HGNC Approved Gene Symbol: SPR
SNOMEDCT: 1187545003;
Cytogenetic location: 2p13.2 Genomic coordinates (GRCh38): 2:72,887,408-72,892,158 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p13.2 | Dystonia, dopa-responsive, due to sepiapterin reductase deficiency | 612716 | ?Autosomal dominant; Autosomal recessive | 3 |
Sepiapterin reductase (7,8-dihydrobiopterin:NADP+ oxidoreductase; EC 1.1.1.153) catalyzes the NADPH-dependent reduction of various carbonyl substances, including derivatives of pteridines, and belongs to a group of enzymes called aldo-keto reductases. SPR plays an important role in the biosynthesis of tetrahydrobiopterin (BH4).
Ichinose et al. (1991) isolated a full-length cDNA clone for sepiapterin reductase from a human liver cDNA library by plaque hybridization. The clone encoded a protein of 261 amino acids with a calculated molecular mass of 28,047 Da. The predicted amino acid sequence of human sepiapterin reductase shows 74% identity with the rat enzyme and a striking homology with human carbonyl reductase (114830), estradiol 17-beta-dehydrogenase (605573), and 3-beta-hydroxy-5-ene steroid dehydrogenase (613890), especially in the N-terminal region.
By isotopic in situ hybridization, Thony et al. (1995) mapped the SPR gene to chromosome 2p14-p12. They commented that all the genes that encode enzymes required for biosynthesis and regeneration of tetrahydrobiopterin had been mapped: these include GTP-cyclohydrolase I (600225) on chromosome 14; 6-pyruvoyl-tetrahydropterin synthase (261640) on chromosome 11; pterin-4-alpha-carbinolamine dehydratase (126090); and dihydropteridine reductase (612676) on chromosome 4.
Murdoch et al. (1997) mapped the mouse homolog to distal chromosome 1.
Bonafe et al. (2001) reported 2 patients with dopa-responsive dystonia associated with SPR deficiency (612716). They had progressive psychomotor retardation and dystonia. Analysis of cerebrospinal fluid (CSF) showed severe dopamine and serotonin deficiencies (low levels of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), respectively), and abnormal pterin pattern (high levels of biopterin and dihydrobiopterin). Urinary pterin levels were normal and there was no hyperphenylalaninemia. Studies of skin fibroblasts revealed inactive sepiapterin reductase, the enzyme catalyzing the final 2-step reaction in the biosynthesis of tetrahydrobiopterin (BH4). Mutations in the SPR gene were detected in both patients: homozygous (182125.0001) in one and compound heterozygous (182125.0002; 182125.0003) in the other. The findings indicated that autosomal recessive deficiency of sepiapterin reductase leads to BH4 and neurotransmitter deficiencies without hyperphenylalaninemia and thus may not be detected by neonatal screening for phenylketonuria.
Bonafe et al. (2001) proposed that the absence of hyperphenylalaninemia and the presence of novel urinary pterin metabolites and of normal SPR-like activity in red blood cells may be explained by alternative pathways for the final 2-step reaction of BH4 biosynthesis in peripheral and neuronal tissues. They proposed that, for the biosynthesis of BH4 in peripheral tissues, SPR activity may be substituted by aldose reductase (AR; 103880), carbonyl reductase (CBR1; 114830), and dihydrofolate reductase (DHRF; 126060), whereas, in the brain, only AR and CR are fully present.
In a patient with sepiapterin reductase deficiency and mild dopa-responsive dystonia, Steinberger et al. (2004) identified a heterozygous mutation in the SPR gene (182125.0004).
Bikker et al. (2006) described a patient homozygous for mutations in 2 genes, MCEE (608419) and SPR, with methylmalonyl-CoA epimerase deficiency and sepiapterin reductase deficiency (see 251120). The patient had developmental delay with dystonia as a prominent symptom, as in sepiapterin reductase deficiency. Since the patient did not appear to be more severely affected than the patient of Bonafe et al. (2001), it appeared that the methylmalonyl-CoA epimerase deficiency did not have a large clinical impact, or could even be considered a nondisease.
