Mechanisms for phenotypic variation in Lesch–Nyhan disease and its variants

• Type of Material: Article
• Authors: Radhika Sampat, Emory University; Rong Fu, Emory University; Laura E. Larovere, Universidad Nacional de Cordoba; Rosa J. Torres, Universidad Autonoma de Madrid; Irene Ceballos-Picot, APHP and Paris Descartes University; Michel Fischbach, University Hospital Hautepierre; Raquel de Kremer, Universidad Nacional de Cordoba; David J. Schretlen, Johns Hopkins University; Juan Garcia Puig, Universidad Autonoma de Madrid; Hyder A Jinnah, Emory University
• Language: English
• Date: 2011-01
• Publisher: Springer Verlag (Germany)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © Springer-Verlag 2010
• Final Published Version (URL): http://dx.crossref.org/10.1007/s00439-010-0901-9
• Title of Journal or Parent Work: Human Genetics
• ISSN: 0340-6717
• Volume: 129
• Issue: 1
• Start Page: 71
• End Page: 78
• Grant/Funding Information: These studies were supported by grants from the NIH (HD 053312 and DK 082840), Fondo de Investigaciones Sanitarias FIS 06/0019 and FIS 08/0009 and CIBERER (Centro de Investigaciones Biomedicas en Red para el Estudio de las Enfermedades Raras), Lesch–Nyhan Action, and Fondation Jerome Lejeune and Association Malaury.
• Research Categories: Biology, Neuroscience

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.