Abstract
We have determined the structure, at the nucleotide sequence level, of a duplication in the hprt gene in a patient with Lesch-Nyhan syndrome (LN). The duplication extends over exons 7 and 8 and approximately 1.8 kb of the surrounding hprt sequence. The duplication junction is localized within two Alu sequences and has apparently been generated by unequal homologous recombination. This is the second reported case of a partial duplication of the hprt gene in an LN patient, and the first that involves an Alu-Alu recombination.
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Andersson B, He S-H, Lambert B (1992) Mutations causing defective splicing in the human hprt gene. Environ Mol Mutagen 20:89–95
Brennand J, Konecki DS, Caskey CT (1983) Expression of human and Chinese hamster hypoxanthine-guanine phosphoribosyltransferase cDNA recombinants in cultured Lesch-Nyhan and Chinese hamster fibroblasts. J Biol Chem 258:9593–9596
Davidson BL, Tarlé SA, Palella TD, Kelley WN (1989) Molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in ten subjects determined by direct sequencing of amplified transcripts. J Clin Invest 84:342–346
Davidson BL, Tarlé SA, Antwerp MV, Gibbs DA, Watts RWE, Kelley WN, Palella TD (1991) Identification of 17 independent mutations responsible for human hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. Am J Hum Genet 48:951–958
Edwards A, Voss H, Rice P, Civitello A, Stegeman J, Schwager C, Zimmerman J, Erfle H, Caskey CT, Ansorge W (1990) Automated DNA sequencing of the human hprt locus. Genomics 6:593–608
Feinberg AP, Vogelstein B (1984) A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Addendum. Anal Biochem 137:266–267
Gibbs RA, Nguyen P-N, McBride LJ, Koepf SM, Caskey CT (1989) Identification of mutations leading to the Lesch-Nyhan syndrome by automated direct DNA sequencing of in vitro amplified cDNA. Proc Natl Acad Sci USA 86:1919–1923
Gibbs RA, Nguyen P-N, Edwards A, Civitello AB, Caskey CT (1990) Multiplex DNA deletion detection and exon sequencing of the hypoxanthine phosphoribosyltransferase gene in Lesch-Nyhan families. Genomics 7:1–10
Henthorn PS, Smithies O, Mager DL (1990) Molecular analysis of deletions in the human β-globin gene cluster: deletion junctions and locations of breakpoints. Genomics 6:226–237
Kelley WN, Wyngaarden JB (1983) Clinical syndromes associated with hypoxanthine phosphoribosyltransferase deficiency. In: Stanbury JB et al (eds) The metabolic basis of inherited disease, 5th edn. McGraw-Hill, New York, pp 1141–1142
Lehrman MA, Schneider WJ, Südhof TC, Brown MS, Goldstein JL, Russel DW (1985) Mutation in LDL receptor: Alu-Alu recombination deletes exons encoding transmembrane and cytoplasmic domains. Science 227:140–146
Lehrman MA, Goldstein JL, Russel DW, Brown MS (1987a) Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolemia. Cell 48:827–835
Lehrman MA, Russel DW, Goldstein JL, Brown MS (1987b) Alu-Alu recombination deletes splice acceptor sites and produces secreted low density lipoprotein receptor in a subject with familial hypercholesterolemia. J Biol Chem 262:3354–3361
Maniatis T, Fritsch EF, Sambrook J (1982) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
Markert ML, Hutton JJ, Wiginton DA, States JC, Kaufman RE (1988) Adenosine deaminase (ADA) deficiency due to deletion of the ADA gene promotor and first exon by homologous recombination between two Alu elements. J Clin Invest 81:1323–1327
Matsuoka M Nagawa F, Okazaki K, Kingsbury L, Yoshida K, Müller U, Larue DT, Winer JA, Sakano H (1991) Detection of somatic DNA recombination in the transgenic mouse brain. Science 254:81–86
Monnat RJ Jr, Chiaverotti TA, Hackmann AFM, Maresh GA (1992a) Molecular structure and genetic stability of human hypoxanthine phosphoribosyltransferase gene duplications. Genomics 13:758–796
Monnat RJ Jr, Hackmann AFM, Chiaverotti TA (1992b) Nucleotide sequence analysis of human hypoxanthine phosphoribosyltransferase gene deletions. Genomics 13:777–787
Nicholls RD, Fischel-Ghodsian N, Higgs DR (1987) Recombination at the human alfa-globin gene cluster: sequence features and topological contstraints. Cell 49:369–378
Patel PI, Framson PE, Caskey CT, Chinault AC (1986) Fine structure of the human hypoxanthine phosphoribosyltransferase gene. Mol Cell Biol 6:393–403
Reed KC, Man DA (1985) Rapid transfer of DNA from agarose gels to nylon membranes. Nucleic Acids Res 13:7207–7221
Steen A-M, Sahlén S, Lambert B (1991) Expression of the hypoxanthine phosphoribosyl transferase gene in resting and growth stimulated human lymphocytes. Biochim Biophys Acta 1088:77–85
Tarlé SA, Davidson BL, Wu VC, Zidar FJ, Seegmiller JE, Kelley WN, Palella TD (1991) Determination of the mutations responsible for the Lesch-Nyhan syndrome in 17 subjects. Genomics 10:499–501
Yang TP, Patel PI, Stout JT, Jackson LG, Hildebrand BM, Caskey CT (1984) Molecular evidence for new mutations in the HPRT locus in Lesch-Nyhan patients. Nature 310:412–414
Yang TP, Stout JT, Konecki DS, Patel PI, Alford RL, Caskey CT (1988) Spontanous reversion of novel Lesch-Nyhan mutation by HPRT gene rearrangement. Somat Cell Mol Genet 14:293–303
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Marcus, S., Hellgren, D., Lambert, B. et al. Duplication in the hypoxanthine phosphoribosyl-transferase gene caused by Alu-Alu recombination in a patient with Lesch Nyhan syndrome. Hum Genet 90, 477–482 (1993). https://doi.org/10.1007/BF00217444
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DOI: https://doi.org/10.1007/BF00217444