A new physiological medium uncovers biochemical and cellular alterations in Lesch-Nyhan disease fibroblasts.

BACKGROUND: Lesch-Nyhan disease (LND) is a severe neurological disorder caused by the genetic deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGprt), an enzyme involved in the salvage synthesis of purines. To compensate this deficiency, there is an acceleration of the de novo purine biosynthetic pathway. Most studies have failed to find any consistent abnormalities of purine nucleotides in cultured cells obtained from the patients. Recently, it has been shown that 5-aminoimidazole-4-carboxamide riboside 5'-monophosphate (ZMP), an intermediate of the de novo pathway, accumulates in LND fibroblasts maintained with RPMI containing physiological levels (25 nM) of folic acid (FA), which strongly differs from FA levels of regular cell culture media (2200 nM). However, RPMI and other standard media contain non-physiological levels of many nutrients, having a great impact in cell metabolism that does not precisely recapitulate the in vivo behavior of cells. METHODS: We prepared a new culture medium containing physiological levels of all nutrients, including vitamins (Plasmax-PV), to study the potential alterations of LND fibroblasts that may have been masked by the usage of non-physiological media. We quantified ZMP accumulation under different culture conditions and evaluated the activity of two known ZMP-target proteins (AMPK and ADSL), the mRNA expression of the folate carrier SLC19A1, possible mitochondrial alterations and functional consequences in LND fibroblasts. RESULTS: LND fibroblasts maintained with Plasmax-PV show metabolic adaptations such a higher glycolytic capacity, increased expression of the folate carrier SCL19A1, and functional alterations such a decreased mitochondrial potential and reduced cell migration compared to controls. These alterations can be reverted with high levels of folic acid, suggesting that folic acid supplements might be a potential treatment for LND. CONCLUSIONS: A complete physiological cell culture medium reveals new alterations in Lesch-Nyhan disease. This work emphasizes the importance of using physiological cell culture conditions when studying a metabolic disorder.

Naringin corrects renal failure related to Lesch-Nyhan disease in a rat model via NOS-cAMP-PKA and BDNF/TrkB pathways.

This study explored the effect of naringin (NAR) on HGPRT1 deficiency and hyperuricemia through NOS-cAMP-PKA and BDNF/TrkB signaling pathways induced by caffeine (CAF) and KBrO3 in a rat model. Sixty-three adult male albino rats were randomly assigned into nine (n = 7) groups. Group I: control animals, Group II was treated with 100 mg/kg KBrO3 , Group III was treated with 250 mg/kg CAF, Group IV was treated with 100 mg/kg KBrO3 + 250 mg/kg CAF, Group V was administered with 100 mg/kg KBrO3 + 100 mg/kg haloperidol, Group VI was administered with 100 mg/kg KBrO3 + 50 mg/kg NAR, Group VII was administered with 500 mg/kg CAF + 50 mg/kg NAR, and Group VIII was administered with 100 mg/kg KBrO3 + 250 mg/kg CAF + 50 mg/kg NAR. Finally, group IX was treated with 50 mg/kg NAR. The exposure of rats to KBrO3 and CAF for 21 days induced renal dysfunction linked with Lesch-Nyhan disease. NAR obliterated renal dysfunction linked with Lesch-Nyhan disease by decreasing uric acid, renal malondialdehyde level, inhibiting the activities of arginase, and phosphodiesterase-51 (PDE-51) with corresponding upregulation of brain derived-neurotrophic factor and its receptor (BDNF-TrkB), Bcl11b, HGPRT1, and DARPP-32. Additionally, renal failure related to Lesch-Nyhan disease was remarkably corrected by NAR as shown by the reduced activities of AChE and enzymes of ATP hydrolysis (ATPase, AMPase, and ADA) with affiliated increase in the NO level. This study therefore validates NAR as nontoxic and effective chemotherapy against kidney-related Lesch-Nyhan disease by mitigating effects of toxic food additives and enzymes of ATP-hydrolysis via NOS-cAMP-PKA and BDNF/TrkB signaling pathways.

Establishment and characterization of Lesch-Nyhan syndrome rabbit model.

