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Daniel Duran, Sheng Chih Jin, Tyrone DeSpenza, Carol Nelson-Williams, Andrea G Cogal, Elizabeth W Abrash, Peter C Harris, John C Lieske, Serena Je Shimshak, Shrikant Mane, Kaya Bilguvar, Michael L DiLuna, Murat Günel, Richard P Lifton, Kristopher T Kahle
OCRL1 and its paralog INPP5B encode phosphatidylinositol 5-phosphatases that localize to the primary cilium and have roles in ciliogenesis. Mutations in OCRL1 cause the X-linked Dent disease type 2 (DD2; OMIM# 300555), characterized by low-molecular weight proteinuria, hypercalciuria, and the variable presence of cataracts, glaucoma and intellectual disability without structural brain anomalies. Disease-causing mutations in INPP5B have not been described in humans. Here, we report the case of an 11-year-old boy with short stature and an above-average IQ; severe proteinuria, hypercalciuria and osteopenia resulting in a vertebral compression fracture; and Chiari I malformation with cervico-thoracic syringohydromyelia requiring suboccipital decompression...
2016: Human Genome Variation
Swati Bhardwaj, Ranjeet Thergaonkar, Aditi Sinha, Pankaj Hari, Cheong Hi, Arvind Bagga
OBJECTIVE: To describe the clinical and genotypic features of Dent disease in children diagnosed at our center over a period of 10 years. DESIGN: Case series. SETTING: Pediatric Nephrology Clinic at a referral center in Northern India. METHODS: The medical records of patients with Dent disease diagnosed and followed up at this hospital from June 2005 to April 2015 were reviewed. The diagnosis of Dent disease was based on presence of all three of the following: (i) low molecular weight proteinuria, (ii) hypercalciuria and (iii) one of the following: nephrolithiasis, hematuria, hypophosphatemia or renal insufficiency, with or without mutation in CLCN5 or OCRL1 genes...
November 15, 2016: Indian Pediatrics
Fucheng Li, Zhihui Yue, Tingting Xu, Minghui Chen, Liangying Zhong, Ting Liu, Xiangyi Jing, Jia Deng, Bin Hu, Yuling Liu, Haiyan Wang, Kar N Lai, Liangzhong Sun, Jinsong Liu, Patrick H Maxwell, Yiming Wang
OBJECTIVE: To characterize the phenotypes of Dent disease in Chinese children and their heterozygous mothers and to establish genetic diagnoses. STUDY DESIGN: Using a modified protocol, we screened 1288 individuals with proteinuria. A diagnosis of Dent disease was established in 19 boys from 16 families by the presence of loss of function/deleterious mutations in CLCN5 or OCRL1. We also analyzed 16 available patients' mothers and examined their pregnancy records...
July 2016: Journal of Pediatrics
Yan Gao, Fang Jiang, Zhi-Ying Ou
BACKGROUND: Lowe syndrome, an X-linked, inheritable disease with clinical symptoms of congenital cataracts, incomplete Fanconi syndrome, and mental retardation, has an approximate incidence of 1 in 500 000. Nearly 200 OCRL mutations related to Lowe syndrome have been found worldwide, with only ten mutations among the Chinese population. Since more mutations may exist in Chinese patients, we sequenced and analyzed the OCRL genes of six children with Lowe syndrome in a medical center in China...
November 2016: World Journal of Pediatrics: WJP
Peter G Billcliff, Christopher J Noakes, Zenobia B Mehta, Guanhua Yan, LokHang Mak, Rudiger Woscholski, Martin Lowe
Mutation of the inositol 5-phosphatase OCRL1 causes Lowe syndrome and Dent-2 disease. Loss of OCRL1 function perturbs several cellular processes, including membrane traffic, but the underlying mechanisms remain poorly defined. Here we show that OCRL1 is part of the membrane-trafficking machinery operating at the trans-Golgi network (TGN)/endosome interface. OCRL1 interacts via IPIP27A with the F-BAR protein pacsin 2. OCRL1 and IPIP27A localize to mannose 6-phosphate receptor (MPR)-containing trafficking intermediates, and loss of either protein leads to defective MPR carrier biogenesis at the TGN and endosomes...
January 1, 2016: Molecular Biology of the Cell
Kayalvizhi Madhivanan, Swetha Ramadesikan, R Claudio Aguilar
Lowe syndrome is a lethal X-linked genetic disorder characterized by congenital cataracts, mental retardation, and kidney dysfunction. It is caused by mutations in the OCRL1 (oculocerebrorenal syndrome of Lowe) gene that encodes a phosphatidylinositol 5-phosphatase (EC The gene product Ocrl1 has been linked to a multitude of functions due to the central role played by phosphoinositides in signaling. Moreover, this protein also has the ability to bind Rho GTPases, the master regulators of the actin cytoskeleton, and to interact with elements of the vesicle trafficking machinery...
