caa a22 4500 445861320 CHVBK 20180317145444.0 cr unu---uuuuu 170323e20110101xx s 000 0 eng 10.1007/s00439-010-0901-9 doi (NATIONALLICENCE)springer-10.1007/s00439-010-0901-9 Mechanisms for phenotypic variation in Lesch-Nyhan disease and its variants [Elektronische Daten] [Radhika Sampat, Rong Fu, Laura Larovere, Rosa Torres, Irene Ceballos-Picot, Michel Fischbach, Raquel de Kremer, David Schretlen, Juan Puig, H. Jinnah] 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. Springer-Verlag, 2010 Sampat Radhika Departments of Neurology, Human Genetics and Pediatrics, Emory University, Suite 6300 Woodruff Memorial Building, 101 Woodruff Circle, 30322, Atlanta, GA, USA aut Fu Rong Departments of Neurology, Human Genetics and Pediatrics, Emory University, Suite 6300 Woodruff Memorial Building, 101 Woodruff Circle, 30322, Atlanta, GA, USA aut Larovere Laura Centro de Estudio de las Metabolopatias Congenitas, Universidad Nacional de Cordoba, Cordoba, Argentina aut Torres Rosa Division of Clinical Biochemistry and Genetic Institute, IdiPaz Hospital Universitario La Paz, Universidad Autonoma de Madrid, Madrid, Spain aut Ceballos-Picot Irene Metabolic Biochemistry Laboratory, Necker-Enfants Malades Hospital, APHP and Paris Descartes University, Paris, France aut Fischbach Michel Pediatrics and Nephrology, University Hospital Hautepierre, Strasbourg, France aut de Kremer Raquel Centro de Estudio de las Metabolopatias Congenitas, Universidad Nacional de Cordoba, Cordoba, Argentina aut Schretlen David Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA aut Puig Juan Division of Internal Medicine, IdiPaz Hospital Universitario La Paz, Universidad Autonoma de Madrid, Madrid, Spain aut Jinnah H. Departments of Neurology, Human Genetics and Pediatrics, Emory University, Suite 6300 Woodruff Memorial Building, 101 Woodruff Circle, 30322, Atlanta, GA, USA aut Human Genetics Springer-Verlag 129/1(2011-01-01), 71-78 0340-6717 129:1<71 2011 129 439 https://doi.org/10.1007/s00439-010-0901-9 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00439-010-0901-9 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Sampat Radhika Departments of Neurology, Human Genetics and Pediatrics, Emory University, Suite 6300 Woodruff Memorial Building, 101 Woodruff Circle, 30322, Atlanta, GA, USA aut NATIONALLICENCE 700 1- Fu Rong Departments of Neurology, Human Genetics and Pediatrics, Emory University, Suite 6300 Woodruff Memorial Building, 101 Woodruff Circle, 30322, Atlanta, GA, USA aut NATIONALLICENCE 700 1- Larovere Laura Centro de Estudio de las Metabolopatias Congenitas, Universidad Nacional de Cordoba, Cordoba, Argentina aut NATIONALLICENCE 700 1- Torres Rosa Division of Clinical Biochemistry and Genetic Institute, IdiPaz Hospital Universitario La Paz, Universidad Autonoma de Madrid, Madrid, Spain aut NATIONALLICENCE 700 1- Ceballos-Picot Irene Metabolic Biochemistry Laboratory, Necker-Enfants Malades Hospital, APHP and Paris Descartes University, Paris, France aut NATIONALLICENCE 700 1- Fischbach Michel Pediatrics and Nephrology, University Hospital Hautepierre, Strasbourg, France aut NATIONALLICENCE 700 1- de Kremer Raquel Centro de Estudio de las Metabolopatias Congenitas, Universidad Nacional de Cordoba, Cordoba, Argentina aut NATIONALLICENCE 700 1- Schretlen David Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA aut NATIONALLICENCE 700 1- Puig Juan Division of Internal Medicine, IdiPaz Hospital Universitario La Paz, Universidad Autonoma de Madrid, Madrid, Spain aut NATIONALLICENCE 700 1- Jinnah H. Departments of Neurology, Human Genetics and Pediatrics, Emory University, Suite 6300 Woodruff Memorial Building, 101 Woodruff Circle, 30322, Atlanta, GA, USA aut NATIONALLICENCE 773 0- Human Genetics Springer-Verlag 129/1(2011-01-01), 71-78 0340-6717 129:1<71 2011 129 439 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer