Advertisement

Pediatric Nephrology

, Volume 30, Issue 6, pp 931–943 | Cite as

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

  • Florian Recker
  • Marcin Zaniew
  • Detlef Böckenhauer
  • Nunzia Miglietti
  • Arend Bökenkamp
  • Anna Moczulska
  • Anna Rogowska-Kalisz
  • Guido Laube
  • Valerie Said-Conti
  • Belde Kasap-Demir
  • Anna Niemirska
  • Mieczysław Litwin
  • Grzegorz Siteń
  • Krystyna H. Chrzanowska
  • Małgorzata Krajewska-Walasek
  • Sidharth K. Sethi
  • Velibor Tasic
  • Franca Anglani
  • Maria Addis
  • Anna Wasilewska
  • Maria Szczepańska
  • Krzysztof Pawlaczyk
  • Przemysław Sikora
  • Michael Ludwig
Original Article

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.

Keywords

Oculocerebrorenal syndrome of Lowe OCRL Cataract CpG dinucleotides Hyperosmia Hyperacusis Thrombocytopenia 

Notes

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.

References

  1. 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 83:164–184PubMedGoogle Scholar
  2. 2.
    Loi M (2006) Lowe syndrome. Orphanet J Rare Dis 1:16CrossRefPubMedCentralPubMedGoogle Scholar
  3. 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 3:1430–1436CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Kleta R (2008) Fanconi or not Fanconi? Lowe syndrome revisited. Clin J Am Soc Nephrol 3:1244–1245CrossRefPubMedGoogle Scholar
  5. 5.
    Laube GF, Russell-Eggitt IM, van’t Hoff WG (2004) Early proximal tubular dysfunction in Lowe’s syndrome. Arch Dis Child 89:479–480CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Charnas L, Bernar J, Pereshkpour GH, Dalakas M, Harper GS, Gahal WA (1988) MRI findings and peripheral neuropathy in Lowe syndrome. Neuropediatrics 19:7–9CrossRefPubMedGoogle Scholar
  7. 7.
    Demmer LA, Wippold FJ 2nd, Dowton SB (1992) Periventricular white matter cystic lesions in Lowe (oculocerebrorenal) syndrome: a new MRI finding. Pediatr Radiol 22:76–77CrossRefPubMedGoogle Scholar
  8. 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 150:685–688CrossRefPubMedGoogle Scholar
  9. 9.
    McSpadden K (2010) Living with Lowe syndrome: a guide for families, friends and professionals, 4th edn. Lowe Syndrome Association, Inc, PlanoGoogle Scholar
  10. 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 99:145–150CrossRefPubMedGoogle Scholar
  11. 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 32:379–388CrossRefPubMedGoogle Scholar
  12. 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 76:260–267CrossRefPubMedCentralPubMedGoogle Scholar
  13. 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 48:942–954CrossRefPubMedGoogle Scholar
  14. 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 1:15–23Google Scholar
  15. 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 155:94–99CrossRefPubMedGoogle Scholar
  16. 16.
    Recker F, Reutter H, Ludwig M (2013) Lowe syndrome/Dent-2 disease: a comprehensive review of known and novel aspects. J Pediatr Genet 2:53–68Google Scholar
  17. 17.
    Mehta ZB, Pietka G, Lowe M (2014) The cellular and physiological functions of the Lowe syndrome protein OCRL1. Traffic 15:471–487CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Ghazali S, Barratt TM (1974) Urinary excretion of calcium and magnesium in children. Arch Intern Med 49:97–101Google Scholar
  19. 19.
    Kruse K, Kracht U, Gopfert G (1982) Renal threshold phosphate concentration (TmPO4/GFR). Arch Intern Med 57:217–223Google Scholar
  20. 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 4:571–590Google Scholar
  21. 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 24:1967–1973CrossRefPubMedGoogle Scholar
  22. 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 129:513–519CrossRefPubMedGoogle Scholar
  23. 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 58:479–482CrossRefPubMedGoogle Scholar
  24. 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 50:79–84CrossRefPubMedGoogle Scholar
  25. 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 21:469–471CrossRefPubMedGoogle Scholar
  26. 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 224:207–209CrossRefPubMedGoogle Scholar
  27. 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 225:29–33PubMedGoogle Scholar
  28. 28.
    Cho HY, Lee BH, Choi HJ, Ha IS, Choi Y, Cheong HI (2008) Renal manifestations of Dent disease and Lowe syndrome. Pediatr Nephrol 23:243–249CrossRefPubMedGoogle Scholar
  29. 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 57:140–148CrossRefPubMedCentralPubMedGoogle Scholar
  30. 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 269:3397–3402PubMedGoogle Scholar
  31. 31.
    Taher AT, Arabi M, Sibai H, Nasreddine W, Otrock ZK, Musallam KM, Beydoun A (2012) Carbamazepine-induced thrombocytopenia. Blood Cells Mol Dis 48:197–198CrossRefPubMedGoogle Scholar
  32. 32.
    Verrotti A, Scaparotta A, Grosso S, Chiarelli F, Coppola G (2014) Anticonvulsant drugs and hematological disease. Neurol Sci 35:983–993CrossRefPubMedGoogle Scholar
  33. 33.
    Forge A, Wright T (2002) The molecular architecture of the inner ear. Br Med Bull 63:5–24CrossRefPubMedGoogle Scholar
  34. 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:e56516CrossRefPubMedCentralPubMedGoogle Scholar
  35. 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. 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 21:1835–1847CrossRefPubMedGoogle Scholar
  37. 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 21:3333–3344CrossRefPubMedCentralPubMedGoogle Scholar
  38. 38.
    Sharma N, Berbari NF, Yoder BK (2008) Ciliary dysfunction in the developmental abnormalities and diseases. Curr Top Dev Biol 85:371–427CrossRefPubMedGoogle Scholar
  39. 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 22:975–980CrossRefPubMedGoogle Scholar
  40. 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 112:27–36CrossRefGoogle Scholar
  41. 41.
    Skuta GL, Sugar J, Ericson ES (1983) Corneal endothelial cell measurements in megalocornea. Arch Ophthalmol 101:51–53CrossRefPubMedGoogle Scholar
  42. 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 90:247–259CrossRefPubMedCentralPubMedGoogle Scholar
  43. 43.
    Hanefeld FA (1999) Oligogyric microcephaly. Neuropediatrics 30:102–103CrossRefPubMedGoogle Scholar
  44. 44.
    Pang T, Atefy R, Sheen V (2008) Malformations of cortical development. Neurologist 14:181–191CrossRefPubMedCentralPubMedGoogle Scholar
  45. 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 95:461–466CrossRefPubMedGoogle Scholar
  46. 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 24:239–242Google Scholar
  47. 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 324:380–382CrossRefPubMedGoogle Scholar
  48. 48.
    Cooper DN, Krawczak M (1993) Human gene mutation. BIOS Scientic Publishers Limited, Oxford, pp 109–127Google Scholar
  49. 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 3–6Google Scholar

