Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  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 83:164–184

    CAS  PubMed  Google Scholar 

  2. Loi M (2006) Lowe syndrome. Orphanet J Rare Dis 1:16

    Article  PubMed Central  PubMed  Google Scholar 

  3. Böckenhauer D, Bokenkamp A, van’t Hoff W, Levtchenko E, Kist-van Holthe JE, Tasic V, Ludwig M (2008) Renal phenotype in Lowe syndrome: a selective proximal tubular dysfunction. Clin J Am Soc Nephrol 3:1430–1436

    Article  PubMed Central  PubMed  Google Scholar 

  4. Kleta R (2008) Fanconi or not Fanconi? Lowe syndrome revisited. Clin J Am Soc Nephrol 3:1244–1245

    Article  PubMed  Google Scholar 

  5. Laube GF, Russell-Eggitt IM, van’t Hoff WG (2004) Early proximal tubular dysfunction in Lowe’s syndrome. Arch Dis Child 89:479–480

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Charnas L, Bernar J, Pereshkpour GH, Dalakas M, Harper GS, Gahal WA (1988) MRI findings and peripheral neuropathy in Lowe syndrome. Neuropediatrics 19:7–9

    Article  CAS  PubMed  Google Scholar 

  7. Demmer LA, Wippold FJ 2nd, Dowton SB (1992) Periventricular white matter cystic lesions in Lowe (oculocerebrorenal) syndrome: a new MRI finding. Pediatr Radiol 22:76–77

    Article  CAS  PubMed  Google Scholar 

  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 150:685–688

    Article  CAS  PubMed  Google Scholar 

  9. McSpadden K (2010) Living with Lowe syndrome: a guide for families, friends and professionals, 4th edn. Lowe Syndrome Association, Inc, Plano

    Google Scholar 

  10. Nussbaum RL, Orrison BM, Jänne PA, Charnas L, Chinault AC (1997) Physical mapping and genomic structure of the Lowe syndrome gene OCRL1. Hum Genet 99:145–150

    Article  CAS  PubMed  Google Scholar 

  11. Hichri H, Rendu J, Monnier N, Coutton C, Dorseuil O, Vargas Poussou R, Beaujat G, Blanchard A, Nobili F, Ranchin B, Remesey M, Salomon R, Satre V, Lunardi J (2011) From Lowe syndrome to Dent disease: correlations between mutations of the OCRL1 gene and clinical and biochemical phenotypes. Hum Mutat 32:379–388

    Article  CAS  PubMed  Google Scholar 

  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 76:260–267

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Utsch B, Bökenkamp A, Benz MR, Besbas N, Dötsch J, Franke I, Fründ S, Gok F, Hoppe B, Karle S, Kuwertz-Bröking 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 48:942–954

    Article  CAS  PubMed  Google Scholar 

  14. Böckenhauer D, Bökenkamp 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 1:15–23

    Google Scholar 

  15. Bökenkamp A, Böckenhauer D, Cheong HI, Hoppe B, Tasic V, Unwin R, Ludwig M (2009) Dent-2 disease: a mild variant of Lowe syndrome. J Pediatr 155:94–99

    Article  PubMed  Google Scholar 

  16. Recker F, Reutter H, Ludwig M (2013) Lowe syndrome/Dent-2 disease: a comprehensive review of known and novel aspects. J Pediatr Genet 2:53–68

    CAS  Google Scholar 

  17. Mehta ZB, Pietka G, Lowe M (2014) The cellular and physiological functions of the Lowe syndrome protein OCRL1. Traffic 15:471–487

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Ghazali S, Barratt TM (1974) Urinary excretion of calcium and magnesium in children. Arch Intern Med 49:97–101

    CAS  Google Scholar 

  19. Kruse K, Kracht U, Gopfert G (1982) Renal threshold phosphate concentration (TmPO4/GFR). Arch Intern Med 57:217–223

    CAS  Google Scholar 

  20. Schwartz GJ, Brion LP, Spitzer A (1987) The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin N Am 4:571–590

    Google Scholar 

  21. Tosetto E, Addis M, Caridi G, Meloni C, Emma F, Vergine G, Stringini G, Papalia T, Barbano G, Ghiggeri GM, Ruggeri L, Miglietti N, D’Angelo A, Melis MA, Anglani F (2009) Locus heterogeneity of Dent’s disease: OCRL1 and TMEM27 genes in patients with no CLCN5 mutations. Pediatr Nephrol 24:1967–1973

