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SPR
sepiapterin reductase
SPR is located on the short (p) arm of chromosome 2, at band 2p13.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The SPR gene, located on chromosome 2, encodes sepiapterin reductase, an enzyme central to tetrahydrobiopterin (BH4) metabolism. BH4 serves as an essential cofactor in multiple biochemical pathways, most notably the synthesis of dopamine and serotonin - neurotransmitters that regulate movement, mood, sleep, and other vital functions. When both copies of SPR carry pathogenic variants, the resulting enzyme deficiency disrupts neurotransmitter production, typically manifesting as movement abnormalities that emerge in early childhood.
Understanding SPR is particularly relevant in the context of carrier screening, as this gene follows an autosomal recessive inheritance pattern. Individuals carrying one pathogenic variant generally remain asymptomatic but can pass the variant to their children. The gene appears on multiple NHS clinical diagnostic panels focused on movement disorders and metabolic conditions, reflecting its clinical significance in neurodevelopmental presentations.
What the gene does
Sepiapterin reductase functions as the final enzyme in a three-step biosynthetic pathway that generates tetrahydrobiopterin from precursor molecules. Specifically, this enzyme converts 6-pyruvoyl-tetrahydropterin into the active BH4 cofactor using NADPH as a cofactor. The protein belongs to the short-chain dehydrogenase/reductase superfamily, operating through conserved catalytic mechanisms typical of this enzyme class.
Tetrahydrobiopterin produced through this pathway serves multiple metabolic roles. It acts as an obligate cofactor for aromatic amino acid hydroxylases, including tyrosine hydroxylase and tryptophan hydroxylase, which represent rate-limiting enzymes in dopamine and serotonin biosynthesis respectively. These neurotransmitters are indispensable for coordinating smooth voluntary movements, regulating emotional states, maintaining sleep-wake cycles, and modulating appetite. BH4 also participates in nitric oxide synthesis and the metabolism of phenylalanine, linking SPR function to broader aspects of cellular signalling and amino acid homeostasis.
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Chromosome location
SPR maps to chromosomal band 2p13.2 on the short arm of chromosome 2. The gene spans this region and encodes a transcript that is translated into a 261-amino-acid protein. This chromosomal location places SPR among other metabolic genes, though its specific genomic neighbourhood does not appear to confer additional regulatory complexity relevant to its primary enzymatic role.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The sepiapterin reductase enzyme comprises 261 amino acids and belongs to the short-chain dehydrogenase/reductase family, suggesting it likely contains characteristic structural motifs common to this enzyme class, including nucleotide-binding regions and a catalytic triad. However, specific domain boundaries have not been formally annotated in structural databases.
Key variants
Pathogenic variants in SPR encompass a range of molecular defects, including missense changes that substitute critical amino acids and splicing alterations that disrupt normal transcript processing. The severity of movement symptoms and the degree of neurotransmitter deficiency often correlate with residual enzyme activity, which varies depending on the specific variants inherited. Both homozygous variants (two copies of the same change) and compound heterozygous variants (two different pathogenic changes) have been documented in affected individuals.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Biallelic pathogenic variants in SPR cause sepiapterin reductase deficiency, an autosomal recessive disorder characterised by progressive movement abnormalities. Affected individuals typically present in infancy or early childhood with features such as dystonia (involuntary muscle contractions causing abnormal postures), tremor, developmental delays, and sleep disturbances. The condition results from inadequate tetrahydrobiopterin production, which in turn limits dopamine and serotonin synthesis in the brain. Some individuals with specific variant combinations may exhibit features of dopa-responsive dystonia, a related movement disorder that can sometimes respond to treatment with L-dopa medication, though sepiapterin reductase deficiency itself generally requires more comprehensive neurotransmitter replacement strategies.
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Inheritance pattern
Conditions caused by pathogenic SPR variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
SPR holds green (high-confidence) status on ten NHS Genomic Medicine Service panels, reflecting strong evidence for its role in specific clinical presentations. These panels include Childhood Onset Dystonia, Chorea or Related Movement Disorder, Early Onset Dystonia, Neurotransmitter Disorders, and Likely Inborn Error of Metabolism, among others. The gene's inclusion on the Intellectual Disability panel and multiple movement disorder panels underscores its relevance when evaluating children with unexplained developmental delays accompanied by motor symptoms. Presence on the Undiagnosed Metabolic Disorders panel highlights SPR as a consideration in complex metabolic investigations where tetrahydrobiopterin deficiency may not be immediately apparent.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does it mean to be a carrier of an SPR variant?
Carrying one pathogenic SPR variant means you have one working copy and one non-working copy of the gene. Carriers typically experience no symptoms because one functional copy produces sufficient sepiapterin reductase enzyme. However, if both parents are carriers, each pregnancy has a 25% chance of inheriting two pathogenic variants, which would cause sepiapterin reductase deficiency.
How is sepiapterin reductase deficiency diagnosed?
Diagnosis generally involves biochemical testing of cerebrospinal fluid to measure neurotransmitter metabolites and pterins, which reveal characteristic patterns when BH4 production is impaired. Genetic testing confirming biallelic pathogenic SPR variants provides definitive diagnosis. Early recognition is important because some treatments aim to supplement deficient neurotransmitters.
Why is SPR included on NHS movement disorder panels?
SPR appears on multiple NHS panels because sepiapterin reductase deficiency presents with movement abnormalities such as dystonia and tremor that overlap with other neurological conditions. Including SPR on these panels ensures clinicians consider tetrahydrobiopterin deficiency when evaluating children with unexplained movement disorders, enabling accurate diagnosis and appropriate management.
References
- Longo N. Disorders of biopterin metabolism. Journal of inherited metabolic disease. 2009. PMID: 19234759