title: Novel nonsense mutation in the hypoxanthine guanine phosphoribosyltransferase gene and nonrandom X-inactivation causing Lesch-Nyhan syndrome in a female patient.
abstract: 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 PstI and BstXI, with or without HpaII, and hybridized with M27 beta 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.
authors.affiliation: CNRS USA 1335, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Aral
authors.forename: G
authors.initials: G
authors.lastname: de Saint Basile
authors.forename: S
authors.initials: S
authors.lastname: Al-Garawi
authors.forename: P
authors.initials: P
authors.lastname: Kamoun
authors.forename: I
authors.initials: I
authors.lastname: Ceballos-Picot
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002478:Cells, Cultured; D004303:Dosage Compensation, Genetic; D005091:Exons; D005260:Female; D005347:Fibroblasts / Q000648:ultrastructure; D006580:Genetic Carrier Screening; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D007926:Lesch-Nyhan Syndrome / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D015183:Restriction Mapping
chemical_list: D007041:Hypoxanthine Phosphoribosyltransferase