Sharma et al. (2006) commented on the accumulated evidence that the SPR gene is a likely candidate for the Parkinson disease-3 (PARK3; 602404) locus which had been mapped to 2p13. DeStefano et al. (2002) found evidence for association between later age at onset of Parkinson disease and an allele of a marker close to the SPR gene. Karamohamed et al. (2003) extended the work by genotyping single-nucleotide polymorphism (SNP) markers in the same region. Sharma et al. (2006) found that DNA polymorphisms in a highly intercorrelated linkage disequilibrium block, which includes the SPR gene, appeared to be associated with both sporadic and familial Parkinson disease.
A proper level of BH4 is necessary for the metabolism of phenylalanine and the production of nitric oxide, catecholamines, and serotonin. BH4 deficiency is closely associated with diverse neurologic-psychiatric disorders. Sepiapterin reductase (SPR) catalyzes the final step of BH4 biosynthesis. Yang et al. (2006) created an Spr knockout mouse (Spr -/-) and found that the deficient mice display disturbed pterin profiles and greatly diminished levels of dopamine, norepinephrine, and serotonin, indicating that SPR is essential for homeostasis of BH4 and for the normal functions of BH4-dependent enzymes. The Spr -/- mice exhibited phenylketonuria, dwarfism, and impaired body movement. Oral supplementation of BH4 and neurotransmitter precursors completely rescued dwarfism and phenylalanine metabolism. The biochemical and behavioral characteristics of Spr -/- mice shared striking similarities with the symptoms observed in SPR-deficient patients.
In a patient with sepiapterin reductase deficiency (612716), Bonafe et al. (2001) found homozygosity for a TC-to-CT dinucleotide transition in exon 2 of the SPR gene, at cDNA position 354-355 and at genomic DNA position 1303-1304. This exchange predicted the mutant allele gln119-to-ter (Q119X). The patient was a 14-year-old adolescent male born to consanguineous parents of Turkish origin. Administration of L-DOPA resulted in clinical improvement. He presented with psychomotor retardation, spasticity, dystonia, microcephaly, and growth retardation (Blau et al., 1998).
In a patient with sepiapterin reductase deficiency (612716), Bonafe et al. (2001) found compound heterozygosity for mutations in the SPR gene: a 5-bp deletion of nucleotides 1397-1401 of genomic DNA (AGAAC) and an A-to-G transition leading to an arg150-to-gln (R150G; 182125.0003) substitution. The patient was a 9-year-old boy born of unrelated parents of Turkish origin. He presented with progressive psychomotor retardation, spasticity, tremor, ataxia, dystonic posturing and falls (initially misinterpreted as epileptic seizures), depressive and aggressive behavior, and oculogyric crises (Blau et al., 1999). There were also marked diurnal fluctuations. Administration of L-DOPA resulted in clinical improvement.
Friedman et al. (2012) identified the R150G mutation in the SPR gene in 14 patients with SPR deficiency, many of whom were of Mediterranean descent (8 Spanish, 2 Turkish, 1 Italian, and 3 unspecified Caucasian).
For discussion of the arg150-to-gly (R150G) mutation in the SPR gene that was found in compound heterozygous state in a patient with sepiapterin reductase deficiency (612716) by Bonafe et al. (2001), see 182125.0002.
In a 27-year-old woman with SPR deficiency, Friedman et al. (2006) identified a homozygous 448A-G transition in the SPR gene, resulting in an R150G substitution. She had delayed childhood development, low IQ, abnormal gait, oculomotor apraxia, dysarthria, weakness, generalized dystonia, myoclonus, choreoathetosis, and hypersomnolence, requiring 13 hours of sleep per day. CSF contained markedly decreased 5-HIAA and HVA, and increased 7,8-dihydropterin, consistent with SPR deficiency. Initial treatment with L-DOPA resulted in marked clinical improvement but also intolerable dyskinesias. Maximal clinical benefit was found with selegiline and melatonin. Maternal relatives of the patient reportedly had abnormal limb posturing.
