Novel OCRL1 Mutations in Patients With the Phenotype of Dent Disease

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Novel OCRL1 Mutations in Patients With the Phenotype of Dent Disease Boris Utsch, MD, Arend Bökenkamp, MD, Marcus R. Benz, MD, Nesrin Besbas, MD, Jörg Dötsch, MD, Ingo Franke, MD, Stefan Fründ, MD, Faysal Gok, MD, Bernd Hoppe, MD, Stephanie Karle, MD, Eberhard Kuwertz-Bröking, MD, Guido Laube, MD, Margarita Neb, Matti Nuutinen, MD, Fatih Ozaltin, MD, Wolfgang Rascher, MD, Troels Ring, MD, Velibor Tasic, MD, Joanna A.E. van Wijk, MD, Michael Ludwig, PhD American Journal of Kidney Diseases Volume 48, Issue 6, Pages 942.e1-942.e14 (December 2006) DOI: 10.1053/j.ajkd.2006.08.018 Copyright © 2006 National Kidney Foundation, Inc. Terms and Conditions

Fig 1 Schematic diagram of OCRL1 cDNA showing type and location of the various mutations found in the genes of (top) patients with Lowe syndrome38-52 and patients with Dent 2 disease. (Bottom) First row, data from Hoopes et al10; second row, this study. *OCRL1 mutations in patients with Dent 2 disease associated with mild mental retardation. Exons are numbered 1 to 23, and alternative splicing of exon 18a leads to the inframe inclusion of 8 additional amino acids. Except for exon 23, cDNA is drawn to scale and untranslated regions are shown in grey.22 Regions of functional significance in the protein (exonuclease-endonuclease-phosphatase family domain [exo/endo/phos], ASH [ASPM (abnormal spindle-like primary microcephaly), SPD-2 (spindle-defective protein 2), Hydin] domain,53 and Rho GAP-like domain) are given above the cDNA. American Journal of Kidney Diseases 2006 48, 942.e1-942.e14DOI: (10.1053/j.ajkd.2006.08.018) Copyright © 2006 National Kidney Foundation, Inc. Terms and Conditions

Fig 2 (A) Pedigrees of families harboring an OCRL1 mutation. Phenotypic findings in males (squares) and females (circles) are coded as follows: black shading of right upper quadrant indicates LMWP; right lower quadrant, hypercalciuria; left lower quadrant, nephrocalcinosis/nephrolithiasis; and left upper quadrant, renal insufficiency. Dot in circle marks carrier status without clinical symptoms. *De novo mutations. The dot in pedigree T2 indicates a spontaneous abortion. Abbreviation: nt, not tested. (B) Sequence analysis in the respective families: OCRL1 mutations detected are indicated by arrows with the respective affected codon underlined; for patients G2 and M1, the reverse sequencing reaction is shown. (C) For restriction analysis, the respective relevant samples were separated on 4% agarose gels. In family G2, the mutation creates a new BsrI (ACTGGN^) site, thereby producing 3 fragments (72, 138, and 117 base pairs [bp]) instead of 2 (210 and 117 bp), obtained from the normal PCR product (327 bp). In family M1, the PCR product (320 bp) is only cut by BseYI (C^CCAGC) into products of 228 and 92 bp if the mutation is present. Individuals are numbered as in A. Abbreviations: MW, molecular weight marker (100-bp ladder); nc, normal control; uc, uncut PCR product. American Journal of Kidney Diseases 2006 48, 942.e1-942.e14DOI: (10.1053/j.ajkd.2006.08.018) Copyright © 2006 National Kidney Foundation, Inc. Terms and Conditions

Fig 3 CK/LDH score associated with different gene defects causing Dent phenotype. Diamond plot presents mean and 95% confidence interval (tip/bottom of diamond). The width of the diamond is proportional to the patient number in the respective subgroup. Gray line indicates the group mean. American Journal of Kidney Diseases 2006 48, 942.e1-942.e14DOI: (10.1053/j.ajkd.2006.08.018) Copyright © 2006 National Kidney Foundation, Inc. Terms and Conditions

Fig 4 Conservation of residues located in the exonuclease-endonuclease-phosphatase domain of Ocrl and related proteins. Missense mutations observed in patients with Dent 2 disease are given above with their respective position in Ocrl according to the numbering outlined in Methods (start methionine at position 18). Amino acid alignment is given with identical residues shown by dashes and conserved residues found to be mutated are shown in bold. Sequences with their respective accession number were obtained from SwissProt and Genbank (*). American Journal of Kidney Diseases 2006 48, 942.e1-942.e14DOI: (10.1053/j.ajkd.2006.08.018) Copyright © 2006 National Kidney Foundation, Inc. Terms and Conditions