TMLHE explained

Trimethyllysine dioxygenase, mitochondrial is an enzyme that in humans is encoded by the TMLHE gene in chromosome X.^{[1] [2] [3]} Mutations in the TMLHE gene resulting in carnitine biosynthesis disruption have been associated with autism symptoms.^[4]

Structure

The TMHLE gene is located at the extreme end of the Xq28 region with high genomic instability,^[5] and encodes a protein trimethyllysine dioxygenase, a, Fe2+ and 2-oxoglytarate dependent non-heme-ferrous iron hydrolase localized to the mitochondrial matrix.^[6]

Function

The trimethyllysine dioxygenase enzyme catalyzes the first step in the carnitine biosynthesis pathway,^[6] which is part of amine biosynthesis. Carnitine is a molecule that play an essential role in the transport of activated fatty acids across the inner mitochondrial membrane where they are metabolized. The encoded protein converts trimethyllysine into hydroxytrimethyllysine with the reaction (EC 1.14.11.8):

N₆,N₆,N(6)-trimethyl-L-lysine + 2-oxoglutarate + O₂ = 3-hydroxy-N₆,N₆,N(6)-trimethyl-L-lysine + succinate + CO₂.

and requires iron and L-ascorbate as co-factors.

Clinical significance

Mutations in the TMLHE gene cause epsilon-trimethyllysine hydroxylase deficiency (TMLHED),^{[7] [8]} an inborn error of metabolism in carnitine biosynthesis, which may increase the risks of developing neurodevelopmental disorders, autism-related behaviors, and autism spectrum disorders.^[9]

Interactions

TMLHE has been shown to have 14 binary protein-protein interactions including 12 co-complex interactions. TMLHE appears to interact with SUGCT.^[10]

Further reading

• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–95 . November 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S . Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing . EMBO Reports . 1 . 3 . 287–92 . September 2000 . 11256614 . 1083732 . 10.1093/embo-reports/kvd058 .
• Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A . From ORFeome to biology: a functional genomics pipeline . Genome Research . 14 . 10B . 2136–44 . October 2004 . 15489336 . 528930 . 10.1101/gr.2576704 .
• Monfregola J, Cevenini A, Terracciano A, van Vlies N, Arbucci S, Wanders RJ, D'Urso M, Vaz FM, Ursini MV . Functional analysis of TMLH variants and definition of domains required for catalytic activity and mitochondrial targeting . Journal of Cellular Physiology . 204 . 3 . 839–47 . September 2005 . 15754339 . 10.1002/jcp.20332 . 25224767 .
• Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S . The LIFEdb database in 2006 . Nucleic Acids Research . 34 . Database issue . D415-8 . January 2006 . 16381901 . 1347501 . 10.1093/nar/gkj139 .
• Monfregola J, Napolitano G, Conte I, Cevenini A, Migliaccio C, D'Urso M, Ursini MV . Functional characterization of the TMLH gene: promoter analysis, in situ hybridization, identification and mapping of alternative splicing variants . Gene . 395 . 1–2 . 86–97 . June 2007 . 17408883 . 10.1016/j.gene.2007.02.012 .

Notes and References

1. Rogner UC, Heiss NS, Kioschis P, Wiemann S, Korn B, Poustka A . Transcriptional analysis of the candidate region for incontinentia pigmenti (IP2) in Xq28 . Genome Research . 6 . 10 . 922–34 . October 1996 . 8908511 . 10.1101/gr.6.10.922 . free .
2. Vaz FM, Ofman R, Westinga K, Back JW, Wanders RJ . Molecular and Biochemical Characterization of Rat epsilon -N-Trimethyllysine Hydroxylase, the First Enzyme of Carnitine Biosynthesis . The Journal of Biological Chemistry . 276 . 36 . 33512–7 . September 2001 . 11431483 . 10.1074/jbc.M105929200 . free .
3. Web site: Entrez Gene: TMLHE trimethyllysine hydroxylase, epsilon.
4. Ziats MN, Comeaux MS, Yang Y, Scaglia F, Elsea SH, Sun Q, Beaudet AL, Schaaf CP . Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation . American Journal of Medical Genetics. Part A . 167A . 9 . 2162–7 . September 2015 . 25943046 . 10.1002/ajmg.a.37144 . 205320608 .
5. Monfregola J, Napolitano G, Conte I, Cevenini A, Migliaccio C, D'Urso M, Ursini MV . Functional characterization of the TMLH gene: promoter analysis, in situ hybridization, identification and mapping of alternative splicing variants . Gene . 395 . 1–2 . 86–97 . 2007 . 17408883 . 10.1016/j.gene.2007.02.012 .
6. Monfregola J, Cevenini A, Terracciano A, van Vlies N, Arbucci S, Wanders RJ, D'Urso M, Vaz FM, Ursini MV . Functional analysis of TMLH variants and definition of domains required for catalytic activity and mitochondrial targeting . J. Cell. Physiol. . 204 . 3 . 839–47 . 2005 . 15754339 . 10.1002/jcp.20332 . 25224767 .
7. Celestino-Soper PB, Shaw CA, Sanders SJ, Li J, Murtha MT, Ercan-Sencicek AG, Davis L, Thomson S, Gambin T, Chinault AC, Ou Z, German JR, Milosavljevic A, Sutcliffe JS, Cook EH, Stankiewicz P, State MW, Beaudet AL . Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE . Hum. Mol. Genet. . 20 . 22 . 4360–70 . 2011 . 21865298 . 3196886 . 10.1093/hmg/ddr363 .
8. Nava C, Lamari F, Héron D, Mignot C, Rastetter A, Keren B, Cohen D, Faudet A, Bouteiller D, Gilleron M, Jacquette A, Whalen S, Afenjar A, Périsse D, Laurent C, Dupuits C, Gautier C, Gérard M, Huguet G, Caillet S, Leheup B, Leboyer M, Gillberg C, Delorme R, Bourgeron T, Brice A, Depienne C . Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE . Transl Psychiatry . 2 . e179 . 2012 . 10 . 23092983 . 3565810 . 10.1038/tp.2012.102 .
9. Web site: OMIM Entry - # 300872 - AUTISM, SUSCEPTIBILITY TO, X-LINKED 6; AUTSX6.
10. Web site: 14 binary interactions found for search term TMLHE . IntAct Molecular Interaction Database . EMBL-EBI . 2018-08-25 .