Mutations in the Sepiapterin Reductase Gene Cause a Novel Tetrahydrobiopterin-Dependent Monoamine-Neurotransmitter Deficiency without Hyperphenylalaninemia

Abstract

Classic tetrahydrobiopterin (BH(4)) deficiencies are characterized by hyperphenylalaninemia and deficiency of monoamine neurotransmitters. In this article, we report two patients with progressive psychomotor retardation, dystonia, severe dopamine and serotonin deficiencies (low levels of 5-hydroxyindoleacetic and homovanillic acids), and abnormal pterin pattern (high levels of biopterin and dihydrobiopterin) in cerebrospinal fluid. Furthermore, they presented with normal urinary pterins and without hyperphenylalaninemia. Investigation of skin fibroblasts revealed inactive sepiapterin reductase (SR), the enzyme catalyzing the final two-step reaction in the biosynthesis of BH(4). Mutations in the SPR gene were detected in both patients and their family members. One patient was homozygous for a TC-->CT dinucleotide exchange, predicting a truncated SR (Q119X). The other patient was a compound heterozygote for a genomic 5-bp deletion (1397-1401delAGAAC) resulting in abolished SPR-gene expression and an A-->G transition leading to an R150G amino acid substitution and to inactive SR as confirmed by recombinant expression. The absence of hyperphenylalaninemia and the presence of normal urinary pterin metabolites and of normal SR-like activity in red blood cells may be explained by alternative pathways for the final two-step reaction of BH(4) biosynthesis in peripheral and neuronal tissues. We propose that, for the biosynthesis of BH(4) in peripheral tissues, SR activity may be substituted by aldose reductase (AR), carbonyl reductase (CR), and dihydrofolate reductase, whereas, in the brain, only AR and CR are fully present. Thus, autosomal recessive SR deficiency leads to BH(4) and to neurotransmitter deficiencies without hyperphenylalaninemia and may not be detected by neonatal screening for phenylketonuria.

The Silkworm Mutant lemon (lemon lethal) Is a Potential Insect Model for Human Sepiapterin Reductase Deficiency

“…These enzymes play an important role in the metabolism of aromatic amino acids and monoamine neurotransmitter biosynthesis (Fig. 1B) (1). Previous reports have shown that BH4 deficiency is associated with numerous metabolic syndromes and neuropsychological disorders (2,3).…”

“…Mammalian SPRs have been a focus of study in recent years. The major symptoms of SPR deficiency are mental retardation, dystonia, spasticity, and movement disorder (1,3). Diagnosis and therapy of SPR and/or BH4 deficiency-dependent genetic diseases, such as recessive DOPA-responsive dystonia and phenylketonuria, have been developed recently (3)(4)(5).…”

Sepiapterin reductase expression is increased in Parkinson's disease brain tissue

“…A few cases of human sepiapterin reductase deficiency, a BH 4 -dependent monoamine neurotransmitter deficiency without hyperphenylalaninemia, have been described in the literature Bonafe et al, 2001). A SPR knockout mouse has been created to model human sepiapterin reductase deficiency (Yang et al, 2006).…”

d‐threo‐tetrahydrobiopterin is synthesized via 1′‐oxo‐2′‐d‐hydroxypropyl‐tetrahydropterin inDictyostelium discoideumAx2

“…The results demonstrated an alternative synthesis of BH4 and DH4 in Dictyostelium in the absence of SR. The alternative synthesis of BH4 in vivo was suggested to be possible by the activities of CR(s) and AR [6,7] and recently identified in human SR deficient patients [8].…”

“…AR specifically reduces C2 0 carbonyl group and generates 1 0 -oxo-2 0 -L L-hydroxypropyl-tetrahydropterin (H4-pterin), which is further reduced to BH4 by SR. In the complete absence of SR activity, an alternative synthesis of BH4 was suggested to be possible by carbonyl reductase (CR) and AR [7] and was recently demonstrated in vivo through finding of human patients deficient in SR [8]. BH4 has two chiral carbons in its C6-side chain and therefore can exist as four different isomers.…”