In a 26-year-old woman with a mild form of dopa-responsive dystonia (612716), Steinberger et al. (2004) identified a heterozygous -13G-A transition in the 5-prime untranslated region of the SPR gene. The mutation was not identified in 100 unaffected controls or in 94 other dystonia patients. Sepiapterin reductase activity was significantly reduced compared to controls (approximately 50%) and western blot analysis showed reduced protein quantities (approximately 39% of normal). Biopterin concentration was also reduced. The patient had walked on tiptoes as a child, suggesting fixed pes equinovarus. At age 15 years, she noticed abnormal movements of the fourth and fifth digits of the left hand; at age 19 years, she developed gait abnormalities with internal rotation, adduction, and extension of the left leg; and at age 23 years, she had dystonic movements and tremor. The biologic parents were unknown. The findings indicated that haploinsufficiency for SPR can result in clinical symptoms.
Bikker et al. (2006) presented a patient with methylmalonyl-CoA epimerase deficiency (251120) and dystonia due to sepiapterin reductase deficiency (612716). The patient was homozygous for mutations in both the MCEE (608419.0001) and SPR genes. Abeling et al. (2006) described the mutation in SPR, a 1437C-T transition in exon 2 that caused a pro163-to-leu (P163L) substitution. Both parents were heterozygous for both mutations.
In 2 Greek sibs with SPR deficiency (612716), Verbeek et al. (2008) identified a homozygous 751A-T transversion in the SPR gene, resulting in a lys251-to-ter (K251X) substitution. Each unaffected parent was heterozygous for the mutation. SPR activity was undetectable in patient fibroblasts.
In a Spanish boy with classic SPR deficiency, Arrabal et al. (2011) identified a homozygous K251X mutation. The K251X mutation results in an SPR protein with a small C-terminal deletion and no residual activity, as it eliminates a critical residue (D257) involved in substrate binding specificity and anchoring. The patient had onset in infancy of psychomotor retardation, hypotonia, hypersalivation, hypersomnolence, ataxia, and extrapyramidal signs. The diagnosis was made after neurotransmitter analysis and genetic testing. Treatment with L-DOPA and 5-hydroxytryptophan resulted in neurologic improvement, although he still had slight psychomotor delay 3 years later.
In 3 Spanish sisters with a mild form of SPR deficiency (612716), Arrabal et al. (2011) identified compound heterozygosity for 2 mutations in the SPR gene: a 304G-T transversion in the last nucleotide of exon 1, and R150G (182125.0003). The 304G-T transversion was predicted to result in a gly102-to-cys (G102C) substitution at a semiconserved residue that is not directly involved in substrate binding or catalysis. The mutation was not found in 200 control alleles. In vitro functional expression studies in E. coli showed that the G102C mutant protein had 15% residual enzyme activity. Minigene analysis showed that the G102C mutation resulted in some splicing abnormalities, although some normal splicing still occurred, resulting in a mutant protein with the missense change. The proband presented at age 7 years with gait difficulties and left foot equinovarus. She also had weakness and weariness with diurnal variation. Other findings included intermittent postural tremor, abnormal ocular movements or oral dyskinesia when stressed, bradykinesia, mask-like facial expression, asymmetric postural dystonia, axial hypotonia, and rigidity. She also had hyperreflexia and myoclonic movements; cognition was normal. Treatment with L-DOPA was highly effective. Her sisters had similar but milder symptoms. Arrabal et al. (2011) concluded that the milder phenotype in the 3 sisters resulted from residual enzyme activity conferred by the G102C mutation, since R150G had been shown to be functionally null.
