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.
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