Molecular analysis of a female Lesch-Nyhan patient.

Abstract

We report the identification of a female patient with the Xlinked recessive Lesch-Nyhan syndrome (hypoxanthine phosphoribosyltransferase [HPRTI deficiency). Cytogenetic and carrier studies revealed structurally normal chromosomes for this patient and her parents and demonstrated that this mutation arose through a de novo gametic event. Comparison of this patient's DNA with the DNA of her parents revealed that a microdeletion, which occurred within a maternal gamete and involved the entire HPRT gene, was partially responsible for the disease in this patient. Somatic cell hybrids, generated to separate maternal and paternal X chromosomes, showed that expression of two additional X-linked enzymes, phosphoglycerate kinase and glucose-6-phosphate dehydrogenase, were expressed only in cells that contained the maternal X chromosome, suggesting the presence of a functionally inactive paternal X chromosome. Furthermore, comparison of methylation patterns within a region of the HPRT gene known to be important in gene regulation revealed differences between DNA from the father and the patient, in keeping with an active HPRT locus in the father and an inactive HPRT locus in the patient. Together these data indicate that nonrandom inactivation of the cytogenetically normal paternal X chromosome and a microdeletion of the HPRT gene on an active maternal X chromosome were responsible for the absence of HPRT in this patient.

Novel nonsense mutation in the hypoxanthine guanine phosphoribosyltransferase gene and nonrandom X-inactivation causing Lesch-Nyhan syndrome in a female patient

“…patient described with LN syndrome were a nonrandom inactivation oi the cytogenetically normal paternal X chromosome and a microdeletion of the HPRT gene on an active maternal X chromosome (Ogasawara et al, 1989). In the patient reported here, the genetic basis of HPRT deficiency resulted from a nonrandom pattern of X chromosome inactivation with a preferential inactivation of the maternal X chromosorne and a de novo point mutation in exon 6 (HPRT PARIS) on an active paternal X chromosome.…”

Clinical utility gene card for: Lesch–Nyhan Syndrome - update 2013

“…However, at least five females with Lesch-Nyhan syndrome have been described, with different molecular alterations accounting for their HPRT deficiency. [12][13][14][15][16] Carrier diagnosis is an important issue for most HPRT-deficient families. Female carriers cannot be detected without the help of a laboratory as they are usually asymptomatic.…”

Clinical utility gene card for: Lesch–Nyhan syndrome

“…[10][11][12][13][14][15][16] Carrier diagnosis is an important issue for most HPRT-deficient families. Female carriers cannot be detected without the help of a laboratory, as they are usually asymptomatic.…”