HGNC Approved Gene Symbol: TH
SNOMEDCT: 715827001;
Cytogenetic location: 11p15.5 Genomic coordinates (GRCh38): 11:2,163,929-2,171,815 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.5 | Segawa syndrome, recessive | 605407 | Autosomal recessive | 3 |
Tyrosine hydroxylase (EC 1.14.16.2) converts L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), the essential and rate-limiting step to formation of dopamine and other catecholamines (summary by Tolleson and Claassen, 2012).
Grima et al. (1985) reported the complete coding sequence of rat tyrosine hydroxylase mRNA.
O'Malley et al. (1987) isolated a full-length human genomic clone for TH. They demonstrated that the gene is present as a single copy and resembles the phenylalanine hydroxylase gene (PAH; 612349).
Kaneda et al. (1987) isolated clones corresponding to the TH gene from a human pheochromocytoma cDNA library. Four types of mRNA were identified, suggesting alternative splicing of a single gene. Grima et al. (1987) also demonstrated that, in man, TH molecules are encoded by 4 distinct mRNAs. Expression of these mRNAs varied in different parts of the nervous system. The sequence differences are confined to the 5-prime termini of the mRNAs and involve alternative splicing. The 4 types vary by the insertion/deletion of 12-bp and 81-bp sequences. The mode of alternative splicing is similar to that responsible for the 4 different mRNA types for myelin basic protein (159430).
Nagatsu and Ichinose (1991) reported that the type-1 through -4 TH transcripts encode proteins of 497, 501, 524, and 528 amino acids, respectively, with molecular masses ranging from 55.5 to 58.5 kD. TH type 1 contains a regulatory domain, a catalytic domain with 6 evolutionarily conserved cysteines, and several phosphorylation sites. Nagatsu and Ichinose (1991) stated that the 4 types of TH were expressed in human brain (substantia nigra and locus ceruleus) and adrenal medulla. Other mammals lack sequences corresponding to human exon 2 and produce only 1 type of TH that is homologous to human TH type 1.
O'Malley et al. (1987) demonstrated that the human TH gene contains 13 primary exons and spans approximately 8 kb. Human TH undergoes alternative RNA processing within intron 1, generating at least 3 distinct mRNAs. A comparison with the PAH gene indicated that although both probably evolved from a common ancestral gene, major changes in the size of introns have occurred since their divergence.
Kobayashi et al. (1988) determined that the TH gene contains 14 exons and spans about 8.5 kb. Alternative splicing results from use of 2 donor sites in exon 1 and inclusion/exclusion of exon 2. The TH gene has a canonical TATA box upstream of the putative initiation site.
Craig et al. (1985, 1986) assigned the human tyrosine hydroxylase gene to chromosome 11p15 using somatic cell hybridization and in situ hybridization, Homology of chromosomes 11 and 12 was further supported by the location of the TH gene on 11p and the PAH gene on 12q.
Moss et al. (1986) did multipoint mapping and suggested the following order: cen--HBB--2.9 cM--D11S12--9.1 cM--INS--3.2 cM--HRAS1--3.8 cM--TH--tel. In family linkage studies of chromosome 11p, the maximum lod score was 7.36 at theta = 0.04 for the linkage of insulin (INS; 176730) and TH. Also by multipoint mapping, Xue et al. (1988) put TH distal to HRAS (190020), which in turn is distal to INS. This means that TH is in the 11p15.5 region, the most distal part of 11p. O'Malley and Rotwein (1988) found that TH is 5-prime to INS and is separated by only 2.7 kb of flanking DNA. The 2 genes have the same transcriptional polarity and form a head-to-tail linkage group with IGF2 (147470).
Brilliant et al. (1987) mapped the mouse Th gene to chromosome 7 by a combination of genetic approaches: analysis of alleles defined by RFLPs both in recombinant inbred strains and in a large set of backcross mice.