    Article  PubMed  Google Scholar 

  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 129:513–519

    Article  PubMed  Google Scholar 

  23. Peverall J, Edkins E, Goldblatt J, Murch A (2000) Identification of a novel deletion of the entire OCRL1 gene detected by FISH analysis in a family with Lowe syndrome. Clin Genet 58:479–482

    Article  CAS  PubMed  Google Scholar 

  24. Addis M, Meloni C, Congiu R, Santaniello S, Emma F, Zuffardi O, Cao A, Ciccone R, Melis MA, Cau M (2007) A novel interstitial deletion in Xq25, identified by array-CGH in a patient with Lowe syndrome. Eur J Med Genet 50:79–84

    Article  PubMed  Google Scholar 

  25. Mahmoudi H, Tug E, Parlak AH, Atasoy HI, Ludwig M, Polat M, Pasternack SM, Betz RC (2012) Identification of an Alu-mediated 12.2-kb deletion of the complete LPAR6 (P2RY5) gene in a Turkish family with hypotrichosis and wolly hair. Exp Dermatol 21:469–471

    Article  CAS  PubMed  Google Scholar 

  26. Keilhauer CN, Gal A, Sold JE, Zimmermann J, Netzer KO, Schramm L (2007) Clinical findings in a patient with Lowe syndrome and a splice site mutation in the OCRL1 gene. Klin Monatsbl Augenheilkd 224:207–209

    Article  CAS  PubMed  Google Scholar 

  27. Pasternack SM, Böckenhauer D, Refke M, Tasic V, Draaken M, Conrad C, Betz RC, Born M, Reutter H, Ludwig M (2013) A premature termination mutation in a patient with Lowe syndrome without congenital cataracts: dropping the “O” in OCRL. Klin Padiatr 225:29–33

    CAS  PubMed  Google Scholar 

  28. Cho HY, Lee BH, Choi HJ, Ha IS, Choi Y, Cheong HI (2008) Renal manifestations of Dent disease and Lowe syndrome. Pediatr Nephrol 23:243–249

    Article  PubMed  Google Scholar 

  29. Kim HK, Kim JH, Kim YM, Kim GH, Lee BH, Choi JH, Yoo HW (2014) Lowe syndrome: a single center’s experience in Korea. Korean J Pediatr 57:140–148

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Matzaris M, Jackson SP, Laxminarayan KM, Speed CJ, Mitchell CA (1994) Identification and characterization of the phosphatidylinositol-(4,5)-bisphosphate 5-phosphatase in human platelets. J Biol Chem 269:3397–3402

    CAS  PubMed  Google Scholar 

  31. Taher AT, Arabi M, Sibai H, Nasreddine W, Otrock ZK, Musallam KM, Beydoun A (2012) Carbamazepine-induced thrombocytopenia. Blood Cells Mol Dis 48:197–198

    Article  PubMed  Google Scholar 

  32. Verrotti A, Scaparotta A, Grosso S, Chiarelli F, Coppola G (2014) Anticonvulsant drugs and hematological disease. Neurol Sci 35:983–993

    Article  CAS  PubMed  Google Scholar 

  33. Forge A, Wright T (2002) The molecular architecture of the inner ear. Br Med Bull 63:5–24

    Article  CAS  PubMed  Google Scholar 

  34. Cao H, Yin X, Cao Y, Jin Y, Wang S, Kong Y, Chen Y, Gao J, Heller S, Xu Z (2013) FCHSD1 and FCHSD2 are expressed in hair cell stereocilia and cuticular plate and regulate actin polymerization in vitro. PLoS ONE 8:e56516

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Nández R, Balkin DM, Messa M, Liang L, Paradise S, Czapla H, Hein MY, Duncan JS, Mann M, De Camilli P (2014) A role of OCRL in clathrin-coated pit dynamics and uncoating revealed by studies of Lowe syndrome cells. Elife 3:e02975. doi: 10.7554/eLife.02975