Copyright information

© IPNA 2014

Authors and Affiliations

  • Florian Recker
    • 1
  • Marcin Zaniew
    • 2
  • Detlef Böckenhauer
    • 3
  • Nunzia Miglietti
    • 4
  • Arend Bökenkamp
    • 5
  • Anna Moczulska
    • 6
  • Anna Rogowska-Kalisz
    • 7
  • Guido Laube
    • 8
  • Valerie Said-Conti
    • 9
  • Belde Kasap-Demir
    • 10
  • Anna Niemirska
    • 11
  • Mieczysław Litwin
    • 11
  • Grzegorz Siteń
    • 12
  • Krystyna H. Chrzanowska
    • 13
  • Małgorzata 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
  • Przemysław Sikora
    • 21
  • Michael Ludwig
    • 1
  1. 1.Department of Clinical Chemistry and Clinical PharmacologyUniversity of BonnBonnGermany
  2. 2.Children’s HospitalPoznańPoland
  3. 3.Institute of Child Health and Great Ormond Street Hospital for Children, National Health Service TrustUniversity College LondonLondonUK
  4. 4.Department of PediatricsUniversity of BresciaBresciaItaly
  5. 5.Department of PediatricsVU University Medical CenterAmsterdamThe Netherlands
  6. 6.Department of Pediatric NephrologyUniversity Children’s Hospital of CracowCracowPoland
  7. 7.Nephrology Division, Department of Pediatrics and ImmunologyPolish Mothers Memorial Hospital Research InstituteLodzPoland
  8. 8.Department of Pediatric NephrologyChildren’s Hospital ZürichZurichSwitzerland
  9. 9.Mater Dei HospitalMsidaMalta
  10. 10.Clinics of PediatricsTepecik Training and Research HospitalIzmirTurkey
  11. 11.Department of Nephrology and Kidney TransplantationThe Children’s Memorial Health InstituteWarsawPoland
  12. 12.Dialysis CenterDistrict HospitalRzeszowPoland
  13. 13.Department of Medical GeneticsThe Children’s Memorial Health InstituteWarsawPoland
  14. 14.Department of Pediatric Nephrology, The Medicity Hospital GurgaonKidney and Urology Institute MedantaGurgaonIndia
  15. 15.Department of Pediatric NephrologyUniversity Children’s HospitalSkopjeMacedonia
  16. 16.Laboratory of Histomorphology and Molecular Biology of the Kidney, Department of MedicineUniversity of PadovaPadovaItaly
  17. 17.Department of Public Health, Clinical and Molecular MedicineUniversity of CagliariCagliariItaly
  18. 18.Department of Pediatrics and NephrologyMedical University of BiałystokBiałystokPoland
  19. 19.Dialysis Division for Children, Department and Clinics of PediatricsMedical University of Silesia in KatowiceZabrzePoland
  20. 20.Department of Nephrology, Transplantology and Internal MedicinePoznań University of Medical SciencesPoznańPoland
  21. 21.Department of Pediatric NephrologyMedical University of LublinLublinPoland

Personalised recommendations