Abstract
Since the identification of the Lowe’s oculocerebrorenal syndrome gene, more than 100 distinct OCRL mutations have been observed. Germline mosaicism has rarely been detected in Lowe families; however, the presence of mosaic mutations, in particular triple mosaicism, may often remain undiagnosed. In the course of OCRL analysis in a Polish family, the index case showed a hemizygous nucleotide transition (c.1736A>G, p.His507Arg). Gene analysis in the patient’s mother not only provided evidence that she is a carrier of the mutant allele transmitted to her son but also showed an additional c.1736A>T (p.His507Leu) transversion affecting the same base position. DNA from a mouthwash sample from the mother showed a similar fluorescence intensity pattern at the affected nucleotide. These data, together with the findings that maternal grandparents solely showed wildtype sequence, implied a de novo mosaicism in the mother. Triple X syndrome was ruled out by karyotype analysis and a partial or complete gene duplication could be excluded. Allele-specific amplification confirmed the results of three alleles being present in the mother. The amount of wildtype allele detected in qPCR implied the presence of cells solely harboring c.1736A and single-cell PCR experiments confirmed the presence of non-mutant cells in the mother’s blood. These data suggest that the mutations observed are the result of two de novo events in early embryogenesis of the mother. To the best of our knowledge, this is the first observation of triple mosaicism at a single nucleotide.
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References
Attree O, Olivos IM, Okabe I, Bailey LC, Nelson DL, Lewis RA, McInnes RR, Nussbaum RL (1992) The Lowe’s oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase. Nature 358:239–242
Böckenhauer D, Bökenkamp 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 3:1430–1436
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 155:94–99
Brown N, Gardner RJ (1976) Lowe syndrome: identification of the carrier state. Birth Defects Orig Artic Ser 12:579–595
Campbell L, Daniels RJ, Dubowitz V, Davies KE (1998) Maternal mosaicism for a second mutational event in a type I spinal muscular atrophy family. Am J Hum Genet 63:37–44
Choudhury R, Diao A, Zhang F et al (2005) Lowe syndrome protein OCRL1 interacts with clathrin and regulates protein trafficking between endosomes and the trans-Golgi network. Mol Biol Cell 16:3467–3479
Davidson S, Leshanski L, Rennert G, Eidelman S, Amikam D (2002) Maternal mosaicism for a second mutational event—a novel deletion—in a familial adenomatous polyposis family harboring a new germ-line mutation in the alternatively spliced-exon 9 region of APC. Hum Mutat 19:83–84
De Boer M, Bakker E, van Lierde S, Roos D (1998) Somatic triple mosaicism in a carrier of X-linked chronic granulomatous disease. Blood 91:252–257
Faucherre A, Desbois P, Satre V, Lunardi J, Dorseuil O, Gacon G (2003) Lowe syndrome protein OCRL1 interacts with Rac GTPase in the trans-Golgi network. Hum Mol Genet 12:2449–2456
Findlay I, Ray P, Quirke P, Rutherford A, Lilford R (1995) Allelic drop-out and preferential amplification in single cells and human blastomeres: implications for preimplantation diagnosis of sex and cystic fibrosis. Hum Reprod 10:1609–1618
Gitschier J (1988) Maternal duplication associated with gene deletion in sporadic hemophilia. Am J Hum Genet 43:274–279
Hezard N, Cornillet P, Droulle C, Gillot L, Potron G, Nguyen P (1997) Factor V Leiden: detection in whole blood by ASA PCR using an additional mismatch in antepenultimate position. Thromb Res 88:59–66
Hook EB (1977) Exclusion of chromosomal mosaicism: tables of 90%, 95%, and 99% confidence limits and comments on use. Am J Hum Genet 29:94–97
Hoopes RR Jr, Shrimpton AE, Knohl SJ et al (2005) Dent disease with mutation in OCRL1. Am J Hum Genet 76:260–267
Kawano T, Indo Y, Nakazato H, Shimadzu M, Matsuda I (1998) Three mutations in the OCRL1 gene derived from three patients with different phenotypes. Am J Med Genet 77:348–355
Kondrashov AS (2003) Direct estimates of human per nucleotide mutation rates at 20 loci causing Mendelian diseases. Hum Mutat 21:12–27
