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Novel nonsense mutation in the hypoxanthine guanine phosphoribosyltransferase gene and nonrandom X‐inactivation causing Lesch‐Nyhan syndrome in a female patient
Author(s) -
Aral Bernard,
de Saint Basile Geneviève,
AlGarawi Sami,
Kamoun Pierre,
CeballosPicot Irène
Publication year - 1996
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/(sici)1098-1004(1996)7:1<52::aid-humu7>3.0.co;2-r
Subject(s) - hypoxanthine guanine phosphoribosyltransferase , biology , exon , microbiology and biotechnology , genetics , hypoxanthine phosphoribosyltransferase , nonsense mutation , lesch–nyhan syndrome , point mutation , mutation , gene , phosphoribosyltransferase , missense mutation , multiplex ligation dependent probe amplification , mutant
Lesch‐Nyhan (LN) disease is a severe X‐linked recessive neurological disorder associated with a loss of hypoxanthine guanine phosphoribosyltransferase activity (HPRT, EC 2.4.2.8). We have studied the second example of a female patient with LN disease. The molecular basis of HPRT deficiency in this patient was a previously undescribed nucleotide substitution in exon 6. In this gene, designated HPRT PARIS, a single nucleotide substitution from T to G at base position 558 changed a tyrosine (TAT) to a codon STOP (TAG) (Y153X). Analysis of the mother revealed a normal sequence of the HPRT cDNA and demonstrated that this mutation arose through a de novo gametic event. Allele‐specific amplification of exon 6 from the patient's genomic DNA confirmed the single base substitution and showed that the patient was heterozygous for this mutation. Investigation of X‐chromosomal inactivation by comparison of methylation patterns of patient's DNA isolated from fibroblasts, T lymphocytes, and polymorphonuclear cells digested with Pst I and Bst XI, with or without Hpa II, and hybridized with M27 β probe indicated a nonrandom pattern of X‐chromosomal inactivation in which there was preferential inactivation of the maternal allele. The data indicate that nonrandom X‐inactivation leading to selective inactivation of the maternal gene and a de novo point mutation in the paternal gene were responsible for the lack of HPRT activity in this patient. © 1996 Wiley‐Liss, Inc.