Reduced thiamine binding is a novel mechanism for TPK deficiency disorder

  • Wenjie Huang
  • Jiao Qin
  • Dingdong Liu
  • Yan Wang
  • Xiaofei Shen
  • Na Yang
  • Hui Zhou
  • Xiao-Tang Cai
  • Zhi-Ling Wang
  • Dan Yu
  • Rong Luo
  • Qingxiang Sun
  • Yong-Mei XieEmail author
  • Da JiaEmail author
Original Article


Thiamine pyrophosphokinase (TPK) converts thiamine (vitamin B1) into thiamine pyrophosphate (TPP), an essential cofactor for many important enzymes. TPK1 mutations lead to a rare disorder: episodic encephalopathy type thiamine metabolism dysfunction. Yet, the molecular mechanism of the disease is not entirely clear. Here we report an individual case of episodic encephalopathy, with familial history carrying a novel homozygous TPK1 mutation (p.L28S). The L28S mutation leads to reduced enzymatic activity, both in vitro and in vivo, without impairing thiamine binding and protein stability. Thiamine supplementation averted encephalopathic episodes and restored the patient’s developmental progression. Biochemical characterization of reported TPK1 missense mutations suggested reduced thiamine binding as a new disease mechanism. Importantly, many disease mutants are directly or indirectly involved in thiamine binding. Thus, our study provided a novel rationale for thiamine supplementation, so far the major therapeutic intervention in TPK deficiency.


Neurological disorder Thiamine metabolism TPK1 Disease mechanism and treatment 



We thank our patients and their families and our coworkers. This research is supported by Natural Science Foundation of China (NSFC) grants (#80502629 to Q.S., and #31671477, #31871429, and #91854121 to D.J.), and Sichuan Science and Technology Program (2018RZ0128 to D.J.).

Author contributions

YMX and DJ conceived and supervised the project. WH, JQ, and DL performed biochemical work with assistance from YW, XS, NY and FX, YMX diagnosed the patient with assistance from HZ, XTC, ZLW, DY and RL, QS and DJ performed structural analysis. YMX and DJ prepared the manuscript. The authors declare no conflict of interest.

Compliance with ethical standards

Research involving human participants and/or animal rights

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Supplementary material

438_2018_1517_MOESM1_ESM.pdf (309 kb)
Supplemental Information includes three figures and one table. (PDF 309 KB)
438_2018_1517_MOESM2_ESM.xlsx (13 kb)
Supplementary Table 1: TPK1 deficiency: patient features and biochemical properties of mutant proteins. (XLSX 13 KB)