Nagatsu and Ichinose (1991) found that type-1 TH had the highest TH activity of the 4 human TH isoforms, indicating that the inserted sequences in the other isoforms inhibit TH activity.
Meloni et al. (1998) suggested that an intronic polymorphic TCAT repeat in the TH gene, the microsatellite HUMTH01, may regulate transcription. Albanese et al. (2001) further showed that allelic variations of HUMTH01 commonly found in humans have a quantitative silencing effect on TH gene expression. Using a yeast 1-hybrid system, genes for 2 specific proteins, ZNF191 (194534), a zinc finger protein, and HBP1, an HMG box transcription factor, which bind the TCAT motif, were cloned. Allelic variations of HUMTH01 correlated with changes in the binding by ZNF191, as shown by an electrophoretic mobility shift assay. The authors hypothesized that the ubiquitous HUMTH01 core motif may contribute to the control of expression of numerous quantitative genetic traits.
Bodeau-Pean et al. (1999) identified a TH protein isoform lacking exon 3 in human adrenal medulla. The skipping of exon 3 resulted in the absence of activation of TH by heparin and increased by 10-fold the retroinhibition constant for dopamine, demonstrating the involvement of exon 3 in the regulation of TH enzymatic activity. Identification of a variably expressed TH isoform that lacks an exon implicated in activity regulation supported the view that TH alternative splicing contributes to the functional diversity within the catecholaminergic system and may be implicated in some neurologic diseases.
Goodwill et al. (1997) reported that the crystal structure of the catalytic and tetramerization domains of tyrosine hydroxylase reveals a novel alpha-helical basket holding the catalytic iron and a 40-angstrom long antiparallel coiled coil that forms the core of the tetramer. The catalytic iron is located 10 angstroms below the enzyme surface in a 17-angstrom deep active site pocket and is coordinated by the conserved residues his331, his336, and glu376. Tyrosine hydroxylase is highly homologous in terms of both protein sequence and catalytic mechanism to phenylalanine hydroxylase and tryptophan hydroxylase (TPH; 191060).
Nomenclature for TH Mutations
Wevers et al. (1999) noted that there have been 2 different nomenclature numbering systems for mutations in the TH gene: that based on the type-1 mRNA, which is missing parts of exons 1 and 2 (Ludecke et al., 1995; Knappskog et al., 1995), and that based on the full-length type-4 mRNA (Nagatsu and Ichinose, 1991). Wevers et al. (1999) provided a table comparing the 2 strategies, and used the mRNA type-4-based nomenclature, which is used here.
Autosomal Recessive Segawa Syndrome
Bartholome et al. (1993) and Ludecke et al. (1995) found linkage between Segawa syndrome (605407) and the TH gene in all of 6 families studied. In 1 family with 2 affected children, Ludecke et al. (1995) demonstrated a mutation in the TH gene (191290.0001). The family was Caucasian, and symptoms disappeared promptly after administering a low dose of levodopa in combination with a decarboxylase inhibitor. Former generations were not affected, suggesting that this is the autosomal recessive form of the disease. Gorke and Bartholome (1990) suggested that there are 2 forms of Segawa disease: one autosomal recessive and the other autosomal dominant (128230). Fletcher et al. (1989) could find no linkage of Segawa syndrome with the tyrosine hydroxylase locus in families with the dominantly inherited form, which is the same as dopa-responsive dystonia, which maps to chromosome 14 and is caused by mutation in the gene for GTP cyclohydrolase I (GCH1; 600225).
In an infant with autosomal recessive parkinsonism, Ludecke et al. (1996) identified a homozygous mutation in the TH gene (191290.0002). They noted that this mutation is positioned in the alpha-helical region of the TH protein. Ludecke et al. (1996) expressed the mutant gene in E. coli and human embryonic kidney cells. Expression of the mutant gene resulted in very low specific activity of the mutant protein as compared with the wildtype protein.