In 7 Maltese patients with classic features of SPR deficiency (612716), Neville et al. (2005) identified a homozygous A-to-G transition in intron 2 of the SPR gene, predicted to impair transcription processing and cause an enzymatic deficiency. Neville et al. (2005) postulated a founder effect in this population.
Abeling, N. G., Duran, M., Bakker, H. D., Stroomer, L., Thony, B., Blau, N., Booij, J., Poll-The, B. T. Sepiapterin reductase deficiency an autosomal recessive DOPA-responsive dystonia. Molec. Genet. Metab. 89: 116-120, 2006. [PubMed: 16650784] [Full Text: https://doi.org/10.1016/j.ymgme.2006.03.010]
Arrabal, L., Teresa, L., Sanchez-Alcudia, R., Castro, M., Medrano, C., Gutierrez-Solana, L., Roldan, S., Ormazabal, A., Perez-Cerda, C., Merinero, B., Perez, B., Artuch, R., Ugarte, M., Desviat, L. R. Genotype-phenotype correlations in sepiapterin reductase deficiency: a splicing defect accounts for a new phenotypic variant. Neurogenetics 12: 183-191, 2011. [PubMed: 21431957] [Full Text: https://doi.org/10.1007/s10048-011-0279-4]
Bikker, H., Bakker, H. D., Abeling, N. G. G. M., Poll-The, B. T., Kleijer, W. J., Rosenblatt, D. S., Waterham, H. R., Wanders, R. J. A., Duran, M. A homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE) results in mild methylmalonic aciduria. Hum. Mutat. 27: 640-643, 2006. [PubMed: 16752391] [Full Text: https://doi.org/10.1002/humu.20373]
Blau, N., Thony, B., Renneberg, A., Arnold, L. A., Hyland, K. Dihydropteridine reductase deficiency localized to the central nervous system. J. Inherit. Metab. Dis. 21: 433-434, 1998. [PubMed: 9700606] [Full Text: https://doi.org/10.1023/a:1005327313348]
Blau, N., Thony, B., Renneberg, A., Penzien, J. M., Hyland, K., Hoffmann, G. Variant of dihydropteridine reductase deficiency without hyperphenylalaninemia: effect of oral phenylalanine loading. J. Inherit. Metab. Dis. 22: 216-220, 1999. [PubMed: 10384371] [Full Text: https://doi.org/10.1023/a:1005584627797]
Bonafe, L., Thony, B., Penzien, J. M., Czarnecki, B., Blau, N. Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine-neurotransmitter deficiency without hyperphenylalaninemia. Am. J. Hum. Genet. 69: 269-277, 2001. [PubMed: 11443547] [Full Text: https://doi.org/10.1086/321970]
DeStefano, A. L., Lew, M. F., Golbe, L. I., Mark, M. H., Lazzarini, A. M., Guttman, M., Montgomery, E., Waters, C. H., Singer, C., Watts, R. L., Currie, L. J., Wooten, G. F., and 19 others. PARK3 influences age at onset in Parkinson disease: a genome scan in the GenePD study. Am. J. Hum. Genet. 70: 1089-1095, 2002. [PubMed: 11920285] [Full Text: https://doi.org/10.1086/339814]
Friedman, J., Hyland, K., Blau, N., MacCollin, M. Dopa-responsive hypersomnia and mixed movement disorder due to sepiapterin reductase deficiency. Neurology 67: 2032-2035, 2006. [PubMed: 17159114] [Full Text: https://doi.org/10.1212/01.wnl.0000247274.21261.b4]
Friedman, J., Roze, E., Abdenur, J. E., Chang, R., Gasperini, S., Saletti, V., Wali, G. M., Eiroa, H., Neville, B., Felice, A., Parascandalo, R., Zafeiriou, D. I., and 17 others. Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy. Ann. Neurol. 71: 520-530, 2012. [PubMed: 22522443] [Full Text: https://doi.org/10.1002/ana.22685]