2015: International Review of Cell and Molecular Biology
Shouan Zhu, Jun Dai, Huanhuan Liu, Xiaoxia Cong, Yishan Chen, Yan Wu, Hu Hu, Boon Chin Heng, Hong Wei Ouyang, Yiting Zhou
OBJECTIVE: Chondrocyte hypertrophy and mineralization are considered to be important pathologic factors in osteoarthritis (OA). We previously reported that Rac1 was aberrantly activated to promote chondrocyte hypertrophy, mineralization, and expression of matrix metalloproteinase 13 and ADAMTS in OA. However, the underlying mechanism of aberrant Rac1 activation in OA is unclear. The present study was undertaken to identify the specific molecular regulator controlling Rac1 activity in OA, as well as to investigate its function in chondrocyte hypertrophy, mineralization, and OA development...
May 2015: Arthritis & Rheumatology
Alejandro Solano, Susie Q Lew, Todd S Ing
Dent-Wrong disease, an X-linked recessive disorder of the proximal tubules, presents with hypercalciuria, nephrocalcinosis, nephrolithiasis, renal insufficiency, low-molecular-weight proteinuria, rickets and/or osteomalacia. Dent and Friedman initially characterized the disorder in 1964 following studies of two patients with rickets who presented with hypercalciuria, hyperphosphaturia, proteinuria and aminoaciduria. Since then, extensive investigation identified two genetic mutations (CLCN5 and OCRL1) to be associated with Dent-Wrong disease...
August 2014: Clinical Kidney Journal
Francesca Oltrabella, Grzegorz Pietka, Irene Barinaga-Rementeria Ramirez, Aleksandr Mironov, Toby Starborg, Iain A Drummond, Katherine A Hinchliffe, Martin Lowe
Lowe syndrome and Dent-2 disease are caused by mutation of the inositol 5-phosphatase OCRL1. Despite our increased understanding of the cellular functions of OCRL1, the underlying basis for the renal tubulopathy seen in both human disorders, of which a hallmark is low molecular weight proteinuria, is currently unknown. Here, we show that deficiency in OCRL1 causes a defect in endocytosis in the zebrafish pronephric tubule, a model for the mammalian renal tubule. This coincides with a reduction in levels of the scavenger receptor megalin and its accumulation in endocytic compartments, consistent with reduced recycling within the endocytic pathway...
April 2015: PLoS Genetics
Ting Liu, Zhihui Yue, Haiyan Wang, Huajuan Tong, Liangzhong Sun
Lowe syndrome is a rare, X-linked recessive genetic disease with multi-organ involvement. The pathogenic gene is OCRL1. The authors analyzed the OCRL1 mutation and summarized the clinical features of a Chinese child with Lowe syndrome. The patient is a 3 year 7 mo-old boy. He presented with hypotonia at birth and gradually presented with bilateral congenital cataracts, psychomotor retardation, hypophosphatemic rickets and renal tubular function disorder. Sequence analysis of OCRL1 revealed a novel insertion mutation, c...
January 2015: Indian Journal of Pediatrics
Li-Na Ji, Chao-Ying Chen, Jing-Jing Wang, Li Cao
BACKGROUND: Dent's disease is a rare X-linked recessive hereditary disease caused by mutations in either the CLCN5 or OCRL1 genes. This disease is characterized by manifestations of proximal renal tubule dysfunction associated with low molecular weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive renal failure. METHODS: We report a Chinese boy with Dent's disease, clinically diagnosed by LMWP and hypercalciuria. Genetic analysis was made of the CLCN5 and OCRL1 genes...
August 2014: World Journal of Pediatrics: WJP
Debarati Mukherjee, Arpita Sen, R Claudio Aguilar
Cell polarity, the asymmetric distribution of proteins and lipids, is essential for a variety of cellular functions. One mechanism orchestrating cell polarity is polarized vesicle trafficking; whereby cargo loaded secretory vesicles are specifically transported to predetermined areas of the cell. The evolutionarily conserved exocyst complex and its small GTPase regulators play crucial roles in spatiotemporal control of polarized vesicle trafficking. In studies on neuronal membrane remodeling and synaptic plasticity, conserved mechanisms of exocyst regulation and cargo recycling during polarized vesicle trafficking are beginning to emerge as well...
2014: Small GTPases
Keisuke Sugimoto, Hitomi Nishi, Tomoki Miyazawa, Shinsuke Fujita, Mitsuru Okada, Tsukasa Takemura
Oculocerebrorenal syndrome of Lowe (OCRL, OMIM 309000), also known as Lowe syndrome, is a rare X-linked multisystem disorder characterized by congenital cataracts, mental retardation, and Fanconi syndrome of the kidney proximal tubules. Lowe syndrome is caused by mutations in the gene encoding a member of the inositol polyphosphate-5-phosphatase protein family (OCRL1) on chromosome Xq26.1. OCRL1 contains 24 exons and encodes a 105-kDa phosphatidylinositol (4,5) bisphosphate 5-phosphatase. An OCRL1 isoform generated by alternative splicing is predominantly expressed in brain, and localizes to the trans-Golgi network, lysosomes, and endosomes...