In patients from each of 2 families, Swaans et al. (2000) found compound heterozygosity for novel missense mutations for the TH gene as the basis of infantile-onset parkinsonism; see 191290.0004- 191290.0007. All 4 patients were in the fourth decade of life at the time of report and for more than 30 years had been able to live a normal life with low-dose L-DOPA medication.
Verbeek et al. (2007) identified 3 different mutations in the promoter region of the TH gene (see, e.g., 191290.0010) in 7 patients with Segawa syndrome. The mutations all occurred within the highly conserved cAMP response element.
Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In family 8600041, they identified a homozygous missense mutation in the TH gene (191290.0012) in 3 sibs with severe intellectual disability and a phenotype compatible with autosomal recessive Segawa syndrome. The parents, who were first cousins, had 3 healthy children.
Other Associations
De Benedictis et al. (1998) explored the possibility that 4 loci, REN (179820), TH, PARP (173870), and SOD2 (147460), are associated with longevity, by comparing the genotypic pools of subjects older than 100 years with those of younger subjects matched for sex and geographic area (northern and southern Italy). To reduce the number of genotypes, multiallelic polymorphisms were recoded as diallelic according to allele size and frequency patterns: small (S) and large (L) alleles. A significant loss of LL homozygous genotypes was found at the tyrosine hydroxylase locus in male but not in female centenarians with respect to matched controls. On the other hand, no significant difference was found between case/control genotypic frequencies at REN, PARP, and SOD2 loci.
The subtelomeric region of 11p (11p15.5) harbors 3 genes, IGF2, INS, and TH, that lie in that order, telomere to centromere, in an interval of less that 50 kb. These genes have been associated with obesity, size at birth, type I diabetes, polycystic ovary syndrome, overgrowth in Beckwith-Wiedemann syndrome, and possibly hypertension. Gu et al. (2002) examined 3 SNP markers in IGF2, and 1 marker each in INS and TH. They concluded that these markers independently predict derived weight indices, with no evidence of interaction. This established that there must be multiple causal sites affecting weight in this genomic region.
Rodriguez et al. (2004) haplotyped 2,743 adult males at the IGF2 (147470)-INS (176730)-TH region and related haplotypes to body weight and composition, blood pressure, and plasma triglycerides. Haplotype *5 protected against obesity; haplotype *6 was associated with raised plasma triglyceride levels. Haplotype *4, defined by the IGF2 ApaI (G), INS class III VNTR, and TH01 9.3 alleles, was associated with significantly higher fat mass and percentage fat, and with significantly higher diastolic blood pressure. Haplotype *8 showed similar magnitude of effects as *4. Haplotypes *4, *6, and *8 were the only INS VNTR class III-bearing haplotypes, although differing in flanking haplotype, whereas *5 displayed unique features in all 3 genes. The authors proposed that the long repeat insertion in the insulin gene promoter ('class III'), reported to result in low insulin production, may predispose to the metabolic syndrome features of elevated blood pressure, fat mass, or triglyceride level, therefore appearing more frequently in type 2 diabetic (see 125853), polycystic ovary syndrome (see 184700), and coronary heart disease cases.
Byerley et al. (1992) excluded the TH gene as the site of the mutation in 7 multigenerational pedigrees with bipolar, recurrent major depressive disorder (125480). One family out of 8 showed low positive lod scores with a maximum at theta = 0.00. Comings et al. (1995) found no association of tyrosine hydroxylase tetranucleotide repeat polymorphism to autism (e.g., 209850), Tourette syndrome (137580), or attention deficit-hyperactivity disorder (143465).