  36. Coon BG, Hernandez V, Madhivanan K, Mukherjee D, Hanna CB, Barinaga-Rementeria RI, Lowe M, Beales PL, Aguilar RC (2012) The Lowe syndrome protein OCRL1 is involved in primary cilia assembly. Hum Mol Genet 21:1835–1847

    Article  CAS  PubMed  Google Scholar 

  37. Luo N, West CC, Murga-Zamalloa CA, Sun L, Anderson RM, Wells CD, Weinreb RN, Travers JB, Khanna H, Sun Y (2012) OCRL localizes to the primary cilium: a new role for cilia in Lowe syndrome. Hum Mol Genet 21:3333–3344

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Sharma N, Berbari NF, Yoder BK (2008) Ciliary dysfunction in the developmental abnormalities and diseases. Curr Top Dev Biol 85:371–427

    Article  CAS  PubMed  Google Scholar 

  39. Sekine T, Nozu K, Iyengar R, Fu XJ, Matsuo M, Tanaka R, Iijima K, Matsui E, Harita Y, Inatomi J, Igarashi T (2007) OCRL1 mutations in patients with Dent disease phenotype in Japan. Pediatr Nephrol 22:975–980

    Article  PubMed  Google Scholar 

  40. Shrimpton AE, Hoopes RR Jr, Knohl SJ, Hueber P, Reed AAC, Christie PT, Igarashi T, Lee P, Lehman A, White C, Milford DV, Sanchez MR, Unwin R, Wrong OM, Thakker RV, Scheinman SJ (2009) OCRL1 mutations in Dent 2 patients suggest a mechanism for phenotypic variability. Nephron Physiol 112:27–36

    Article  Google Scholar 

  41. Skuta GL, Sugar J, Ericson ES (1983) Corneal endothelial cell measurements in megalocornea. Arch Ophthalmol 101:51–53

    Article  CAS  PubMed  Google Scholar 

  42. Webb TR, Matarin M, Gardner JC, Kelberman D, Hassan H, Ang W, Michaelides M, Ruddle JB, Pennell CE, Yazar S, Khor CC, Aung T, Yogarajah M, Robson AG, Holder GE, Cheetham ME, Traboulsi EI, Moore AT, Sowden JC, Sisodiya SM, Mackey DA, Tuft SJ, Hardcastle AJ (2012) X-linked megalocornea caused by mutations in CHRDL1 identifies an essential role for venotropin in anterior segment development. Am J Hum Genet 90:247–259

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Hanefeld FA (1999) Oligogyric microcephaly. Neuropediatrics 30:102–103

    Article  CAS  PubMed  Google Scholar 

  44. Pang T, Atefy R, Sheen V (2008) Malformations of cortical development. Neurologist 14:181–191

    Article  PubMed Central  PubMed  Google Scholar 

  45. Gropman A, Levin S, Yao L, Lin T, Suchy S, Sabnis S, Hadley D, Nussbaum R (2000) Unusual renal features of Lowe syndrome in a mildly affected boy. Am J Med Genet 95:461–466

    Article  CAS  PubMed  Google Scholar 

  46. Marques A, Ramos L, Gomes C, Correia AJ (2010) Lowe syndrome. Case report of a patient with a missense mutation in the OCRL1 gene. Port J Nephrol Hypertens 24:239–242

    Google Scholar 

  47. Youssoufian H, Kazazian HH Jr, Phillips DG, Aronis S, Tsiftis G, Brown VA, Antonarakis SE (1986) Recurrent mutations in haemophilia A give evidence for CpG mutation hotspots. Nature 324:380–382

    Article  CAS  PubMed  Google Scholar 

  48. Cooper DN, Krawczak M (1993) Human gene mutation. BIOS Scientic Publishers Limited, Oxford, pp 109–127

    Google Scholar 

  49. Ten Kate LP (1984) The significance of new mutations for the genetic epidemiology of Duchenne muscular dystrophy. In: Ten Kate LP, Pearson PL, Stadhouders AM (eds) Research into the origin and treatment of muscular dystrophy. Excerpta Medica, Amsterdam, pp 3–6

    Google Scholar 

Download references

Acknowledgments

We are grateful to the patients and their parents for their invaluable contributions. We thank Dr. Andrzej Blumczyński for his help with patient recruitment. We would also like to thank Hartmut Engels for performing array analysis and Pia Uerdingen and Markus Draaken for excellent technical assistance. Funding for this study was provided by the European Union, FP7 (grant agreement 2012-305608 “European Consortium for High-Throughput Research in Rare Kidney Diseases (EURenOmics)” to DB.

