Mutations in the gene encoding hypoxanthine-guanine phosphoribosyltransferase (HPRT) cause Lesch-Nyhan disease, which is characterized by hyperuricemia, severe motor disability, and self-injurious behavior. Mutations in the same gene also cause less severe clinical phenotypes with only some portions of the full syndrome. A large database of 271 mutations associated with both full and partial clinical phenotypes was recently compiled. Since the original database was assembled, 31 additional mutations have been identified, bringing the new total to 302. The results demonstrate a very heterogeneous collection of mutations for both LND and its partial syndromes. The differences between LND and the partial phenotypes cannot be explained by differences in the locations of mutations, but the partial phenotypes are more likely to have mutations predicted to allow some residual enzyme function. The reasons for some apparent exceptions to this proposal are addressed.
"A partial deficiency of HPRT leads to Kelley-Seegmiller syndrome (MIM300323), which results in hyperuricemia, hyperuricaciduria, uric acid nephrolithiasis, and precocious gout arthritis . While many different clinical phenotypes manifesting different levels of hyperuricemia are reported, the most severe form is the classical Lesch- Nyhan disease (LND) and the least is characterized by hyperuricemia without any neurological or behavioral abnormality and termed as HPRT-related hyperuricemia (HRH)  . "
[Show abstract][Hide abstract] ABSTRACT: Over the past decade, a steady increase in the incidence of HPRT-related hyperuricemia (HRH) has been observed in Saudi Arabia. We examined all the nine exons of HPRT gene for mutations in ten biochemically confirmed hyperuricemia patients, including one female and three normal controls. In all, we identified 13 novel mutations in Saudi Arabian HPRT-related hyperuricemia patients manifesting different levels of uric acid. The Lys103Met alteration was highly recurrent and was observed in 50% of the cases, while Ala160Thr and Lys158Asn substitutions were found in two patients. Moreover, in 70% of the patients ≥2 mutations were detected concurrently in the HPRT gene. Interestingly, one of the patients that harbored Lys103Met substitution along with two frameshift mutations at codons 85 and 160 resulting in shortened protein demonstrated unusually high serum uric acid level of 738 íµí¼mol/L. Two of the seven point mutations that resulted in amino acid change (Lys103Met and Val160Gly) were predicted to be damaging by SIFT and Polyphen and were further analyzed for their protein stability and function by molecular dynamics simulation. The identified novel mutations in the HPRT gene may prove useful in the prenatal diagnosis and genetic counseling.
BioMed Research International 07/2014; 2014. DOI:10.1155/2014/290325 · 3.17 Impact Factor
"Some individuals with the classic LND phenotype and greater than expected residual HGprt activity have been reported (Holland et al. 1976; Rijksen et al. 1981) as have other individuals with attenuated phenotypes and no detectable HGprt activity (Cossu et al. 2002; Hersh et al. 1986). These discrepancies typically arise when HGprt is measured via assays that do not replicate the natural state of the enzyme in vivo (Jinnah et al. 2004). For example, mutations resulting in enzymes that are structurally unstable outside of the normal cellular environment may yield unnaturally low activity when measured via assays employing cell lysates (Bakay et al. 1979; Dancis et al. 1973; Fairbanks et al. 1987). "
[Show abstract][Hide abstract] ABSTRACT: Lesch-Nyhan disease is a neurogenetic disorder caused by mutation of the HPRT1 gene on the X chromosome. There is significant variation in the clinical phenotype, with more than 300 different known mutations. There are few studies that have addressed whether similar mutations result in similar phenotypes across different patients because hypoxanthine-guanine phosphoribosyltransferase (HGprt) deficiency is rare, and most mutations are unique or limited to individual families. However, recent studies have revealed multiple unrelated patients with similar mutations, providing an opportunity to examine genotype-phenotype correlations. We found significant variation among the clinical features of 10 patients from 8 unrelated families all carrying a mutation replacing guanine with adenine at base position 143 (c.143G>A) in the HPRT1 gene. This mutation results in replacement of arginine by histidine at amino acid position 48 (p.arg48his) in the HGprt enzyme. Biochemically, the enzyme exhibits reduced thermal integrity, a mechanism that may explain clinical variation. The literature reveals similar clinical variation among other patients with similar mutations, although the variation is relatively minor across the whole population of patients. Identifiable sources of clinical variation include known limitations of clinical ascertainment and mechanisms that affect residual enzyme activity and stability. These results are helpful for understanding genotype-phenotype correlations and discordance and likely are applicable to other neurogenetic disorders where similar variation occurs.
Human Genetics 10/2010; 129(1):71-8. DOI:10.1007/s00439-010-0901-9 · 4.82 Impact Factor
"Rare case reports where enzyme activity lacks correlation with phenotypic severity sometimes are presented as evidence against this idea (Rijksen et al., 1981; Cossu et al., 2002). These apparent exceptions most often occur when the enzyme is measured via assays that do not replicate natural conditions (McDonald and Kelley, 1971; Dancis et al., 1973; Holland et al., 1976; Bakay et al., 1979; Cameron et al., 1984; Hersh et al., 1986; Fairbanks et al., 1987; Zoref-Shani et al., 2000; Jinnah et al., 2004). All of our LND variants who had enzyme activity measured in live cells displayed measurable residual activity, and discrepancies between assays from live cells versus lysates were evident for many cases that had both assays (Table 1). "
[Show abstract][Hide abstract] ABSTRACT: Lesch-Nyhan disease is a neurogenetic disorder caused by deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase. The classic form of the disease is described by a characteristic syndrome that includes overproduction of uric acid, severe generalized dystonia, cognitive disability and self-injurious behaviour. In addition to the classic disease, variant forms of the disease occur wherein some clinical features are absent or unusually mild. The current studies provide the results of a prospective and multi-centre international study focusing on neurological manifestations of the largest cohort of Lesch-Nyhan disease variants evaluated to date, with 46 patients from 3 to 65 years of age coming from 34 families. All had evidence for overproduction of uric acid. Motor abnormalities were evident in 42 (91%), ranging from subtle clumsiness to severely disabling generalized dystonia. Cognitive function was affected in 31 (67%) but it was never severe. Though none exhibited self-injurious behaviours, many exhibited behaviours that were maladaptive. Only three patients had no evidence of neurological dysfunction. Our results were compared with a comprehensive review of 78 prior reports describing a total of 127 Lesch-Nyhan disease variants. Together these results define the spectrum of clinical features associated with hypoxanthine-guanine phosphoribosyltransferase deficiency. At one end of the spectrum are patients with classic Lesch-Nyhan disease and the full clinical phenotype. At the other end of the spectrum are patients with overproduction of uric acid but no apparent neurological or behavioural deficits. Inbetween are patients with varying degrees of motor, cognitive, or behavioural abnormalities. Recognition of this spectrum is valuable for understanding the pathogenesis and diagnosis of all forms of hypoxanthine-guanine phosphoribosyltransferase deficiency.
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