) localizes to cis-Golgi in HEK293 cells via its signal peptide (aa 1-22). We further verify the interaction of LpnE(73-375) and LpnE(22-375) with Oculocerebrorenal syndrome of Lowe protein (OCRL) residues 10-208, restricting the known interacting residues for both proteins. To further characterize the SLR region of LpnE, we solved the crystal structure of LpnE(73-375) to 1.75Å resolution. This construct comprises all SLRs, which are arranged in a superhelical fold. The α-helices forming the inner concave surface of the LpnE superhelix suggest a potential protein-protein interaction interface. DATABASE: Coordinates and structure factors were deposited in the Protein Data Bank with the accession number 6DEH.