  1. Banka S, de Goede C, Yue WW, Morris AAM, von Bremen B, Chandler KE, Feichtinger RG, Hart C, Khan N, Lunzer V, Mataković L, Marquardt T, Makowski C, Prokisch H, Debus O, Nosaka K, Sonwalkar H, Zimmermann FA, Sperl W, Mayr JA (2014) Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: a treatable neurological disorder caused by TPK1 mutations. Mol Genet Metab 113:301–306CrossRefGoogle Scholar
  2. Brown G (2014) Defects of thiamine transport and metabolism. J Inherit Metab Dis 37:577–585CrossRefGoogle Scholar
  3. Bunik VI, Tylicki A, Lukashev NV (2013) Thiamin diphosphate-dependent enzymes: from enzymology to metabolic regulation, drug design and disease models. FEBS J 280:6412–6442CrossRefGoogle Scholar
  4. Chenna R, Sugawara H, Koike T, Lopez R, Gibson TJ, Higgins DG, Thompson JD (2003) Multiple sequence alignment with the clustal series of programs. Nucleic Acids Res 31:3497–3500CrossRefGoogle Scholar
  5. Fraser JL, Vanderver A, Yang S, Chang T, Cramp L, Vezina G, Lichter-Konecki U, Cusmano-Ozog KP, Smpokou P, Chapman KA, Zand DJ (2014) Thiamine pyrophosphokinase deficiency causes a Leigh Disease like phenotype in a sibling pair: identification through whole exome sequencing and management strategies. Mol Genet Metab Rep 1:66–70CrossRefGoogle Scholar
  6. Gangolf M, Czerniecki J, Radermecker M, Detry O, Nisolle M, Jouan C, Martin D, Chantraine F, Lakaye B, Wins P, Grisar T, Bettendorff L (2010) Thiamine status in humans and content of phosphorylated thiamine derivatives in biopsies and cultured cells. PLoS One 5:e13616CrossRefGoogle Scholar
  7. Iacobazzi V, Ventura M, Fiermonte G, Prezioso G, Rocchi M, Palmieri F (2001) Genomic organization and mapping of the gene (SLC25A19) encoding the human mitochondrial deoxynucleotide carrier (DNC). Cytogenet Cell Genet 93:40–42CrossRefGoogle Scholar
  8. Invernizzi F, Panteghini C, Chiapparini L, Moroni I, Nardocci N, Garavaglia B, Tonduti D (2017) Thiamine-responsive disease due to mutation of tpk1: Importance of avoiding misdiagnosis. Neurology 89:870–871CrossRefGoogle Scholar
  9. Jia D, Zhang JS, Li F, Wang J, Deng Z, White MA, Osborne DG, Phillips-Krawczak C, Gomez TS, Li H, Singla A, Burstein E, Billadeau DD, Rosen MK (2016) Structural and mechanistic insights into regulation of the retromer coat by TBC1d5. Nat Commun 7:13305CrossRefGoogle Scholar
  10. Keller S, Vargas C, Zhao H, Piszczek G, Brautigam CA, Schuck P (2012) High-precision isothermal titration calorimetry with automated peak-shape analysis. Anal Chem 84:5066–5073CrossRefGoogle Scholar
  11. Kelley RI, Robinson D, Puffenberger EG, Strauss KA, Morton DH (2002) Amish lethal microcephaly: a new metabolic disorder with severe congenital microcephaly and 2-ketoglutaric aciduria. Am J Med Genet 112:318–326CrossRefGoogle Scholar
  12. Kril JJ (1996) Neuropathology of thiamine deficiency disorders. Metab Brain Dis 11:9–17CrossRefGoogle Scholar
  13. Labay V, Raz T, Baron D, Mandel H, Williams H, Barrett T, Szargel R, McDonald L, Shalata A, Nosaka K, Gregory S, Cohen N (1999) Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness. Nat Genet 22:300–304CrossRefGoogle Scholar
  14. Mahajan A, Sidiropoulos C (2017) TPK1 mutation induced childhood onset idiopathic generalized dystonia: Report of a rare mutation and effect of deep brain stimulation. J Neurol Sci 376:42–43CrossRefGoogle Scholar
  15. Manzetti S, Zhang J, van der Spoel D (2014) Thiamin function, metabolism, uptake, and transport. Biochemistry 53:821–835CrossRefGoogle Scholar
  16. Mayr Johannes A, Freisinger P, Schlachter K, Rolinski B, Zimmermann Franz A, Scheffner T, Haack Tobias B, Koch J, Ahting U, Prokisch H, Sperl W (2011) Thiamine pyrophosphokinase deficiency in encephalopathic children with defects in the pyruvate oxidation pathway. Am J Hum Genet 89:806–812CrossRefGoogle Scholar
  17. Nosaka K, Onozuka M, Nishino H, Nishimura H, Kawasaki Y, Ueyama H (1999) Molecular cloning and expression of a mouse thiamin pyrophosphokinase cDNA. J Biol Chem 274:34129–34133CrossRefGoogle Scholar
  18. Ogershok PR, Rahman A, Nestor S, Brick J (2002) Wernicke encephalopathy in nonalcoholic patients. Am J Med Sci 323:107–111CrossRefGoogle Scholar
  19. Onozuka M, Nosaka K (2003) Steady-state kinetics and mutational studies of recombinant human thiamin pyrophosphokinase. J Nutr Sci Vitaminol (Tokyo) 49:156–162CrossRefGoogle Scholar
  20. Rosenberg MJ, Agarwala R, Bouffard G, Davis J, Fiermonte G, Hilliard MS, Koch T, Kalikin LM, Makalowska I, Morton DH, Petty EM, Weber JL, Palmieri F, Kelley RI, Schaffer AA, Biesecker LG (2002) Mutant deoxynucleotide carrier is associated with congenital microcephaly. Nat Genet 32:175–179CrossRefGoogle Scholar
  21. Spiegel R, Shaag A, Edvardson S, Mandel H, Stepensky P, Shalev SA, Horovitz Y, Pines O, Elpeleg O (2009) SLC25A19 mutation as a cause of neuropathy and bilateral striatal necrosis. Ann Neurol 66:419–424CrossRefGoogle Scholar
  22. Sun Q, Yong X, Sun X, Yang F, Dai Z, Gong Y, Zhou L, Zhang X, Niu D, Dai L, Liu J-J, Jia D (2017) Structural and functional insights into sorting nexin 5/6 interaction with bacterial effector IncE. Signal Transduct Target Ther 2:17030CrossRefGoogle Scholar
  23. Timm DE, Liu J, Baker LJ, Harris RA (2001) Crystal structure of thiamin pyrophosphokinase. J Mol Biol 310:195–204CrossRefGoogle Scholar
  24. Yao J, Yang F, Sun X, Wang S, Gan N, Liu Q, Liu D, Zhang X, Niu D, Wei Y, Ma C, Luo ZQ, Sun Q, Jia D (2018) Mechanism of inhibition of retromer transport by the bacterial effector RidL. Proc Natl Acad Sci USA 115:E1446–E1454CrossRefGoogle Scholar
  25. Zeng WQ, Al-Yamani E, Acierno JS Jr, Slaugenhaupt S, Gillis T, MacDonald ME, Ozand PT, Gusella JF (2005) Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3. Am J Hum Genet 77:16–26CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of BiotherapySichuan UniversityChengduChina
  2. 2.Department of Pathology, West China HospitalSichuan UniversityChengduChina

Personalised recommendations