Lesch-Nyhan syndrome (LNS) is a congenital defect disease that results in defective purine metabolism. It is caused by pathogenic variants of the HPRT gene. Its clinical symptoms mainly include high uric acid levels, gout, and kidney stones and damage. The mechanism of LNS has not been fully elucidated, and no cure exists. Animal models have always played an important role in exploring causative mechanisms and new therapies. This study combined CRISPR/Cas9 and microinjection to knock out the HPRT gene to create an LNS rabbit model. A sgRNA targeting exon 3 of HPRT gene was designed. Subsequently, Cas9 mRNA and sgRNA were injected into rabbit zygotes, and injected embryos were transferred to the uterus. The genotype and phenotype of rabbits were analyzed after birth. Four infant rabbits (named R1, R2, R3 and R4), which showed varying levels of gene modification, were born. The gene-editing efficiency was 100%. No wild-type sequences at the target HPRT gene were detected in R4 rabbit. Next, 6-thioguanine drug testing confirmed that HPRT enzymatic activity was deficient in R4 infant rabbit. HE staining revealed kidney abnormalities in all infant rabbits. Overall, an sgRNA capable of knocking out the HPRT gene in rabbits was successfully designed, and HPRT gene-modified rabbits were successfully constructed by using CRISPR/Cas9 technology and microinjection. This study provides a new nonrodent animal model for studying LNS syndrome.

HGprt deficiency disrupts dopaminergic circuit development in a genetic mouse model of Lesch-Nyhan disease.

In Lesch-Nyhan disease (LND), deficiency of the purine salvage enzyme hypoxanthine guanine phosphoribosyl transferase (HGprt) leads to a characteristic neurobehavioral phenotype dominated by dystonia, cognitive deficits and incapacitating self-injurious behavior. It has been known for decades that LND is associated with dysfunction of midbrain dopamine neurons, without overt structural brain abnormalities. Emerging post mortem and in vitro evidence supports the hypothesis that the dopaminergic dysfunction in LND is of developmental origin, but specific pathogenic mechanisms have not been revealed. In the current study, HGprt deficiency causes specific neurodevelopmental abnormalities in mice during embryogenesis, particularly affecting proliferation and migration of developing midbrain dopamine (mDA) neurons. In mutant embryos at E14.5, proliferation was increased, accompanied by a decrease in cell cycle exit and the distribution and orientation of dividing cells suggested a premature deviation from their migratory route. An abnormally structured radial glia-like scaffold supporting this mDA neuronal migration might lie at the basis of these abnormalities. Consequently, these abnormalities were associated with an increase in area occupied by TH+ cells and an abnormal mDA subpopulation organization at E18.5. Finally, dopaminergic innervation was disorganized in prefrontal and decreased in HGprt deficient primary motor and somatosensory cortices. These data provide direct in vivo evidence for a neurodevelopmental nature of the brain disorder in LND. Future studies should not only focus the specific molecular mechanisms underlying the reported neurodevelopmental abnormalities, but also on optimal timing of therapeutic interventions to rescue the DA neuron defects, which may also be relevant for other neurodevelopmental disorders.

Deep brain stimulation in Lesch-Nyhan syndrome: a systematic review.

Given the good results of deep brain stimulation (DBS) in the treatment of movement disorders, DBS was initially tried to treat Lesch-Nyhan syndrome (LNS) with the aim to alleviate LNS-related dystonia. Some cases have reported clinical results of DBS in LNS thus far. This systematic review was conducted to comprehensively summarize cases of LNS treated with DBS and evaluate the efficacy and safety of DBS in LNS. Eight publications covering 12 LNS patients were included in this review. DBS improved dystonia of the LNS to varying degrees. All the included cases achieved partial or complete control of self-injurious behavior (SIB). Overall, DBS is a promising treatment for both motor and behavior disorders of LNS patients, but the results reported thus far have varied widely, especially for motor outcomes. The ultimate clinical benefits in LNS patients were still unpredictable. DBS-related complications were rather common, which raised questions about the safety of the procedure in LNS. More research is needed to further clarify the safety and effectiveness of this treatment.

Physiological levels of folic acid reveal purine alterations in Lesch-Nyhan disease.

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.

[Genetic analysis of a Chinese pedigree with Lesch-Nyhan syndrome].

