rs104893665 — SPR Arg150Gly

Pathogenic missense variant in sepiapterin reductase that abolishes BH4 biosynthesis, causing dopamine and serotonin deficiency in the brain; homozygosity or compound heterozygosity causes DOPA-responsive dystonia (SPR deficiency, OMIM

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SPR Arg150Gly — The Most Common SPR Deficiency Missense Variant

The arginine at position 150 in sepiapterin reductase sits in the heart of the enzyme's active site, within a beta-strand that is conserved across all vertebrates. The Arg150Gly substitution — the only single-nucleotide change possible at c.448 of NM_003124.5 that creates a glycine — replaces a large, positively charged residue with the smallest amino acid in the genetic code, disrupting the active-site geometry and completely abolishing the enzyme's ability to reduce sepiapterin to tetrahydrobiopterin11 tetrahydrobiopterin
BH4 — the essential cofactor for tyrosine hydroxylase, tryptophan hydroxylase, and all nitric oxide synthase isoforms. This is the most common pathogenic missense variant in SPR, identified in approximately 14 of the first 43 published patients with confirmed SPR deficiency.

The Mechanism

Sepiapterin reductase catalyses the NADPH-dependent reduction of sepiapterin to (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) in the final step of the de novo BH4 biosynthesis pathway. BH4 acts as an essential cofactor for three critical neurotransmitter-synthesis enzymes: tyrosine hydroxylase (which converts tyrosine to L-DOPA, the precursor of dopamine and norepinephrine), tryptophan hydroxylase (which converts tryptophan to 5-HTP, the serotonin precursor), and nitric oxide synthase. The arginine at position 150 anchors the substrate within the enzyme's NADPH-binding pocket. Recombinant expression of the p.Arg150Gly protein confirms completely absent SPR enzyme activity22 Recombinant expression of the p.Arg150Gly protein confirms completely absent SPR enzyme activity, a more severe biochemical loss than many SPR missense variants.

Unlike GCH1 and PTS deficiencies (which impair upstream BH4 biosynthesis and elevate blood phenylalanine), SPR deficiency does not cause hyperphenylalaninemia because the liver's alternative BH4 recycling pathway (via QDPR/dihydropteridine reductase) maintains adequate hepatic BH4. The brain, however, is heavily dependent on de novo BH4 synthesis and lacks effective recycling compensation — so neuronal dopamine and serotonin synthesis collapses while peripheral phenylalanine metabolism appears normal. This is why SPR deficiency completely escapes standard PKU newborn screening and is typically diagnosed only after years of unexplained motor and cognitive symptoms.

The Evidence

The pathogenicity of Arg150Gly is established at the highest ClinVar evidence tier: VCV000012941 carries multi-submitter review status with no conflicts across nine independent laboratory submissions, all classifying the variant as pathogenic for dopa-responsive dystonia due to sepiapterin reductase deficiency. OMIM catalogues it as allelic variant 182125.0003.

Bonafé et al. (2001)33 Bonafé et al. (2001) — the landmark paper establishing SPR deficiency as a disease entity — first described Arg150Gly in a 9-year-old Turkish boy with compound heterozygosity (R150G plus a 5-bp genomic deletion). Recombinant expression confirmed that the substitution abolished enzyme activity. CSF analysis showed markedly reduced HVA and 5-HIAA with elevated biopterin, consistent with downstream dopamine and serotonin depletion.

Friedman et al. (2012)44 Friedman et al. (2012) extended the clinical picture across 43 patients at 23 international centres. Arg150Gly was identified in 14 patients — the most frequent single missense variant in this cohort — predominantly in individuals of Mediterranean descent (Spanish, Turkish, Italian). The defining clinical features were axial hypotonia, dystonia with diurnal fluctuation (worse in the afternoon, partially relieved by sleep), oculogyric crises, and developmental delay. Average time from symptom onset to correct diagnosis was 9.1 years; the vast majority of patients had been misdiagnosed with cerebral palsy. Treatment response to levodopa/carbidopa was described as dramatic, with further benefit from adding 5-HTP.

A 27-year-old homozygous Arg150Gly patient described by Bonafé et al. developed delayed childhood development, low IQ, abnormal gait, oculomotor apraxia, dysarthria, weakness, generalized dystonia, myoclonus, choreoathetosis, and hypersomnolence (requiring 13 hours of sleep daily). Initial levodopa produced marked clinical improvement but also dose-limiting dyskinesias, illustrating that treatment titration in this condition requires specialist involvement.

Practical Actions

For heterozygous carriers, one functional SPR allele is sufficient for normal BH4 production. Carrier parents of affected children are obligate heterozygotes and do not themselves develop SPR deficiency. The primary clinical significance of carrier status is reproductive: two carriers have a 25% chance per pregnancy of an affected (biallelic) child.