Leuer M, Oldenburg J, Lavergne JM et al (2001) Somatic mosaicism in hemophilia A: a fairly common event. Am J Hum Genet 69:75–87
Lin T, Orrison BM, Leahey AM, Suchy SF, Bernard DJ, Lewis RA, Nussbaum RL (1997) Spectrum of mutations in the OCRL1 gene in the Lowe oculocerebrorenal syndrome. Am J Hum Genet 60:1384–1388
Lowe C, Terrey M, MacLachan E (1952) Organic aciduria, decreased renal ammonia production, hydrophtalmos, and mental retardation: a clinical entity. Am J Dis Child 83:164–184
Lynch M (2010) Rate, molecular spectrum, and consequences of human mutation. Proc Natl Acad Sci USA 107:961–968
MacLean HE, Favaloro JM, Warne GL, Zajac JD (2006) Double-strand DNA break repair with replication slippage on two strands: a novel mechanism of deletion formation. Hum Mutat 27:483–489
Marchler-Bauer A, Anderson JB, Chitsaz F et al (2009) CDD: specific functional annotation with the Conserved Domain Database. Nucleic Acids Res 37(D):205–210
Monnier N, Satre V, Lerouge E, Berthoin F, Lunardi J (2000) OCRL1 mutation analysis in French Lowe syndrome patients: implications for molecular diagnosis strategy and genetic counseling. Hum Mutat 16:157–165
Neitzel H (1986) A routine method for the establishment of permanent growing lymphoblastoid cell lines. Hum Genet 73:320–326
Noack D, Heyworth PG, Kyono W, Cross AR (2001) A second case of somatic triple mosaicism in the CYBB gene causing chronic granulomatous disease. Hum Genet 109:234–238
Nussbaum RL, Suchy SF (2001) The oculocerebrorenal syndrome of Lowe (Lowe syndrome). In: Scriver CR, Beaudet Al, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, 8th edn. McGraw-Hill, New York, pp 6257–6266
Nussbaum RL, Orrison BM, Jänne PA, Charnas L, Chinault AC (1997) Physical mapping and genomic structure of the Lowe syndrome gene OCRL1. Hum Genet 99:145–150
Olivos-Glander IM, Jänne PA, Nussbaum RL (1995) The oculocerebrorenal syndrome gene product is a 105-kD protein localized to the Golgi complex. Am J Hum Genet 57:817–823
Raucher D, Stauffer T, Chen W et al (2000) Phosphatidylinositol 4,5-bisphosphate functions as a second messenger that regulates cytoskeleton-plasma membrane adhesion. Cell 100:221–228
Röschinger W, Muntau AC, Rudolph G, Roscher AA, Kammerer S (2000) Carrier assessment in families with Lowe oculocerebrorenal syndrome: novel mutations in the OCRL1 gene and correlation of direct DNA diagnosis with ocular examination. Mol Genet Metab 69:213–222
Satre V, Monnier N, Berhoin F, Ayuso C et al (1999) Characterization of a germline mosaicism in families with Lowe syndrome, and identification of seven novel mutations in the OCRL1 gene. Am J Hum Genet 65:68–76
Sharp A, Robinson D, Jacobs P (2000) Age- and tissue-specific variation of X chromosome inactivation ratios in normal women. Hum Genet 107:343–349
Trümper LH, Brady G, Bagg A et al (1993) Single-cell analysis of Hodgkin and Reed-Sternberg cells: molecular heterogeneity of gene expression and p53 mutations. Blood 81:3097–3115
Ungewickell A, Ward ME, Ungewickell E, Majerus PW (2004) The inositol polyphosphate 5-phosphatase Ocrl associates with endosomes that are partially coated with clathrin. Proc Natl Acad Sci USA 101:13501–13506
Utsch B, Bökenkamp A, Benz MR et al (2006) Novel OCRL1 mutations in patients with the phenotype of Dent disease. Am J Kidney Dis 48:942–954
Wagenstaller J, Spranger S, Lorenz-Depiereux B et al (2007) Copy-number variations measured by single-nucleotide-polymorphism oligonucleotide arrays in patients with mental retardation. Am J Hum Genet 81:768–779
Wylie C (1999) Germ cells. Cell 96:165–174
Zhang X, Jefferson AB, Auethavekiat V, Majerus PW (1995) The protein deficient in Lowe syndrome is a phosphatidylinositol-4,5-biphosphate 5-phosphatase. Proc Natl Acad Sci USA 92:4853–4856
Acknowledgments
We thank the family for their participation in this study and Pia Uerdingen, Bärbel Lippke, Maria Schubert and Dietlinde Stienen for laboratory technical assistance.
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Draaken, M., Giesen, C.A., Kesselheim, A.L. et al. 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, 513–519 (2011). https://doi.org/10.1007/s00439-010-0944-y
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DOI: https://doi.org/10.1007/s00439-010-0944-y