Catecholamines that are produced by the catecholamine biosynthetic pathway, in which tyrosine hydroxylase catalyzes the initial, rate-limiting step, include dopamine, noradrenaline, and adrenaline. These 3 catecholamines are important neurotransmitters and hormones that regulate visceral functions, motor coordination, and arousal in adults. The TH gene becomes transcriptionally active in developing neuroblasts during midgestation of rodent embryos, before the onset of neurotransmission. Zhou et al. (1995) showed that inactivation of both tyrosine hydroxylase alleles by gene targeting in embryonic stem cells results in midgestational lethality. About 90% of mutant embryos died between embryonic days 11.5 and 15.5, apparently of cardiovascular failure. Administration of L-DOPA (dihydroxyphenylalanine), the product of the tyrosine hydroxylase reaction, to pregnant females resulted in complete rescue of mutant mice in utero. Without further treatment, however, the TH-disrupted mutants died before weaning. Zhou et al. (1995) concluded that catecholamines are essential for mouse fetal development and postnatal survival. In an accompanying report, Thomas et al. (1995) reported that knockout of the gene encoding dopamine beta-hydroxylase (DBH; 223360), resulting in the inability to synthesize noradrenaline or adrenaline, caused fetal death. The DBH-knockout mutant embryos had a histologic phenotype similar to that of those mice deficient in TH, suggesting that death might also have been due to cardiovascular failure.
Zhou and Palmiter (1995) developed dopamine-deficient mice by inactivating the tyrosine hydroxylase gene, then restoring tyrosine hydroxylase functioning noradrenergic cells. Dopamine-deficient mice were born at expected frequency but became hypoactive and stopped feeding a few weeks after birth. Midbrain dopaminergic neurons, their projections, and most characteristics of their target neurons in the striatum appeared normal. Within a few minutes of being injected with L-DOPA, the dopamine-deficient mice became more active and consumed more food than control mice. With continued administration of L-DOPA, nearly normal growth was achieved. Zhou and Palmiter (1995) concluded that their studies indicate that dopamine is essential for movement and feeding, but is not required for the development of neural circuits that control these behaviors. Szczypka et al. (2000) generated mice lacking both dopamine and leptin by breeding to determine if leptin deficiency overcomes the aphagia of dopamine-deficient mice. Dopamine- and leptin-deficient mice became obese when treated daily with L-DOPA, but when L-DOPA treatment was terminated the double mutants were capable of movement but did not feed. Szczypka et al. (2000) concluded that their data show that dopamine is required for feeding in leptin-null mice.
To test the hypothesis that dopamine is an essential mediator of various opiate-induced responses, Hnasko et al. (2005) administered morphine to mice unable to synthesize dopamine (Zhou and Palmiter, 1995). Hnasko et al. (2005) found that dopamine-deficient mice were unable to mount a normal locomotor response to morphine, but a small dopamine-independent increase in locomotion remained. Dopamine-deficient mice had a rightward shift in the dose-response curve to morphine on the tail-flick test (a pain sensitivity assay), suggesting either a decreased sensitivity to the analgesic effects of morphine and/or basal hyperalgesia. In contrast, dopamine-deficient mice displayed a robust conditioned place preference for morphine when given either caffeine or L-dihydroxyphenylalanine (a dopamine precursor that restores dopamine throughout the brain) during the testing phases. Hnasko et al. (2005) concluded that dopamine is a crucial component of morphine-induced locomotion and may contribute to morphine analgesia, but that dopamine is not required for morphine-induced reward as measured by conditioned place preference.
Ludecke et al. (1995) studied 6 families containing 7 children affected with Segawa syndrome (605407); all were Caucasian. In the family with 2 affected sibs, they found a point mutation in exon 11 of the TH gene, resulting in a gln381-to-lys (GLN381LYS) amino acid exchange. One sister and both parents were heterozygous for this mutation, which was not found in 5 other families. Knappskog et al. (1995) demonstrated that the mutant enzyme had reduced affinity for L-tyrosine. Residual activity of about 15% of normal, at substrate concentrations prevailing in vivo, was considered compatible with the clinical phenotype of 2 homozygous sibs.
In a revised nomenclature numbering system, Wevers et al. (1999) noted that this mutation is a 1234C-A transversion in exon 12, resulting in a gln412-to-lys (Q412K) substitution.
