Characterization of 28 novel patients expands the mutational and phenotypic spectrum of Lowe syndrome
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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.
Twenty-eight novel patients with suspected Lowe syndrome were studied.
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.
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.
KeywordsOculocerebrorenal syndrome of Lowe OCRL Cataract CpG dinucleotides Hyperosmia Hyperacusis Thrombocytopenia
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.
- 9.McSpadden K (2010) Living with Lowe syndrome: a guide for families, friends and professionals, 4th edn. Lowe Syndrome Association, Inc, PlanoGoogle 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 32:379–388CrossRefPubMedGoogle 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 48:942–954CrossRefPubMedGoogle 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 1:15–23Google 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 2:53–68Google Scholar
- 18.Ghazali S, Barratt TM (1974) Urinary excretion of calcium and magnesium in children. Arch Intern Med 49:97–101Google Scholar
- 19.Kruse K, Kracht U, Gopfert G (1982) Renal threshold phosphate concentration (TmPO4/GFR). Arch Intern Med 57:217–223Google 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 4:571–590Google 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 24:1967–1973CrossRefPubMedGoogle 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
- 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
- 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
- 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
- 48.Cooper DN, Krawczak M (1993) Human gene mutation. BIOS Scientic Publishers Limited, Oxford, pp 109–127Google 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 3–6Google Scholar