2014: Tohoku Journal of Experimental Medicine
Zenobia B Mehta, Grzegorz Pietka, Martin Lowe
Phosphoinositide lipids play a key role in cellular physiology, participating in a wide array of cellular processes. Consequently, mutation of phosphoinositide-metabolizing enzymes is responsible for a growing number of diseases in humans. Two related disorders, oculocerebrorenal syndrome of Lowe (OCRL) and Dent-2 disease, are caused by mutation of the inositol 5-phosphatase OCRL1. Here, we review recent advances in our understanding of OCRL1 function. OCRL1 appears to regulate many processes within the cell, most of which depend upon coordination of membrane dynamics with remodeling of the actin cytoskeleton...
May 2014: Traffic
Takashi Sekine, Fusako Komoda, Kenichiro Miura, Junko Takita, Mitsunobu Shimadzu, Takeshi Matsuyama, Akira Ashida, Takashi Igarashi
Dent disease is an X-linked disorder characterized by low-molecular-weight (LMW) proteinuria, hypercalciuria, nephrocalcinosis, urolithiasis and renal dysfunction. Dent disease is caused by mutations in at least two genes, i.e. CLCN5 and OCRL1, and its genetic background and phenotypes are common among European countries and the USA. However, only few studies on Dent disease in Japan, which was originally called 'low-molecular-weight proteinuric disease', have been reported thus far. In this study, we analysed genetic background and clinical phenotype and laboratory data of 86 unrelated Japanese Dent disease patients...
February 2014: Nephrology, Dialysis, Transplantation
Kayalvizhi Madhivanan, Debarati Mukherjee, R Claudio Aguilar
Lowe syndrome (LS) is a lethal X-linked genetic disease caused by functional deficiencies of the phosphatidlyinositol 5-phosphatase, Ocrl1. In the past four years, our lab described the first Ocrl1-specific cellular phenotypes using dermal fibroblasts from LS patients. These phenotypes, validated in an ocrl1-morphant zebrafish model, included membrane remodeling (cell migration/spreading, fluid-phase uptake) defects and primary cilia assembly abnormalities. On one hand, our findings unraveled cellular phenotypes likely to be involved in the observed developmental defects; on the other hand, these discoveries established LS as a ciliopathy-associated disease...
November 1, 2012: Communicative & Integrative Biology
Ali Kanık, Belde Kasap-Demir, Rüya Ateşli, Kayı Eliaçık, Onder Yavaşcan, Mehmet Helvacı
Oculocerebrorenal syndrome, also known as Lowe syndrome, is an X-linked recessive disorder that predominantly affects males and is characterized by growth and mental retardation, congenital cataract and renal Fanconi syndrome. OCRL1 is the gene responsible for Lowe syndrome and encodes an inositol polyphosphate-5-phosphatase. We present an 11-year-old boy with Lowe syndrome, who had a de novo frameshift mutation in exon 22 that resulted in amino acid substitution and premature codon termination at position 788...
January 2013: Turkish Journal of Pediatrics
Fang Jiang, Yan Gao, Zhi-ying Ou
No abstract text is available yet for this article.
September 2012: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
Khaled Ben El Kadhi, Grégory Emery, Sebastien Carreno
Inositides are intrinsic components of cell membranes that regulate a wide variety of cellular functions. PtdIns(4,5)P(2,) one of the most abundant phosphoinositides, is restricted at the plasma membrane where it regulates numerous functions including cell division. We have recently established that the Drosophila inositol 5-phosphatase, dOCRL, is essential for cytokinesis, the last step of cell division (Ben El Kadhi et al. 2011).(8) We demonstrated that dOCRL is required for the dephosphorylation of PtdIns(4,5)P(2) at the surface of endosomes, resulting in the restriction of this phosphoinositide to the cell cortex during cytokinesis...
May 1, 2012: Communicative & Integrative Biology
Ramón Peces, Carlos Peces, Erika de Sousa, Cristina Vega, Rafael Selgas, Julián Nevado
The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder. The mutation of the gene OCRL1 localized at Xq26.1, coding for the enzyme phosphatidylinositol (4,5) bisphosphate (PIP2P) 5-phosphatase, is responsible for the phenotypic characteristics of the disease. We report a 22-year-old male with a severe form of OCRL syndrome, diagnosed on the basis of congenital cataracts, severe psychomotor and cognitive deficits, and renal tubular dysfunction without Fanconi syndrome. The patient presented low molecular weight proteinuria, nephrocalcinosis, nephrolithiasis, rickets, and growth retardation and developed progressive renal failure...
December 2013: International Urology and Nephrology
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