Characterization of a Germline Mosaicism in Families with Lowe Syndrome, and Identification of Seven Novel Mutations in the OCRL1 Gene Véronique Satre,

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Characterization of a Germline Mosaicism in Families with Lowe Syndrome, and Identification of Seven Novel Mutations in the OCRL1 Gene Véronique Satre, Nicole Monnier, Florence Berthoin, Carmen Ayuso, Alain Joannard, Pierre-Simon Jouk, Isidora Lopez-Pajares, André Megabarne, Henri Jean Philippe, Henri Plauchu, Maria Luisa Torres, Joël Lunardi The American Journal of Human Genetics Volume 65, Issue 1, Pages 68-76 (July 1999) DOI: 10.1086/302443 Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 1 Segregation of mutations and of chromosome-X markers in families with Lowe syndrome. Patients with OCRL syndrome are indicated by blackened symbols. The presence of the OCRL1 mutation is indicated by a plus sign (+) or a minus sign (−). Results of typing for the polymorphic microsatellite markers—DXS1206, DXS1047, DXS6854, OCRL1 mutation, DXS6855, DXS994, and HPRT—are shown in order, from top to bottom. For clarity of presentation, alleles associated with the disease are boxed. Arrows indicate recombination events. The American Journal of Human Genetics 1999 65, 68-76DOI: (10.1086/302443) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 2 SSCA of c1738g mutation in different tissues of obligate-carrier grandmother in family LS04FR. SSCA was performed as described in Material and Methods. The left panel shows the SSCA profiles of exon 15, amplified from DNA samples extracted from different tissues (blood, hair roots, buccal swabs, and urinary cells) and from different individuals: I-2 (obligate-carrier grandmother), II-4 (carrier mother), and III-4 (affected child). Lane 1, Blood of the grandmother; Lane 2, Hair-root cells of grandmother; Lane 3, Buccal swab of grandmother; Lane 4, urinary cells of grandmother; Lane 5, Blood of the mother; Lane 6, Blood of the affected child. Scanned profiles of lanes 1, 4, and 6, corresponding to the framed area, are presented in the right panel. For the sake of clarity, the plots of lanes 2 and 3 (which were similar to that of lane 1) are not presented. Gel pictures were analyzed by use of NIH image software. Arrows indicate the position of the mutated conformer in the different samples. The American Journal of Human Genetics 1999 65, 68-76DOI: (10.1086/302443) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 3 Blocks of highly conserved amino acid sequences shared by five human phosphoinositide and inositol polyphosphate 5-phosphatases. Numbers indicate the amino acid residue for each protein and are derived from their GenBank entries (OCRL1, U57627; INPP5B [inositol polyphosphate 5-phosphatase type II], M74161; INPPL1 [inositol polyphosphate-like protein 1], L36818; SHIP [SH2-containing inositol 5-phosphatase], U57650; and synaptojanin, AF009040). Amino acids that are conserved in all five proteins are shaded. Amino acid changes of OCRL1 that correspond to missense mutations or in-frame deletions associated with Lowe syndrome are indicated above the sequences. Exon position is indicated below the sequences, and amino acids participating in the 5-phosphatase active site are dotted. Protein alignments were performed by use of Megalign sofware (DNASTAR). The American Journal of Human Genetics 1999 65, 68-76DOI: (10.1086/302443) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 4 Schematic representation of exonic location of known mutations along the human OCRL1 gene. Exons are numbered 1–23, with an alternatively spliced exon shown as 18a, in accordance with the report by Nussbaum et al. (1997). “Number of patients” refers to the number of unrelated patients tested who had the same mutation. a = Leahey et al. 1993; b = Lin et al. 1997; c = Lin et al. 1998; d = Kawano et al. 1998; e = Kubota et al. 1998; f = present study. The American Journal of Human Genetics 1999 65, 68-76DOI: (10.1086/302443) Copyright © 1999 The American Society of Human Genetics Terms and Conditions