OBJECTIVE: To explore the genetic etiology for a Chinese pedigree affected with Lesch-Nyhan syndrome. METHODS: Members of the pedigree who had visited the Genetic Counseling Clinic of Linyi People's Hospital on February 10, 2022 were selected as the study subjects. Clinical data and family history of the proband were collected, and trio-whole exome sequencing (trio-WES) was carried out for the proband and his parents. Candidate variants were verified by Sanger sequencing. RESULTS: Trio-WES revealed that both the proband and his cousin brother had harbored a hemizygous c.385-1G>C variant in intron 4 of the HPRT1 gene, which was unreported previously. A heterozygous c.385-1G>C variant of the HPRT1 gene was also found in the proband's mother, grandmother, two aunts, and a female cousin, whilst all phenotypically normal males in his pedigree were found to have a wild type for the locus, which has conformed to an X-linked recessive inheritance. CONCLUSION: The heterozygous c.385-1G>C variant of the HPRT1 gene probably underlay the Lesch-Nyhan syndrome in this pedigree.

Microstructural white matter abnormalities in Lesch-Nyhan disease.

Lesch-Nyhan disease is a rare, sex-linked, genetic neurodevelopmental disorder that is characterized by hyperuricemia, dystonia, cognitive impairment and recurrent self-injury. We previously found reduced brain white matter volume in patients with Lesch-Nyhan disease compared with healthy adults using voxel-based morphometry. Here, we address the structural integrity of white matter via diffusion tensor imaging. We hypothesized that white matter integrity would be decreased in men with Lesch-Nyhan disease and to a lesser extent in men with a milder variant of the disease (Lesch-Nyhan variant) relative to healthy men. After acquiring diffusion-weighted brain images from Lesch-Nyhan disease (n = 5), Lesch-Nyhan variant (n = 6) and healthy participants (n = 10), we used both tract-based spatial statistics and a regions of interest approach to analyse between-group fractional anisotropy differences. We first replicated earlier findings of reduced intracranial, grey matter and white matter volumes in patients. We then discovered marked reductions of fractional anisotropy relative to the healthy control group. The Lesch-Nyhan disease group showed more pronounced reductions in white matter integrity than the Lesch-Nyhan variant group. In addition to whole brain fractional anisotropy group differences, reductions in white matter integrity were observed in the corpus callosum, corona radiata, cingulum, internal capsule and superior longitudinal fasciculus. Moreover, the variant group had attenuated dystonia severity symptoms and cognitive deficits. These findings highlight the need to better understand the role of white matter in Lesch-Nyhan disease.

PUS7 deficiency in human patients causes profound neurodevelopmental phenotype by dysregulating protein translation.

Protein translation is a highly regulated process involving the interaction of numerous genes on every component of the protein translation machinery. Upregulated protein translation is a hallmark of cancer and is implicated in autism spectrum disorder, but the risks of developing each disease do not appear to be correlated with one another. In this study we identified two siblings from the NIH Undiagnosed Diseases Program with loss of function variants in PUS7, a gene previously implicated in the regulation of total protein translation. These patients exhibited a neurodevelopmental phenotype including autism spectrum disorder in the proband. Both patients also had features of Lesch-Nyhan syndrome, including hyperuricemia and self-injurious behavior, but without pathogenic variants in HPRT1. Patient fibroblasts demonstrated upregulation of protein synthesis, including elevated MYC protein, but did not exhibit increased rates of cell proliferation. Interestingly, the dysregulation of protein translation also resulted in mildly decreased levels of HPRT1 protein suggesting an association between dysregulated protein translation and the LNS-like phenotypic findings. These findings strengthen the correlation between neurodevelopmental disease, particularly autism spectrum disorders, and the rate of protein translation.

Abnormalities of neural stem cells in Lesch-Nyhan disease.