For biallelic Arg150Gly — or for compound heterozygotes combining this allele with another pathogenic SPR variant — first-line treatment is levodopa/carbidopa (0.1–16 mg/kg/day at a 4:1 levodopa:inhibitor ratio) combined with 5-HTP (1–6 mg/kg/day). Early initiation, ideally in the first year of life, produces the best cognitive and motor outcomes. Motor responses are typically more complete than cognitive recovery when treatment is delayed past infancy.

Interactions

Arg150Gly at codon 150 and the nonsense variants at codon 251 (rs121917747, Lys251Ter) and codon 119 (rs121917746, Gln119Ter) all abolish SPR enzyme function through different mechanisms. A compound heterozygote inheriting Arg150Gly on one allele and any of these loss-of-function variants on the other will express the full SPR deficiency phenotype, because both alleles are non-functional. This genotypic constellation is clinically indistinguishable from homozygous deficiency. The SPR protein's interaction with the broader BH4 pathway means that any SPR deficiency also secondarily impairs nitric oxide synthase function, contributing to the autonomic dysfunction (temperature dysregulation, excessive sweating) seen in approximately half of affected patients.

Nutrient Interactions

tetrahydrobiopterin (BH4) impaired_conversion
levodopa increased_need
5-hydroxytryptophan (5-HTP) increased_need

Genotype Interpretations

What each possible genotype means for this variant.

AA Non-Carrier Normal

No SPR Arg150Gly allele — full sepiapterin reductase activity

With two intact SPR alleles (both Arg150), the de novo BH4 synthesis pathway functions normally. BH4 cofactor availability supports tyrosine hydroxylase (dopamine/norepinephrine), tryptophan hydroxylase (serotonin), and nitric oxide synthase across all tissues. You do not carry a pathogenic SPR allele that could cause sepiapterin reductase deficiency in offspring unless your partner also carries one. No specific supplementation or neurological monitoring is warranted on the basis of this variant.

GG SPR Deficiency Deficient

Homozygous Arg150Gly — sepiapterin reductase completely non-functional; severe dopamine and serotonin deficiency

With two copies of Arg150Gly, neither SPR allele can produce functional sepiapterin reductase. Recombinant expression studies confirm completely absent enzyme activity — among the most severe biochemical outcomes documented for any SPR missense variant. The metabolic consequence is sepiapterin accumulation in CSF and urine (the diagnostic hallmark) and collapse of BH4-dependent neurotransmitter synthesis in the central nervous system.

Clinical presentation typically emerges in the first year of life with axial hypotonia, oculogyric crises, and dystonia that fluctuates diurnally — worse in the afternoon as dopamine stores are depleted across the waking day and partially restored after sleep. Additional features include autonomic dysfunction (temperature dysregulation, excessive sweating), cognitive delay, and hypersomnolence. Unlike PKU-associated BH4 deficiency, blood phenylalanine remains normal — making this condition invisible to standard newborn PKU screening. Typical diagnostic delay in published cohorts is over nine years.

CSF analysis is diagnostic: markedly reduced HVA (dopamine metabolite) and 5-HIAA (serotonin metabolite), elevated sepiapterin and biopterin, normal to slightly elevated neopterin. Urinary sepiapterin is a non-invasive supplementary biomarker.

Treatment is well-established and often produces dramatic improvement: L-DOPA/ carbidopa (0.1–16 mg/kg/day at a 4:1 levodopa:inhibitor ratio) combined with 5-HTP (1–6 mg/kg/day). Outcomes are substantially better when treatment is initiated in the first year of life. Motor responses are typically more complete than cognitive recovery, particularly when treatment is delayed past infancy. Some centres add folinic acid as an adjunct, though this is not universally standardised.

AG Carrier Carrier

Heterozygous carrier of SPR Arg150Gly — one functional allele retained, no BH4 deficiency syndrome

One functional SPR allele supports normal de novo BH4 synthesis under all typical physiological conditions. Parents of confirmed SPR-deficient children — who are obligate heterozygotes — do not develop dystonia or neurotransmitter deficiency themselves. Clinical SPR deficiency requires biallelic loss of function.

The primary clinical significance of carrier status is reproductive. SPR deficiency follows autosomal recessive inheritance: if both parents carry a pathogenic SPR variant (on different alleles), each pregnancy has a 25% chance of a biallelic (affected) child, 50% chance of a carrier, and 25% chance of a non-carrier. Arg150Gly is the most common pathogenic SPR missense variant and has been reported at modestly elevated carrier frequency in Mediterranean populations.

There is no published evidence that heterozygous SPR carriers have measurably reduced BH4 levels or increased neurological risk under normal conditions.