Characterization of 28 novel patients expands the mutational and phenotypic spectrum of Lowe syndrome

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• 作者：Florian Recker ; Marcin Zaniew ; Detlef B?ckenhauer ; Nunzia Miglietti…
• 关键词：Oculocerebrorenal syndrome of Lowe ; OCRL ; Cataract ; CpG dinucleotides ; Hyperosmia ; Hyperacusis ; Thrombocytopenia
• 刊名：Pediatric Nephrology
• 出版年：2015
• 出版时间：June 2015
• 年：2015
• 卷：30
• 期：6
• 页码：931-943
• 全文大小：496 KB
• 参考文献：1.Lowe CU, Terrey M, MacLachlan EA (1952) Organic-aciduria, decreased renal ammonia production, hydrophthalmos, and mental retardation; a clinical entity. AMA Am J Dis Child 83:164-84PubMed
  2.Loi M (2006) Lowe syndrome. Orphanet J Rare Dis 1:16View Article PubMed Central PubMed
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  7.Demmer LA, Wippold FJ 2nd, Dowton SB (1992) Periventricular white matter cystic lesions in Lowe (oculocerebrorenal) syndrome: a new MRI finding. Pediatr Radiol 22:76-7View Article PubMed
  8.Lasne D, Baujat G, Mirault T, Lunardi J, Grelac F, Egot M, Salomon R, Bachelot-Loza C (2010) Bleeding disorders in Lowe syndrome patients: evidence for a link between OCRL mutations and primary haemostasis disorders. Br J Haematol 150:685-88View Article PubMed
  9.McSpadden K (2010) Living with Lowe syndrome: a guide for families, friends and professionals, 4th edn. Lowe Syndrome Association, Inc, Plano
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  12.Hoopes RR Jr, Shrimpton AE, Knohl SJ, Hueber P, Hoppe B, Matyus J, Simckes A, Tasic V, Toenshoff B, Suchy SF, Nussbaum RL, Scheinman SJ (2005) Dent disease with mutation in OCRL1. Am J Hum Genet 76:260-67View Article PubMed Central PubMed
  13.Utsch B, B?kenkamp A, Benz MR, Besbas N, D?tsch J, Franke I, Fründ S, Gok F, Hoppe B, Karle S, Kuwertz-Br?king E, Laube G, Neb M, Nuutinen M, Ozaltin F, Rascher W, Ring T, Tasic V, van Wijk JA, Ludwig M (2006) Novel OCRL1 mutations in patients with the phenotype of Dent disease. Am J Kidney Dis 48:942-54View Article PubMed
  14.B?ckenhauer D, B?kenkamp A, Nuutinen M, Unwin R, van’t Hoff W, Sirimanna T, Vrljicak K, Ludwig M (2012) Novel OCRL mutations in patients with Dent-2 disease. J Pediatr Genet 1:15-3
  15.B?kenkamp A, B?ckenhauer D, Cheong HI, Hoppe B, Tasic V, Unwin R, Ludwig M (2009) Dent-2 disease: a mild variant of Lowe syndrome. J Pediatr 155:94-9View Article PubMed
  16.Recker F, Reutter H, Ludwig M (2013) Lowe syndrome/Dent-2 disease: a comprehensive review of known and novel aspects. J Pediatr Genet 2:53-8
  17.Mehta ZB, Pietka G, Lowe M (2014) The cellular and physiological functions of the Lowe syndrome protein OCRL1. Traffic 15:471-87View Article PubMed Central PubMed
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  22.Draaken M, Giesen CA, Kesselheim AL, Jabs R, Aretz S, Kugaudo M, Chrzanowska KH, Krajewska-Walasek M, Ludwig M (2011) Maternal de novo triple mosaicism for two single OCRL nucleotide substitutions (c.1736A>T, c.1736A>G) in a Lowe syndrome family. Hum Genet 129:513-19View Article PubMed
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  25.Mahmoudi H, Tug E, Parlak AH, Atasoy HI, Ludwig M, Polat
• 作者单位：Florian Recker (1)
  Marcin Zaniew (2)
  Detlef B?ckenhauer (3)
  Nunzia Miglietti (4)
  Arend B?kenkamp (5)
  Anna Moczulska (6)
  Anna Rogowska-Kalisz (7)
  Guido Laube (8)
  Valerie Said-Conti (9)
  Belde Kasap-Demir (10)
  Anna Niemirska (11)
  Mieczys?aw Litwin (11)
  Grzegorz Siteń (12)
  Krystyna H. Chrzanowska (13)
  Ma?gorzata Krajewska-Walasek (13)
  Sidharth K. Sethi (14)
  Velibor Tasic (15)
  Franca Anglani (16)
  Maria Addis (17)
  Anna Wasilewska (18)
  Maria Szczepańska (19)
  Krzysztof Pawlaczyk (20)
  Przemys?aw Sikora (21)
  Michael Ludwig (1)
  