Lesch-Nyhan disease (LND) is a neurodevelopmental disorder caused by variants in the HPRT1 gene, which encodes the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGprt). HGprt deficiency provokes numerous metabolic changes which vary among different cell types, making it unclear which changes are most relevant for abnormal neural development. To begin to elucidate the consequences of HGprt deficiency for developing human neurons, neural stem cells (NSCs) were prepared from 6 induced pluripotent stem cell (iPSC) lines from individuals with LND and compared to 6 normal healthy controls. For all 12 lines, gene expression profiles were determined by RNA-seq and protein expression profiles were determined by shotgun proteomics. The LND lines revealed significant changes in expression of multiple genes and proteins. There was little overlap in findings between iPSCs and NSCs, confirming the impact of HGprt deficiency depends on cell type. For NSCs, gene expression studies pointed towards abnormalities in WNT signaling, which is known to play a role in neural development. Protein expression studies pointed to abnormalities in the mitochondrial F0F1 ATPase, which plays a role in maintaining cellular energy. These studies point to some mechanisms that may be responsible for abnormal neural development in LND.

Ethical implications of early genetic diagnosis in an infant with Lesch-Nyhan syndrome.

Pathogenic variants in HPRT1 lead to deficiency in hypoxanthine-guanine phosphoribosyltransferase and are responsible for a spectrum of disorders. The severe phenotype is termed Lesch-Nyhan syndrome (LNS) and is inherited in an X-linked recessive manner. Most individuals with LNS have profound intellectual and physical disabilities throughout life including self-mutilating behaviors. Here, we present the case of a male infant who was diagnosed with LNS at 3 weeks of age via rapid exome sequencing (ES), which revealed a hemizygous maternally inherited deletion of at least 1.3 Mb of Xq26.3, including exons 2 to 9 of HPRT1. We discuss the critical time points leading to this diagnosis while highlighting his parents' values that guided the decision-making. Genetic testing provided an early diagnosis for this infant that led to important considerations regarding goals of care in addition to raising new ethical concerns. This highlights the important role that early and rapid diagnostic genetic testing can play in helping families make difficult decisions. Additionally, this case highlights the complexity of discussing rare genetic diagnoses with families and facilitating critical discussions to empower the family toward making an informed decision.

[Analysis of HPRT1 gene variant and prenatal diagnosis for a Chinese pedigree with Lesch-Nyhan syndrome but no specimen from affected probands].

OBJECTIVE: To carry out genetic testing and prenatal diagnosis for a Chinese pedigree with Lesch-Nyhan syndrome (LNS) but no specimen from the affected probands. METHODS: All affected individuals in this pedigrees were male and had deceased during childhood, with no biological specimen left. Based on their typical neurological dysfunction and tendency for self-mutilation, the diagnosis of LNS was suspected. Sanger sequencing was carried out to detect potential variant of the HPRT1 gene among female members from the pedigree. Following the identification of the pathogenic variant, prenatal diagnosis was provided for a high-risk fetus. RESULTS: The proband's mother and three other females were found to harbor heterozygous c.500_501delGGinsC (p.Arg167fs*23) variant of the HPRT1 gene, which was unreported previously. Prenatal diagnosis showed that the fetus was a male and had inherited the same pathogenic variant. CONCLUSION: The c.500_501delGGinsC variant of the HPRT1 gene probably underlay the LNS in this pedigree. Above finding has provided a basis for prenatal diagnosis and genetic counseling for this pedigree.

Congenital anomalies-associated Riga-Fede disease as an early manifestation of Lesch-Nyhan syndrome: rare entities in the same pediatric patient-a case report.

BACKGROUND: Riga-Fede disease is a rare begnin disorder of the oral tissues, it can be associated with congenital anomalies and neurological disturbances. Lesch-Nyhan syndrome is a rare X-linked recessive disorder characterized by neurological and behavioral manifestations. A patient can rarely be diagnosed with both diseases in a lifetime. Therefore, reporting manifestations from such disorders is important to avoid misdiagnosis and help in timely intervention. CASE PRESENTATION: This case report presents an 8-months-old male infant with traumatic oral ulcers from deciduous teeth. A diagnosis of Riga-Fede disease was made. Teeth grinding was performed and the oral lesions were healed. At the age of 2.5 years, the patient presented with neurological manifestations as well as facial tissue and premature teeth loss from self mutilation. Genetic sequencing revealed a variant of uncertain significance in the Hypoxanthine Phosphoribosyltransferase 1 gene. He was diagnosed with Lesch-Nyhan syndrome. Cleft palate, ventricular septal defect, congenitally undescended testis and ectopic left iliac kidney were also reported. The patient was scheduled on psychiatric treatment and after about six months of follow-up, both the behavioral and neurological symptoms were improved. CONCLUSIONS: Riga-Fede disease can be an early manifestation of Lesch-Nyhan syndrome. To the best of our knowledge, this is the first reported case with the incidence of all the mentioned entities in one pediatric patient.

