TMLHE

{{Short description|Protein-coding gene in the species Homo sapiens}} {{Infobox_gene}} '''Trimethyllysine dioxygenase, mitochondrial''' is an enzyme that in humans is encoded by the ''TMLHE'' gene in chromosome X.<ref name="pmid8908511">{{cite journal | vauthors = Rogner UC, Heiss NS, Kioschis P, Wiemann S, Korn B, Poustka A | title = Transcriptional analysis of the candidate region for incontinentia pigmenti (IP2) in Xq28 | journal = Genome Research | volume = 6 | issue = 10 | pages = 922–34 | date = October 1996 | pmid = 8908511 | doi = 10.1101/gr.6.10.922 | doi-access = free }}</ref><ref name="pmid11431483">{{cite journal | vauthors = Vaz FM, Ofman R, Westinga K, Back JW, Wanders RJ | title = Molecular and Biochemical Characterization of Rat epsilon -N-Trimethyllysine Hydroxylase, the First Enzyme of Carnitine Biosynthesis | journal = The Journal of Biological Chemistry | volume = 276 | issue = 36 | pages = 33512–7 | date = September 2001 | pmid = 11431483 | doi = 10.1074/jbc.M105929200 | doi-access = free }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: TMLHE trimethyllysine hydroxylase, epsilon| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=55217}}</ref> Mutations in the ''TMLHE'' gene resulting in carnitine biosynthesis disruption have been associated with autism symptoms.<ref name=":0">{{cite journal | vauthors = Ziats MN, Comeaux MS, Yang Y, Scaglia F, Elsea SH, Sun Q, Beaudet AL, Schaaf CP | title = Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation | journal = American Journal of Medical Genetics. Part A | volume = 167A | issue = 9 | pages = 2162–7 | date = September 2015 | pmid = 25943046 | doi = 10.1002/ajmg.a.37144 | s2cid = 205320608 }}</ref>

== Structure ==

The ''TMHLE'' gene is located at the extreme end of the Xq28 region with high genomic instability,<ref>{{cite journal |vauthors=Monfregola J, Napolitano G, Conte I, Cevenini A, Migliaccio C, D'Urso M, Ursini MV |title=Functional characterization of the TMLH gene: promoter analysis, in situ hybridization, identification and mapping of alternative splicing variants |journal=Gene |volume=395 |issue=1–2 |pages=86–97 |year=2007 |pmid=17408883 |doi=10.1016/j.gene.2007.02.012 }}</ref> and encodes a protein trimethyllysine dioxygenase, a, Fe2+ and 2-oxoglytarate dependent non-heme-ferrous iron hydrolase localized to the mitochondrial matrix.<ref name="ReferenceA">{{cite journal |vauthors=Monfregola J, Cevenini A, Terracciano A, van Vlies N, Arbucci S, Wanders RJ, D'Urso M, Vaz FM, Ursini MV |title=Functional analysis of TMLH variants and definition of domains required for catalytic activity and mitochondrial targeting |journal=J. Cell. Physiol. |volume=204 |issue=3 |pages=839–47 |year=2005 |pmid=15754339 |doi=10.1002/jcp.20332 |s2cid=25224767 }}</ref>

== Function == The trimethyllysine dioxygenase enzyme catalyzes the first step in the carnitine biosynthesis pathway,<ref name="ReferenceA"/> 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),<ref>{{cite journal |vauthors=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 |title=Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE |journal=Hum. Mol. Genet. |volume=20 |issue=22 |pages=4360–70 |year=2011 |pmid=21865298 |pmc=3196886 |doi=10.1093/hmg/ddr363 }}</ref><ref>{{cite journal |vauthors=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 |title=Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE |journal=Transl Psychiatry |volume=2 |pages=e179 |year=2012 |issue=10 |pmid=23092983 |pmc=3565810 |doi=10.1038/tp.2012.102 }}</ref> an inborn error of metabolism in carnitine biosynthesis, which may increase the risks of developing neurodevelopmental disorders, autism-related behaviors, and autism spectrum disorders.<ref name=":0" /><ref>{{Cite web|url=http://www.omim.org/entry/300872|title = OMIM Entry - # 300872 - AUTISM, SUSCEPTIBILITY TO, X-LINKED 6; AUTSX6}}</ref><ref>{{cite journal |last1=Verthoeven |first1=Willem M A |last2=Pfundt |first2=Rolph |last3=Engelke |first3=Udo F H |last4=Kluijtmans |first4=Leo A J |last5=Egger |first5=Jos I M |date= 2025|title=X-Linked Autism Type 9 Caused by a Hemizygote Pathogenic Variant in the TMLHE Gene: Etiological Diagnosis in an Adult Male with Moderate Intellectual Disability |journal=International Medical Case Reports Journal |volume=18 |issue=18 |pages=111–16 |doi=10.2147/IMCRJ.S506204 |doi-access=free |pmc=11753900 |pmid=39845198 }} </ref>

== Interactions == TMLHE has been shown to have 14 binary protein-protein interactions including 12 co-complex interactions. TMLHE appears to interact with SUGCT.<ref>{{cite web | url = https://www.ebi.ac.uk/intact/interactions?conversationContext=3&query=TMLHE | title = 14 binary interactions found for search term TMLHE | work = IntAct Molecular Interaction Database | publisher = EMBL-EBI | access-date = 2018-08-25 }}</ref>

== References == {{reflist}}

== Further reading == {{refbegin | 2}} * {{cite journal | vauthors = Hartley JL, Temple GF, Brasch MA | title = DNA cloning using in vitro site-specific recombination | journal = Genome Research | volume = 10 | issue = 11 | pages = 1788–95 | date = November 2000 | pmid = 11076863 | pmc = 310948 | doi = 10.1101/gr.143000 }} * {{cite journal | vauthors = Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S | title = Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing | journal = EMBO Reports | volume = 1 | issue = 3 | pages = 287–92 | date = September 2000 | pmid = 11256614 | pmc = 1083732 | doi = 10.1093/embo-reports/kvd058 }} * {{cite journal | vauthors = Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A | title = From ORFeome to biology: a functional genomics pipeline | journal = Genome Research | volume = 14 | issue = 10B | pages = 2136–44 | date = October 2004 | pmid = 15489336 | pmc = 528930 | doi = 10.1101/gr.2576704 }} * {{cite journal | vauthors = Monfregola J, Cevenini A, Terracciano A, van Vlies N, Arbucci S, Wanders RJ, D'Urso M, Vaz FM, Ursini MV | title = Functional analysis of TMLH variants and definition of domains required for catalytic activity and mitochondrial targeting | journal = Journal of Cellular Physiology | volume = 204 | issue = 3 | pages = 839–47 | date = September 2005 | pmid = 15754339 | doi = 10.1002/jcp.20332 | s2cid = 25224767 }} * {{cite journal | vauthors = 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 | title = The LIFEdb database in 2006 | journal = Nucleic Acids Research | volume = 34 | issue = Database issue | pages = D415-8 | date = January 2006 | pmid = 16381901 | pmc = 1347501 | doi = 10.1093/nar/gkj139 }} * {{cite journal | vauthors = Monfregola J, Napolitano G, Conte I, Cevenini A, Migliaccio C, D'Urso M, Ursini MV | title = Functional characterization of the TMLH gene: promoter analysis, in situ hybridization, identification and mapping of alternative splicing variants | journal = Gene | volume = 395 | issue = 1–2 | pages = 86–97 | date = June 2007 | pmid = 17408883 | doi = 10.1016/j.gene.2007.02.012 }} {{refend}}

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