TY - JOUR
T1 - The spectrum of inherited mutations causing HPRT deficiency
T2 - 75 new cases and a review of 196 previously reported cases
AU - Jinnah, H. A.
AU - De Gregorio, Laura
AU - Harris, James C.
AU - Nyhan, William L.
AU - O'Neill, J. Patrick
N1 - Funding Information:
This work was supported by The Lesch–Nyhan Syndrome Children’s Research Foundation, NINDS 01985, NICHD 33095, and NIH NIAID 2 P30 AI36214.
PY - 2000/10
Y1 - 2000/10
N2 - In humans, mutations in the gene encoding the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) are associated with a spectrum of disease that ranges from hyperuricemia alone to hyperuricemia with profound neurological and behavioral dysfunction. Previous attempts to correlate different types or locations of mutations with different elements of the disease phenotype have been limited by the relatively small numbers of available cases. The current article describes the molecular genetic basis for 75 new cases of HPRT deficiency, reviews 196 previously reported cases, and summarizes four main conclusions that may be derived from the entire database of 271 mutations. First, the mutations associated with human disease appear dispersed throughout the hprt gene, with some sites appearing to represent relative mutational hot spots. Second, genotype-phenotype correlations provide no indication that specific disease features associate with specific mutation locations. Third, cases with less severe clinical manifestations typically have mutations that are predicted to permit some degree of residual enzyme function. Fourth, the nature of the mutation provides only a rough guide for predicting phenotypic severity. Though mutation analysis does not provide precise information for predicting disease severity, it continues to provide a valuable tool for genetic counseling in terms of confirmation of diagnoses, for identifying potential carriers, and for prenatal diagnosis. (C) 2000 Elsevier Science B.V.
AB - In humans, mutations in the gene encoding the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) are associated with a spectrum of disease that ranges from hyperuricemia alone to hyperuricemia with profound neurological and behavioral dysfunction. Previous attempts to correlate different types or locations of mutations with different elements of the disease phenotype have been limited by the relatively small numbers of available cases. The current article describes the molecular genetic basis for 75 new cases of HPRT deficiency, reviews 196 previously reported cases, and summarizes four main conclusions that may be derived from the entire database of 271 mutations. First, the mutations associated with human disease appear dispersed throughout the hprt gene, with some sites appearing to represent relative mutational hot spots. Second, genotype-phenotype correlations provide no indication that specific disease features associate with specific mutation locations. Third, cases with less severe clinical manifestations typically have mutations that are predicted to permit some degree of residual enzyme function. Fourth, the nature of the mutation provides only a rough guide for predicting phenotypic severity. Though mutation analysis does not provide precise information for predicting disease severity, it continues to provide a valuable tool for genetic counseling in terms of confirmation of diagnoses, for identifying potential carriers, and for prenatal diagnosis. (C) 2000 Elsevier Science B.V.
KW - HPRT, hypoxanthine-guanine phosphoribosyltransferase
KW - HRH, HPRT-related hyperuricemia
KW - HRND, HPRT-related neurologic dysfunction
KW - LND, Lesch-Nyhan disease
KW - LNV, Lesch-Nyhan variants
KW - NA, not available
KW - NS, not specified
UR - http://www.scopus.com/inward/record.url?scp=0033799868&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033799868&partnerID=8YFLogxK
U2 - 10.1016/S1383-5742(00)00052-1
DO - 10.1016/S1383-5742(00)00052-1
M3 - Article
C2 - 11018746
AN - SCOPUS:0033799868
SN - 1383-5742
VL - 463
SP - 309
EP - 326
JO - Mutation Research - Reviews in Mutation Research
JF - Mutation Research - Reviews in Mutation Research
IS - 3
ER -