Clinical and molecular findings in a Turkish family with an ultra-rare condition, ELP2-related neurodevelopmental disorder.

Elongator is a multi-subunit protein complex bearing six different protein subunits, Elp1 to -6, that are highly conserved among eukaryotes. Elp2 is the second major subunit of Elongator and, together with Elp1 and Elp3, form the catalytic core of this essential complex. Pathogenic variants that affect the structure and function of the Elongator complex may cause neurodevelopmental disorders. Here, we report on a new family with three children affected with a severe form of intellectual disability along with spastic tetraparesis, choreoathetosis, and self injury. Molecular genetic analyses reveal a homozygous missense variant in the ELP2 gene (NM_018255.4 (ELP2): c.1385G > A (p.Arg462Gln)), while in silico studies suggest a loss of electrostatic interactions that may contribute to the overall stability of the encoded protein. We also include a comparison of the patients with ELP2-related neurodevelopmental disorder to those previously reported in the literature. Apart from being affected with intellectual disability, we have extremely limited clinical knowledge about patients harboring ELP2 variants. Besides providing support to the causal role of p.Arg462Gln in ELP2-related neurodevelopmental disorder, we add self-injurious behavior to the clinical phenotypic repertoire of the disease.

Deep brain stimulation in Lesch-Nyhan disease: outcomes from the patient's perspective.

AIM: To provide insight into outcome and long-term safety and efficacy of deep brain stimulation (DBS), from the perspective of individuals with Lesch-Nyhan disease (LND) and their families. METHOD: We used patient-centered outcome measures to assess long-term outcomes of DBS for 14 individuals (mean [SD] age 10y 10mo [5y 6mo], range 5-23y, all males) with LND, after an average duration of 5y 6mo (range 11mo-10y 5mo) after surgery. We compared these results with a comprehensive review of previously published cases. RESULTS: Patients and their families reported that DBS of the globus pallidus can be effective both for motor and behavioral disturbances in LND. However, outcome measures were often not significantly changed owing to substantial variability among individuals, and were overall less positive than in previous reports based on clinician assessments. In addition, there was an unexpectedly high rate of adverse events, tempering overall enthusiasm for the procedure. INTERPRETATION: Although DBS might be an effective treatment for LND, more research is needed to understand the reasons for response variability and the unusually high rates of adverse events before DBS can be recommended for these patients. What this paper adds Individuals with Lesch-Nyhan disease and their families report variable efficacy of deep brain stimulation. Long-term outcomes are associated with a high adverse event rate.

Lesch-Nyhan syndrome due to a splice-site mutation in a 14-month-old boy presenting as acute renal failure.

Lesch-Nyhan disease (LND) is a rare X-linked recessive inherited disorder caused by mutations in HPRT1 gene resulting in deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT). LND is characterized by hyperuricemia and a spectrum of neurological and behavioral manifestations. We describe a rare case of a 14-month-old boy presenting with acute renal failure and hyperuricemia. The patient exhibited all features of LNS apart from self-injurious behavior. The enzymatic analysis demonstrated total inactivity of the HPRT, and the molecular analysis revealed a splice-site mutation in intron 3 leading to exon 4 exclusion. This splice-site mutation has been previously reported only twice.

Deep Brain Stimulation of the Internal Pallidum in Lesch-Nyhan Syndrome: Clinical Outcomes and Connectivity Analysis.