Ichinose, H., Katoh, S., Sueoka, T., Titani, K., Fujita, K., Nagatsu, T. Cloning and sequencing of cDNA encoding human sepiapterin reductase: an enzyme involved in tetrahydrobiopterin biosynthesis. Biochem. Biophys. Res. Commun. 179: 183-189, 1991. [PubMed: 1883349] [Full Text: https://doi.org/10.1016/0006-291x(91)91352-d]
Karamohamed, S., DeStefano, A. L., Wilk, J. B., Shoemaker, C. M., Golbe, L. I., Mark, M. H., Lazzarini, A. M., Suchowersky, O., Labelle, N., Guttman, M., Currie, L. J., Wooten, G. F., and 22 others. A haplotype at the PARK3 locus influences onset age for Parkinson's disease: the GenePD study. Neurology 61: 1557-1561, 2003. [PubMed: 14663042] [Full Text: https://doi.org/10.1212/01.wnl.0000095966.99430.f4]
Murdoch, J. N., Eddleston, J., Stanier, P., Copp, A. J. Localization of the mouse gene encoding tyrosine kinase receptor type 10 on distal chromosome 1. Mammalian Genome 8: 941-952, 1997. [PubMed: 9383291] [Full Text: https://doi.org/10.1007/s003359900617]
Neville, B. G. R., Parascandalo, R., Farrugia, R., Felice, A. Sepiapterin reductase deficiency: a congenital dopa-responsive motor and cognitive disorder. Brain 128: 2291-2296, 2005. [PubMed: 16049044] [Full Text: https://doi.org/10.1093/brain/awh603]
Sharma, M., Mueller, J. C., Zimprich, A., Lichtner, P., Hofer, A., Leitner, P., Maass, S., Berg, D., Durr, A., Bonifati, V., De Michele, G., Oostra, B., Brice, A., Wood, N. W., Muller-Myhsok, B., Gasser, T., European Consortium on Genetic Susceptibility in Parkinson's Disease (GSPD). The sepiapterin reductase gene region reveals association in the PARK3 locus: analysis of familial and sporadic Parkinson's disease in European populations. J. Med. Genet. 43: 557-562, 2006. [PubMed: 16443856] [Full Text: https://doi.org/10.1136/jmg.2005.039149]
Steinberger, D., Blau, N., Goriuonov, D., Bitsch, J., Zuker, M., Hummel, S., Muller, U. Heterozygous mutation in 5-prime-untranslated region of sepiapterin reductase gene (SPR) in a patient with dopa-responsive dystonia. Neurogenetics 5: 187-190, 2004. [PubMed: 15241655] [Full Text: https://doi.org/10.1007/s10048-004-0182-3]
Thony, B., Heizmann, C. W., Mattei, M.-G. Human GTP-cyclohydrolase I gene and sepiapterin reductase gene map to region 14q21-q22 and 2p14-p12, respectively, by in situ hybridization. Genomics 26: 168-170, 1995. [PubMed: 7782081] [Full Text: https://doi.org/10.1016/0888-7543(95)80101-q]
Verbeek, M. M., Willemsen, M. A. A. P., Wevers, R. A., Lagerwerf, A. J., Abeling, N. G. G. M., Blau, N., Thony, B., Vargiami, E., Zafeiriou, D. I. Two Greek siblings with sepiapterin reductase deficiency. Molec. Genet. Metab. 94: 403-409, 2008. [PubMed: 18502672] [Full Text: https://doi.org/10.1016/j.ymgme.2008.04.003]
Yang, S., Lee, Y. J., Kim, J.-M., Park, S., Peris, J., Laipis, P., Park, Y. S., Chung, J. H., Oh, S. P. A murine model for human sepiapterin-reductase deficiency. Am. J. Hum. Genet. 78: 575-587, 2006. [PubMed: 16532389] [Full Text: https://doi.org/10.1086/501372]