TY - JOUR
T1 - Physiological levels of folic acid reveal purine alterations in Lesch-Nyhan disease
AU - Torres, Rosa J.
AU - López, José M.
AU - Jinnah, H. A.
AU - Fu, Rong
AU - Outtrim, Esther L.
AU - Sutcliffe, Diane J.
N1 - Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/6/2
Y1 - 2020/6/2
N2 - Lesch-Nyhan disease (LND), caused by a deficient salvage purine pathway, is characterized by severe neurological manifestations and uric acid overproduction. However, uric acid is not responsible for brain dysfunction, and it has been suggested that purine nucleotide depletion, or accumulation of other toxic purine intermediates, could be more relevant. Here we show that purine alterations in LND fibroblasts depend on the level of folic acid in the culture media. Thus, physiological levels of folic acid induce accumulation of 5-aminoimidazole-4-carboxamide riboside 5'-monophosphate (ZMP), an intermediary of de novo purine biosynthetic pathway, and depletion of ATP. Additionally, Z-nucleotide derivatives (AICAr, AICA) are detected at high levels in the urine of patients with LND and its variants (hypoxanthine-guanine phosphoribosyltransferase [HGprt]-related neurological dysfunction and HGprt-related hyperuricemia), and the ratio of AICAr/AICA is significantly increased in patients with neurological problems (LND and HGprt-related neurological dysfunction). Moreover, AICAr is present in the cerebrospinal fluid of patients with LND, but not in control individuals. We hypothesize that purine alterations detected in LND fibroblasts may also occur in the brain of patients with LND.
AB - Lesch-Nyhan disease (LND), caused by a deficient salvage purine pathway, is characterized by severe neurological manifestations and uric acid overproduction. However, uric acid is not responsible for brain dysfunction, and it has been suggested that purine nucleotide depletion, or accumulation of other toxic purine intermediates, could be more relevant. Here we show that purine alterations in LND fibroblasts depend on the level of folic acid in the culture media. Thus, physiological levels of folic acid induce accumulation of 5-aminoimidazole-4-carboxamide riboside 5'-monophosphate (ZMP), an intermediary of de novo purine biosynthetic pathway, and depletion of ATP. Additionally, Z-nucleotide derivatives (AICAr, AICA) are detected at high levels in the urine of patients with LND and its variants (hypoxanthine-guanine phosphoribosyltransferase [HGprt]-related neurological dysfunction and HGprt-related hyperuricemia), and the ratio of AICAr/AICA is significantly increased in patients with neurological problems (LND and HGprt-related neurological dysfunction). Moreover, AICAr is present in the cerebrospinal fluid of patients with LND, but not in control individuals. We hypothesize that purine alterations detected in LND fibroblasts may also occur in the brain of patients with LND.
KW - Purines
KW - AICAr
KW - ZMP
KW - Folic acid
KW - Lesch-Nyhan disease
UR - http://www.scopus.com/inward/record.url?scp=85085905360&partnerID=8YFLogxK
U2 - 10.1073/pnas.2003475117
DO - 10.1073/pnas.2003475117
M3 - Article
C2 - 32430324
AN - SCOPUS:85085905360
SN - 0027-8424
VL - 117
SP - 12071
EP - 12079
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 22
ER -