BACKGROUND: Lesch-Nyhan syndrome (LNS) is a rare genetic disorder characterized by a deficiency of hypoxanthine-guanine phosphoribosyltransferase enzyme. It manifests during infancy with compulsive self-mutilation behavior associated with disabling generalized dystonia and dyskinesia. Clinical management of these patients poses an enormous challenge for medical teams and carers. OBJECTIVES: We report our experience with bilateral deep brain stimulation (DBS) of the globus pallidus internus (GPi) in the management of this complex disorder. MATERIALS AND METHODS: Preoperative and postoperative functional assessment data prospectively collected by a multidisciplinary pediatric complex motor disorders team, including imaging, neuropsychology, and neurophysiology evaluations were analyzed with regards to motor and behavioral control, goal achievement, and patient and caregivers' expectations. RESULTS: Four male patients (mean age 13 years) underwent DBS implantation between 2011 and 2018. Three patients received double bilateral DBS electrodes within the posteroventral GPi and the anteromedial GPi, whereas one patient had bilateral electrodes placed in the posteroventral GPi only. Median follow-up was 47.5 months (range 22-98 months). Functional improvement was observed in all patients and discussed in relation to previous reports. Analysis of structural connectivity revealed significant correlation between the involvement of specific cortical regions and clinical outcome. CONCLUSION: Combined bilateral stimulation of the anteromedial and posteroventral GPi may be considered as an option for managing refractory dystonia and self-harm behavior in LNS patients. A multidisciplinary team-based approach is essential for patient selection and management, to support children and families, to achieve functional improvement and alleviate the overall disease burden for patients and caregivers.

CRISPR/Cas9-Mediated Scanning for Regulatory Elements Required for HPRT1 Expression via Thousands of Large, Programmed Genomic Deletions.

The extent to which non-coding mutations contribute to Mendelian disease is a major unknown in human genetics. Relatedly, the vast majority of candidate regulatory elements have yet to be functionally validated. Here, we describe a CRISPR-based system that uses pairs of guide RNAs (gRNAs) to program thousands of kilobase-scale deletions that deeply scan across a targeted region in a tiling fashion ("ScanDel"). We applied ScanDel to HPRT1, the housekeeping gene underlying Lesch-Nyhan syndrome, an X-linked recessive disorder. Altogether, we programmed 4,342 overlapping 1 and 2 kb deletions that tiled 206 kb centered on HPRT1 (including 87 kb upstream and 79 kb downstream) with median 27-fold redundancy per base. We functionally assayed programmed deletions in parallel by selecting for loss of HPRT function with 6-thioguanine. As expected, sequencing gRNA pairs before and after selection confirmed that all HPRT1 exons are needed. However, HPRT1 function was robust to deletion of any intergenic or deeply intronic non-coding region, indicating that proximal regulatory sequences are sufficient for HPRT1 expression. Although our screen did identify the disruption of exon-proximal non-coding sequences (e.g., the promoter) as functionally consequential, long-read sequencing revealed that this signal was driven by rare, imprecise deletions that extended into exons. Our results suggest that no singular distal regulatory element is required for HPRT1 expression and that distal mutations are unlikely to contribute substantially to Lesch-Nyhan syndrome burden. Further application of ScanDel could shed light on the role of regulatory mutations in disease at other loci while also facilitating a deeper understanding of endogenous gene regulation.

HPRT and Purine Salvaging Are Critical for Hematopoietic Stem Cell Function.

Adult hematopoietic stem cells (HSCs) maintain tissue homeostasis and regenerative capacity of the hematopoietic system through self-renewal and differentiation. Metabolism is recognized as an important regulatory entity controlling stem cells. As purine nucleotides are essential for metabolic functions, we analyzed the role of hypoxanthine guanine phosphoribosyl transferase (HPRT)-associated purine salvaging in HSCs. Here, we demonstrate that hematopoietic stem and progenitor cells (HSPCs) show a strong dependence on HPRT-associated purine salvaging. HSPCs with lower HPRT activity had a severely reduced competitive repopulation ability upon transplantation. Strikingly, HPRT deficiency resulted in altered cell-cycle progression, proliferation kinetics and mitochondrial membrane potential primarily in the HSC compartment, whereas more committed progenitors were less affected. Our data thus imply a unique and important role of HPRT and the purine salvage pathway for HSC function. Stem Cells 2019;37:1606-1614.

Hypoxanthine phosphoribosyltransferase (HPRT)-deficiency is associated with impaired fertility in the female rat.

The purine hypoxanthine plays important role in regulating oocyte maturation and early embryonic development. The enzyme hypoxanthine phosphoribosyltransferase (HPRT) recycles hypoxanthine to generate substrates for nucleotide synthesis and key metabolites, and here we show that HPRT deficiency in the rat disrupts early embryonic development and causes infertility in females.