Alternative titles; symbolsTHIAMINE KINASEHGNC Approved Gene Symbol: TPK1Cytogenetic location: 7q35 Genomic coordinates (GRCh38): 7:144,451,940-144,836,423 (...
Alternative titles; symbols
HGNC Approved Gene Symbol: TPK1
Cytogenetic location: 7q35 Genomic coordinates (GRCh38): 7:144,451,940-144,836,423 (from NCBI)
Thiamine pyrophosphokinase (TPK; EC 220.127.116.11) is a cellular enzyme involved in the regulation of thiamine metabolism. TPK catalyzes the conversion of thiamine, a form of vitamin B1, to thiamine pyrophosphate (TDP, or TPP). TDP is an active cofactor for enzymes involved in glycolysis and energy production, including transketolase, pyruvate dehydrogenase, and alpha-ketoglutarate dehydrogenase (summary by Nosaka et al., 1999).
▼ Cloning and Expression
By EST database searching with the S. pombe TPK gene (tnr3), Nosaka et al. (1999) identified the mouse Tpk1 gene. Using mouse Tpk1 to screen a human liver cDNA library, Nosaka et al. (2001) identified the human counterpart, TPK1, which was independently cloned by Zhao et al. (2001). Both groups found that TPK1 encodes a deduced 243-amino acid protein that shares 89% sequence identity with the mouse Tpk1 protein. TPK1 has a molecular mass of 28 kD. By expressing a tagged TPK1 fusion protein in E. coli cells, Nosaka et al. (2001) observed TPK activity and concluded that the native TPK1 exists in the dimer form of identical subunits.
By Northern blot analysis, Nosaka et al. (1999) detected expression of mouse Tpk1 predominantly in kidney and liver, with very faint expression in heart, brain, and testis. In contrast to the tissue-specific expression of mouse Tpk1, Nosaka et al. (2001) reported broad expression of a human 2.5-kb TPK1 transcript. They detected very low expression in a variety of human tissues and relatively abundant expression in heart, kidney, and peripheral leukocytes. By Northern blot analysis, Zhao et al. (2001) detected broad expression of a 2.6-kb TPK1 transcript, with highest levels in testis and in those tissues involved in thiamine absorption (small intestine) and reabsorption (kidney). They also detected a smaller (1-1.5 kb), testis-specific TPK1 transcript.
From results of cell culture experiments, Nosaka et al. (1999) and Nosaka et al. (2001) concluded that thiamine or a thiamine derivative does not participate in the regulation of TPK1. Nosaka et al. (2001) detected no difference in TPK1 expression in cultured fibroblasts from normal subjects or from patients with thiamine-responsive megaloblastic anemia (249270).
▼ Gene Structure
Nosaka et al. (2001) determined that the TPK1 gene contains at least 8 exons and spans over 420 kb of genomic DNA.
By fluorescence in situ hybridization, Nosaka et al. (2001) mapped the TPK1 gene to chromosome 7q34.
▼ Molecular Genetics
In 5 patients from 3 unrelated families with episodic encephalopathy due to thiamine metabolism dysfunction syndrome-5 (THMD5; 614458), Mayr et al. (2011) identified homozygous or compound heterozygous mutations in the TPK1 gene (606370.0001-606370.0005). The phenotype was highly variable, but in general, affected individuals had onset in early childhood of acute encephalopathic episodes associated with increased serum and CSF lactate. These episodes resulted in progressive neurologic dysfunction manifest as gait disturbances, ataxia, dystonia, and spasticity, which in some cases resulted in loss of ability to walk. Cognitive function was usually preserved, although mildly delayed development was present in 1 case. These episodes were associated with infection and metabolic decompensation.
▼ ALLELIC VARIANTS ( 5 Selected Examples):
.0001 THIAMINE METABOLISM DYSFUNCTION SYNDROME 5 (EPISODIC ENCEPHALOPATHY TYPE)
In 2 sisters with episodic encephalopathy due to thiamine metabolism dysfunction syndrome-5 (THMD5; 614458), Mayr et al. (2011) identified compound heterozygosity for 2 mutations in the TPK1 gene: a 148A-C transversion resulting in an asn50-to-his (N50H) substitution in a highly conserved residue, and an A-to-T transversion in intron 7 (501+4A-T; 606370.0002) resulting in a decrease in the splice efficiency of exon 7 and a transcript lacking exon 7 (val199_pro167). Immunoblot analysis of patient cell extracts showed a clear decrease of the full-length TPK1 protein. The N50H mutation occurs close to the conserved asp46 that is involved in magnesium binding. These girls showed a more severe phenotype compared to other patients with TPK1 mutations reported by Mayr et al. (2011). The older sister showed developmental delay from the first year of life, and lost the ability to walk after an infection-induced encephalopathic episode at age 15 months. During this episode, she had increased serum and CSF lactate. She started to walk again at 3 years of age, but continued to show muscular hypotonia and delayed psychomotor development. She had 2 further crises with encephalopathy and lactic acidosis triggered by viral infections, and died during the last crisis at the age of 8.5 years. Her sister showed normal development until she presented with an episode of ataxia and disturbed gait associated with increased CSF lactate; she only partially recovered. At age 2 years, she presented with truncal ataxia, was unable to walk, and showed slight dystonia of the upper limbs. She died at the age of 3.5 years during a viral infection. Both girls showed episodic increased urinary alpha-ketoglutaric acid.