In an infant with Segawa syndrome (605407), Ludecke et al. (1996) identified a homozygous 614T-C transition in exon 5 of the TH gene, resulting in a leu205-to-pro (LEU205PRO) substitution. The patient's parents were heterozygous for the mutation. The mutation is positioned in the alpha-helical region of the tyrosine hydroxylase protein. Functional expression of the mutant gene in E. coli and human embryonic kidney cells resulted in very low specific activity of the mutant protein compared to the wildtype protein.
In a revised nomenclature numbering system, Wevers et al. (1999) noted that this mutation is a 707T-C transition in exon 6, resulting in a leu236-to-pro (L236P) substitution.
In 3 patients originating from 3 unrelated Dutch families with autosomal recessive dopa-responsive dystonia (605407), van den Heuvel et al. (1998) identified a homozygous 698G-A transition in exon 6 of the TH gene, resulting in an arg233-to-his (R233H) substitution. The Dutch families studied by van den Heuvel et al. (1998) lived in various parts of the country. No patient was the offspring of a consanguineous mating. All children were born following a normal pregnancy and delivery, but hypokinetic rigidity and severe psychomotor delay became clear after the first months of life. No diurnal fluctuations in symptoms were observed. Low CSF HVA (homovanillic acid) and MHPG (3-methoxy-4-hydroxyphenyl ethylene glycol) in combination with normal CSF 5-HIAA (5-hydroxyindol acetic acid) strongly suggested tyrosine hydroxylase deficiency. Following treatment with L-DOPA and the decarboxylase inhibitor carbidopa, all children showed a rapid and spectacular clinical improvement, supporting the putative enzyme deficiency.
Brautigam et al. (1998) and Wevers et al. (1999) identified a homozygous R233H substitution in 3 unrelated Dutch patients with tyrosine-hydroxylase deficiency. A fourth patient was compound heterozygous for the R233H mutation and a 1-bp deletion in the TH gene (191290.0009).
Swaans et al. (2000) described compound heterozygosity for 2 mutations in the TH gene as the basis of infantile parkinsonism (605407) in 2 brothers: 1010G-A (arg337 to his) and a 1481C-T (thr494 to met; 191290.0005). The disease began with gait disturbance at the age of 2 years in one brother, and with a tremor of the hand at the age of 5 years in the other. The motor disturbance spread to the limbs, preventing all voluntary movements for the first brother. At the age of 5 years he was no longer able to walk. In his older brother, severe lordosis developed as well as an extension attitude of the lower limbs hindering gait. By the age of 9 years he could no longer walk. After 1 month of low-dose L-DOPA treatment in combination with carbidopa, motor performance normalized for both patients. Thirty years later the treatment was still continued without fluctuation of efficacy.
For discussion of the thr494-to-met (T494M) mutation in the TH gene that was found in compound heterozygous state in 2 sibs with infantile parkinsonism (605407) by Swaans et al. (2000), see 191290.0004.
Swaans et al. (2000) found compound heterozygosity for 2 missense mutations of the TH gene to be the cause of infantile-onset parkinsonism (605407) in a 34-year-old male of Belgian ancestry: 826A-C (T276P) and 941C-T (T314M; 191290.0007). The man's development had been normal until the age of 20 months when his motor development worsened; after 4 months he was no longer able to walk without support. By the age of 5, he was wheelchair-bound and completely dependent for the activities of daily life. At the age of 12 years, the diagnosis of hypokinetic rigid syndrome of infantile onset was made and low-dose treatment with L-DOPA in combination with benserazide started. Within a few days, a spectacular recuperation of motor function was observed; with medication he could pursue a normal education. Thirty years later he was working as an educator. Two sisters, with progressive rigidity from infancy, had died at a young age.
For discussion of the thr314-to-met (T314M) mutation in the TH gene that was found in compound heterozygous state in a patient with infantile-onset parkinsonism (605407) by Swaans et al. (2000), see 191290.0006.
