TMLHE

TMLHE
Identifiers
Aliases	TMLHE , AUTSX6, BBOX2, TMLD, TMLH, TMLHED, XAP130, D430017M14Rik, trimethyllysine hydroxylase, epsilon
External IDs	OMIM: 300777 MGI: 2180203 HomoloGene: 21853 GeneCards: TMLHE
Gene location (Human) Chr. X chromosome (human) [1] Band Xq28 Start 155,489,011 bp [1] End 155,719,098 bp [1]
RNA expression pattern Bgee Top expressed in skeletal muscle tissue gastrocnemius muscle blood left ventricle monocyte islet of Langerhans Ganglionic eminence smooth muscle tissue Right adrenal gland rectum More reference expression data BioGPS n/a
Gene ontology Molecular function iron ion binding oxidoreductase activity oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen metal ion binding dioxygenase activity trimethyllysine dioxygenase activity GO:0001948 protein binding Cellular component mitochondrial matrix mitochondrion Biological process negative regulation of oxidoreductase activity carnitine biosynthetic process Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	55217	192289
Ensembl	ENSG00000185973	ENSMUSG00000079834
UniProt	Q9NVH6	Q91ZE0
RefSeq (mRNA)	NM_001184797 NM_018196	NM_138758
RefSeq (protein)	NP_001171726 NP_060666	NP_620097
Location (UCSC)	Chr X: 155.49 – 155.72 Mb	n/a
PubMed search	[2]	[3]
Wikidata
View/Edit Human View/Edit Mouse

Trimethyllysine dioxygenase, mitochondrial is an enzyme that in humans is encoded by the TMLHE gene in chromosome X. ^{[4] [5] [6]} Mutations in the TMLHE gene resulting in carnitine biosynthesis disruption have been associated with autism symptoms. ^[7]

Structure

The TMHLE gene is located at the extreme end of the Xq28 region with high genomic instability, ^[8] and encodes a protein trimethyllysine dioxygenase, a, Fe2+ and 2-oxoglytarate dependent non-heme-ferrous iron hydrolase localized to the mitochondrial matrix. ^[9]

Function

The trimethyllysine dioxygenase enzyme catalyzes the first step in the carnitine biosynthesis pathway, ^[9] 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), ^{[10] [11]} an inborn error of metabolism in carnitine biosynthesis, which may increase the risks of developing neurodevelopmental disorders, autism-related behaviors, and autism spectrum disorders. ^{[12] [7]}

Interactions

TMLHE has been shown to have 14 binary protein-protein interactions including 12 co-complex interactions. TMLHE appears to interact with SUGCT. ^[13]

References

1. GRCh38: Ensembl release 89: ENSG00000185973 - Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. Rogner UC, Heiss NS, Kioschis P, Wiemann S, Korn B, Poustka A (October 1996). "Transcriptional analysis of the candidate region for incontinentia pigmenti (IP2) in Xq28". Genome Research. 6 (10): 922–34. doi: 10.1101/gr.6.10.922 . PMID   8908511.
5. Vaz FM, Ofman R, Westinga K, Back JW, Wanders RJ (September 2001). "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. doi: 10.1074/jbc.M105929200 . PMID   11431483.
6. "Entrez Gene: TMLHE trimethyllysine hydroxylase, epsilon".
7. Ziats MN, Comeaux MS, Yang Y, Scaglia F, Elsea SH, Sun Q, Beaudet AL, Schaaf CP (September 2015). "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. doi:10.1002/ajmg.a.37144. PMID   25943046. S2CID   205320608.
8. Monfregola J, Napolitano G, Conte I, Cevenini A, Migliaccio C, D'Urso M, Ursini MV (2007). "Functional characterization of the TMLH gene: promoter analysis, in situ hybridization, identification and mapping of alternative splicing variants". Gene. 395 (1–2): 86–97. doi:10.1016/j.gene.2007.02.012. PMID   17408883.
9. Monfregola J, Cevenini A, Terracciano A, van Vlies N, Arbucci S, Wanders RJ, D'Urso M, Vaz FM, Ursini MV (2005). "Functional analysis of TMLH variants and definition of domains required for catalytic activity and mitochondrial targeting". J. Cell. Physiol. 204 (3): 839–47. doi:10.1002/jcp.20332. PMID   15754339. S2CID   25224767.
10. 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 (2011). "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. doi:10.1093/hmg/ddr363. PMC   3196886 . PMID   21865298.
11. 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 (2012). "Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE". Transl Psychiatry. 2 (10): e179. doi:10.1038/tp.2012.102. PMC   3565810 . PMID   23092983.
12. "OMIM Entry - # 300872 - AUTISM, SUSCEPTIBILITY TO, X-LINKED 6; AUTSX6".
13. "14 binary interactions found for search term TMLHE". IntAct Molecular Interaction Database. EMBL-EBI. Retrieved 2018-08-25.

Further reading

• Hartley JL, Temple GF, Brasch MA (November 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC   310948 . PMID   11076863.
• Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S (September 2000). "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing". EMBO Reports. 1 (3): 287–92. doi:10.1093/embo-reports/kvd058. PMC   1083732 . PMID   11256614.
• Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A (October 2004). "From ORFeome to biology: a functional genomics pipeline". Genome Research. 14 (10B): 2136–44. doi:10.1101/gr.2576704. PMC   528930 . PMID   15489336.
• Monfregola J, Cevenini A, Terracciano A, van Vlies N, Arbucci S, Wanders RJ, D'Urso M, Vaz FM, Ursini MV (September 2005). "Functional analysis of TMLH variants and definition of domains required for catalytic activity and mitochondrial targeting". Journal of Cellular Physiology. 204 (3): 839–47. doi:10.1002/jcp.20332. PMID   15754339. S2CID   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 (January 2006). "The LIFEdb database in 2006". Nucleic Acids Research. 34 (Database issue): D415-8. doi:10.1093/nar/gkj139. PMC   1347501 . PMID   16381901.
• Monfregola J, Napolitano G, Conte I, Cevenini A, Migliaccio C, D'Urso M, Ursini MV (June 2007). "Functional characterization of the TMLH gene: promoter analysis, in situ hybridization, identification and mapping of alternative splicing variants". Gene. 395 (1–2): 86–97. doi:10.1016/j.gene.2007.02.012. PMID   17408883.