.0002 THIAMINE METABOLISM DYSFUNCTION SYNDROME 5 (EPISODIC ENCEPHALOPATHY TYPE)
TPK1, IVS7DS, A-T, +4
For discussion of the splice site mutation in the TPK1 gene (501+4A-T) that was found in compound heterozygous state in 2 sisters with episodic encephalopathy due to thiamine metabolism dysfunction syndrome-5 (THMD5; 614458) by Mayr et al. (2011), see 606370.0001.
.0003 THIAMINE METABOLISM DYSFUNCTION SYNDROME 5 (EPISODIC ENCEPHALOPATHY TYPE)
In 2 sibs, born of consanguineous Iraqi parents with thiamine metabolism dysfunction syndrome-5 (THMD5; 614458), Mayr et al. (2011) identified a homozygous 119T-C transition in the TPK1 gene, resulting in a leu40-to-pro (L40P) substitution between the first alpha helix and a following beta-sheet, close to the conserved asp46 that is involved in magnesium binding. Immunoblot analysis of patient cell extracts showed a clear decrease of the full-length TPK1 protein. Both showed normal development during the first 3 years of life, but developed progressive spasticity, dystonia, and eventual loss of gait starting at age 4. The girl lost the ability to speak, developed seizures, and was wheelchair-bound at age 11 years; however, cognition was intact. Brain MRI showed global brain atrophy and increased signal intensities in the globus pallidus, and MR spectroscopy showed a lactate peak in the basal ganglia. Urinary organic acids showed elevated alpha-ketoglutaric acid and 3-hydroxyisovaleric acid. She also had mild left ventricular hypertrophy. Her younger brother had progressive dystonia, walking difficulties, and mild microcephaly, but he had adequate cognitive development at age 7 years, and brain MRI was normal.
.0004 THIAMINE METABOLISM DYSFUNCTION SYNDROME 5 (EPISODIC ENCEPHALOPATHY TYPE)
TPK1, 4-BP DEL, 179GAGA
In a patient with thiamine metabolism dysfunction syndrome-5 (THMD5; 614458), Mayr et al. (2011) identified compound heterozygosity for 2 mutations in the TPK1 gene: a 4-bp deletion (179delGAGA), resulting in premature termination and most likely a nonfunctional protein, and a 656A-G transition resulting in an asn219-to-ser (N219S; 606370.0005) substitution in a highly conserved residue in the C-terminal part of the protein close to the binding site for thiamine. Immunoblot analysis of patient cell extracts showed a clear decrease of the full-length TPK1 protein. The patient had a relatively mild form of the disorder. Beginning at age 2 years, he had several episodes of dizziness and vertigo, as well as intermittent gait ataxia, but all episodes showed spontaneous remission. At age 10.5 years, he had loss of speech, headache, seizures, and extensor plantar responses. Brain CT was normal, but he soon developed cerebellar and bulbar signs, with dysarthria, intention tremor, confusion, episodic ataxia, and nystagmus. Serum and CSF lactate were increased, and MRI showed changes in the white matter of the cerebellum, increased signal intensities in the corticospinal tract at the medulla oblongata, and slightly increased intensities in the dorsal pons. He fell into a coma and had to be intubated. This episode was followed by slow regression of clinical signs in the following months. At age 17 years, he had normal mental development and attended high school.
.0005 THIAMINE METABOLISM DYSFUNCTION SYNDROME 5 (EPISODIC ENCEPHALOPATHY TYPE)
For discussion of the asn219-to-ser (N219S) mutation in the TPK1 gene that was found in compound heterozygous state in a patient with thiamine metabolism dysfunction syndrome-5 (THMD5; 614458) by Mayr et al. (2011), see 606370.0004.