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

Radhika Sampat, Rong Fu, Laura E. Larovere, Rosa J. Torres, Irene Ceballos-Picot, Michel Fischbach, Raquel De Kremer, David Schretlen, Juan Garcia Puig, H. A. Jinnah

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)71-78
Number of pages8
JournalHuman Genetics
Volume129
Issue number1
DOIs
StatePublished - Jan 2011

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Lesch-Nyhan Syndrome
Mutation
Genetic Association Studies
Phenotype
Hypoxanthine Phosphoribosyltransferase
Enzyme Stability
X-Linked Genes
Guanine
Adenine
Enzymes
Histidine
Arginine
Hot Temperature
Amino Acids

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Sampat, R., Fu, R., Larovere, L. E., Torres, R. J., Ceballos-Picot, I., Fischbach, M., ... Jinnah, H. A. (2011). Mechanisms for phenotypic variation in Lesch-Nyhan disease and its variants. Human Genetics, 129(1), 71-78. https://doi.org/10.1007/s00439-010-0901-9

Mechanisms for phenotypic variation in Lesch-Nyhan disease and its variants. / Sampat, Radhika; Fu, Rong; Larovere, Laura E.; Torres, Rosa J.; Ceballos-Picot, Irene; Fischbach, Michel; De Kremer, Raquel; Schretlen, David; Puig, Juan Garcia; Jinnah, H. A.

In: Human Genetics, Vol. 129, No. 1, 01.2011, p. 71-78.

Research output: Contribution to journalArticle

Sampat, R, Fu, R, Larovere, LE, Torres, RJ, Ceballos-Picot, I, Fischbach, M, De Kremer, R, Schretlen, D, Puig, JG & Jinnah, HA 2011, 'Mechanisms for phenotypic variation in Lesch-Nyhan disease and its variants', Human Genetics, vol. 129, no. 1, pp. 71-78. https://doi.org/10.1007/s00439-010-0901-9
Sampat R, Fu R, Larovere LE, Torres RJ, Ceballos-Picot I, Fischbach M et al. Mechanisms for phenotypic variation in Lesch-Nyhan disease and its variants. Human Genetics. 2011 Jan;129(1):71-78. https://doi.org/10.1007/s00439-010-0901-9
Sampat, Radhika ; Fu, Rong ; Larovere, Laura E. ; Torres, Rosa J. ; Ceballos-Picot, Irene ; Fischbach, Michel ; De Kremer, Raquel ; Schretlen, David ; Puig, Juan Garcia ; Jinnah, H. A. / Mechanisms for phenotypic variation in Lesch-Nyhan disease and its variants. In: Human Genetics. 2011 ; Vol. 129, No. 1. pp. 71-78.
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