Author information

Authors and Affiliations

  1. Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany

    Florian Recker & Michael Ludwig

  2. Children’s Hospital, Poznań, Poland

    Marcin Zaniew

  3. Institute of Child Health and Great Ormond Street Hospital for Children, National Health Service Trust, University College London, London, UK

    Detlef Böckenhauer

  4. Department of Pediatrics, University of Brescia, Brescia, Italy

    Nunzia Miglietti

  5. Department of Pediatrics, VU University Medical Center, Amsterdam, The Netherlands

    Arend Bökenkamp

  6. Department of Pediatric Nephrology, University Children’s Hospital of Cracow, Cracow, Poland

    Anna Moczulska

  7. Nephrology Division, Department of Pediatrics and Immunology, Polish Mothers Memorial Hospital Research Institute, Lodz, Poland

    Anna Rogowska-Kalisz

  8. Department of Pediatric Nephrology, Children’s Hospital Zürich, Zurich, Switzerland

    Guido Laube

  9. Mater Dei Hospital, Msida, Malta

    Valerie Said-Conti

  10. Clinics of Pediatrics, Tepecik Training and Research Hospital, Izmir, Turkey

    Belde Kasap-Demir

  11. Department of Nephrology and Kidney Transplantation, The Children’s Memorial Health Institute, Warsaw, Poland

    Anna Niemirska & Mieczysław Litwin

  12. Dialysis Center, District Hospital, Rzeszow, Poland

    Grzegorz Siteń

  13. Department of Medical Genetics, The Children’s Memorial Health Institute, Warsaw, Poland

    Krystyna H. Chrzanowska & Małgorzata Krajewska-Walasek

  14. Department of Pediatric Nephrology, The Medicity Hospital Gurgaon, Kidney and Urology Institute Medanta, Gurgaon, India

    Sidharth K. Sethi

  15. Department of Pediatric Nephrology, University Children’s Hospital, Skopje, Macedonia

    Velibor Tasic

  16. Laboratory of Histomorphology and Molecular Biology of the Kidney, Department of Medicine, University of Padova, Padova, Italy

    Franca Anglani

  17. Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy

    Maria Addis

  18. Department of Pediatrics and Nephrology, Medical University of Białystok, Białystok, Poland

    Anna Wasilewska

  19. Dialysis Division for Children, Department and Clinics of Pediatrics, Medical University of Silesia in Katowice, Zabrze, Poland

    Maria Szczepańska

  20. Department of Nephrology, Transplantology and Internal Medicine, Poznań University of Medical Sciences, Poznań, Poland

    Krzysztof Pawlaczyk

  21. Department of Pediatric Nephrology, Medical University of Lublin, Lublin, Poland

    Przemysław Sikora

Authors
  1. Florian Recker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marcin Zaniew
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Detlef Böckenhauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nunzia Miglietti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Arend Bökenkamp
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anna Moczulska
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anna Rogowska-Kalisz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Guido Laube
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Valerie Said-Conti
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Belde Kasap-Demir
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Anna Niemirska
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mieczysław Litwin
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Grzegorz Siteń
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Krystyna H. Chrzanowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Małgorzata Krajewska-Walasek
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Sidharth K. Sethi
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Velibor Tasic
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Franca Anglani
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Maria Addis
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Anna Wasilewska
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Maria Szczepańska
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Krzysztof Pawlaczyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Przemysław Sikora
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Michael Ludwig
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Ludwig.

Additional information

Florian Recker and Marcin Zaniew contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Recker, F., Zaniew, M., Böckenhauer, D. et al. Characterization of 28 novel patients expands the mutational and phenotypic spectrum of Lowe syndrome. Pediatr Nephrol 30, 931–943 (2015). https://doi.org/10.1007/s00467-014-3013-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-014-3013-2

Keywords

Search

Navigation