  1. Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany
  2. Children’s Hospital, Poznań, Poland
  3. Institute of Child Health and Great Ormond Street Hospital for Children, National Health Service Trust, University College London, London, UK
  4. Department of Pediatrics, University of Brescia, Brescia, Italy
  5. Department of Pediatrics, VU University Medical Center, Amsterdam, The Netherlands
  6. Department of Pediatric Nephrology, University Children’s Hospital of Cracow, Cracow, Poland
  7. Nephrology Division, Department of Pediatrics and Immunology, Polish Mothers Memorial Hospital Research Institute, Lodz, Poland
  8. Department of Pediatric Nephrology, Children’s Hospital Zürich, Zurich, Switzerland
  9. Mater Dei Hospital, Msida, Malta
  10. Clinics of Pediatrics, Tepecik Training and Research Hospital, Izmir, Turkey
  11. Department of Nephrology and Kidney Transplantation, The Children’s Memorial Health Institute, Warsaw, Poland
  12. Dialysis Center, District Hospital, Rzeszow, Poland
  13. Department of Medical Genetics, The Children’s Memorial Health Institute, Warsaw, Poland
  14. Department of Pediatric Nephrology, The Medicity Hospital Gurgaon, Kidney and Urology Institute Medanta, Gurgaon, India
  15. Department of Pediatric Nephrology, University Children’s Hospital, Skopje, Macedonia
  16. Laboratory of Histomorphology and Molecular Biology of the Kidney, Department of Medicine, University of Padova, Padova, Italy
  17. Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy
  18. Department of Pediatrics and Nephrology, Medical University of Bia?ystok, Bia?ystok, Poland
  19. Dialysis Division for Children, Department and Clinics of Pediatrics, Medical University of Silesia in Katowice, Zabrze, Poland
  20. Department of Nephrology, Transplantology and Internal Medicine, Poznań University of Medical Sciences, Poznań, Poland
  21. Department of Pediatric Nephrology, Medical University of Lublin, Lublin, Poland
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Pediatrics
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-198X

文摘

Background The oculocerebrorenal syndrome of Lowe (OCRL) is a rare X-linked multi-systemic disorder, almost always characterized by the triad of congenital cataract, cognitive and behavioral impairment and a proximal tubulopathy. Methods Twenty-eight novel patients with suspected Lowe syndrome were studied. Results All patients carried OCRL gene defects with mutational hot spots at CpG dinucleotides. Mutations previously unknown in Lowe syndrome were observed in ten of the 28 patients, and carriership was identified in 30.4?% of the mothers investigated. Mapping the exact breakpoints of a complete OCRL gene deletion revealed involvement of several flanking repeat elements. We noted a similar pattern of documented clinically relevant symptoms, and even though the patient cohort comprised relatively young patients, 32?% of these patients already showed advanced chronic kidney disease. Thrombocytopenia was seen in several patients, and hyperosmia and/or hyperacusis were reported recurrently. A p.Asp523Asn mutation in a Polish patient, associated with the typical cerebrorenal spectrum but with late cataract (10?year), was also evident in two milder affected Italian brothers with ocular involvement of similar progression. Conclusions We have identified clinical features in 28 patients with suspected Lowe syndrome that had not been recognized in Lowe syndrome prior to our study. We also provide further evidence that OCRL mutations cause a phenotypic continuum with selective and/or time-dependent organ involvement. At least some of these mutants might exhibit a genotype–phenotype correlation.