Janssen et al. (2000) reported a branch site mutation in the TH gene: a T-to-A transversion at position -24, 2 bases upstream of the adenosine in the branchpoint sequence (BPS) of intron 11. As normal lariat formation was abrogated by the mutation, alternative splicing occurred. Use of the BPS of intron 12 resulted in skipping of exon 12, whereas use of a cryptic branch site in intron 11 led to partial retention of this intron in the mRNA. Both errors led to an aberrant protein product. In one case, skipping of exon 12 resulted in the absence of 32 amino acids. In the other case, retention of 36 nucleotides of intron 11 in the mRNA resulted in the incorporation of 12 additional amino acids. The functional consequences of this mutation for the patient, who was compound heterozygous for this and a previously identified mutation (R233H; 191290.0003), were apparent in a severe clinical phenotype (605407). The 8-year-old girl was 1 of 2 children with a progressive motor syndrome. A brother had died at the age of 9. She had been delivered by cesarean section 4 weeks before term because of fetal growth retardation and heart rate abnormalities. At the age of 4 months motor development stopped. At the age of 5 months she showed severe hypotonia. This turned into a severe generalized rigidity with a mask face and absence of voluntary movements at the age of 5 years and 7 months. There was no dystonia. She had oculogyric crises of several hours' duration. She had a severe extrapyramidal movement disorder. L-DOPA therapy with decarboxylase inhibitor led to a definite improvement and stabilization of the clinical course, but motor impairment remained severe.
Janssen et al. (2000) noted that mutations in branchpoint sequences are rare. Examples had been found in the FBN2 gene (612570.0006) associated with congenital contractural arachnodactyly (121050); in the LCAT gene (245900.0019) associated with fish-eye disease (136120); in the COL5A1 gene (120215.0006) associated with Ehlers-Danlos syndrome type II (130010); and in the L1CAM gene (308840.0014) associated with X-linked hydrocephalus (307000). In at least 2 of these cases as well as in the patient reported by Janssen et al. (2000), the mutation was located in the thymidine residue 2 basepairs upstream of the branchpoint adenosine residue, indicating the importance of that thymidine residue for proper lariat formation and subsequent splicing of pre-mRNA.
In a Dutch patient with Segawa syndrome (605407), Brautigam et al. (1998) and Wevers et al. (1999) identified compound heterozygosity for 2 mutations in the TH gene: a 1-bp deletion (291delC) in exon 3, resulting in premature termination, and the R233H mutation (191290.0003).
In 4 affected members of 2 unrelated families with Segawa syndrome (605407), Verbeek et al. (2007) identified a homozygous -70G-A transition in the promoter region of the TH gene. The mutation occurred within a conserved consensus sequence of the cAMP response element. Site-directed mutagenesis of the cAMP response element in the rat promoter region showed significantly decreased basal TH expression (Tinti et al., 1997).
In an Italian boy, born of consanguineous parents, with a severe form of Segawa syndrome (605407), Brautigam et al. (1999) identified a homozygous 1076G-T transversion in exon 10 of the TH gene, resulting in a cys359-to-phe (C359F) substitution in a highly conserved residue. The mutation was predicted to alter the secondary structure of the protein. The patient was born prematurely, showed respiratory distress, progressive hypotonia, dysphagia, hypokinesia, and reduced facial mimicry. He also had prolonged diurnal periods of lethargy with increased sweating alternative with irritability and rare sporadic dystonic movements. Brain MRI at age 5 months showed cerebral atrophy. CSF homovanillic acid (HVA) was undetectable. Response to L-DOPA treatment was limited and not as favorable as reported in other patients with the disorder.
In family 8600041, Najmabadi et al. (2011) identified a homozygous C-to-T transition in the TH gene at chr11:2145711 (NCBI36), resulting in an arg202-to-his substitution, in 3 sibs with severe intellectual disability and a phenotype compatible with autosomal recessive Segawa syndrome (605407). The parents, who were first cousins, had 3 healthy children.
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