TMEM126B

TMEM126B is located on the q arm of chromosome 11 in position 14.1 and has 7 exons. The TMEM126B gene produces a 4.6 kDa protein composed of 54 amino acids.

{{cite journal | vauthors = Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P | display-authors = 6 | title = Integration of cardiac proteome biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | pages = 1043–53 | date = October 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }}{{Cite web|url=https://amino.heartproteome.org/web/protein/E9PJQ6|title=Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information|last=Yao|first=Daniel|website=amino.heartproteome.org|access-date=2018-07-27}}

It is a part of the mitochondrial complex I assembly (MCIA) complex, composed of NDUFAF1, ECSIT, and ACAD9 (by similarity). It associates with the intermediate 370 kDa subcomplex of incompletely assembled complex I.

{{Cite web|url=https://www.uniprot.org/uniprot/Q8IUX1|title=Complex I assembly factor TMEM126B, mitochondrial|website=www.uniprot.org|language=en|access-date=2018-07-27}}

Complex I is composed of 45 evolutionally conserved core subunits, including both mitochondrial DNA and nuclear encoded subunits. One of its arms is embedded in the inner membrane of the mitochondria, and the other is embedded in the organelle. The two arms are arranged in an L-shaped configuration. The total molecular weight of the complex is 1MDa.{{cite journal | vauthors = Rhein VF, Carroll J, Ding S, Fearnley IM, Walker JE | title = NDUFAF5 Hydroxylates NDUFS7 at an Early Stage in the Assembly of Human Complex I | journal = The Journal of Biological Chemistry | volume = 291 | issue = 28 | pages = 14851–60 | date = July 2016 | pmid = 27226634 | pmc = 4938201 | doi = 10.1074/jbc.M116.734970 | doi-access = free }} A cartoon representation of the predicted orientation of TMEM126B within cell membrane, tentatively based on the phosphorylation and hydrophobicity data is shown below.

File:Tmem126B cartoon2.jpg

{{Clear}}

The TMEM126B gene encodes a mitochondrial transmembrane protein which is a component of the mitochondrial complex I assembly complex. The encoded protein serves as an assembly factor that is required for formation of the membrane arm of the complex. TMEM126B comigrates with other assembly factors including ACAD9, CIA30, and ECSIT. In the absence of TMEM126B, such assembly factors were not recruited into the mitochondrial membrane, and did not participate in complex I assembly. Dysfunction of TMEM126B has known to cause several complications in complex I characterized by severe difficulties in mitochondrial respiration and the complete failure of complex I assembly. However, it is not known to have significant effect on the assemblies of mitochondrial complexes III, IV, and V.

{{cite journal | vauthors = Alston CL, Compton AG, Formosa LE, Strecker V, Oláhová M, Haack TB, Smet J, Stouffs K, Diakumis P, Ciara E, Cassiman D, Romain N, Yarham JW, He L, De Paepe B, Vanlander AV, Seneca S, Feichtinger RG, Płoski R, Rokicki D, Pronicka E, Haller RG, Van Hove JL, Bahlo M, Mayr JA, Van Coster R, Prokisch H, Wittig I, Ryan MT, Thorburn DR, Taylor RW | display-authors = 6 | title = Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype | journal = American Journal of Human Genetics | volume = 99 | issue = 1 | pages = 217–27 | date = July 2016 | pmid = 27374774 | pmc = 5005451 | doi = 10.1016/j.ajhg.2016.05.021 }}

Mutations in TMEM126B is known to result in mitochondrial diseases and associated disorders. It is majorly associated with a complex I deficiency, a deficiency in the first complex of the mitochondrial respiratory chain. A complex I deficiency involving the dysfunction of the mitochondrial respiratory chain may cause a wide range of clinical manifestations from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, Leigh syndrome, myopathy, liver disease, Leber hereditary optic neuropathy, and some forms of Parkinson disease. In addition to complex I deficiency, TMEM126B mutations also show association with severe multi-system disorders during infancy, such as chronic renal failure and cardiomyopathy, and myopathy in childhood or adulthood.

TMEM126B was first discovered in a study of protein expression in tissues of the hypothalamus-pituitary-adrenal axis using full cDNA cloning. It has since been detected in other tissues.{{cite journal | vauthors = Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA | display-authors = 6 | title = Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 26 | pages = 16899–903 | date = December 2002 | pmid = 12477932 | pmc = 139241 | doi = 10.1073/pnas.242603899 | bibcode = 2002PNAS...9916899M | doi-access = free }}

TMEM126B is located on chromosome 11 in humans, flanked by the following genes:{{cite web | title = TMEM126B in Map Viewer| url = https://www.ncbi.nlm.nih.gov/mapview/maps.cgi?TAXID=9606&CHR=11&MAPS=model,ugHs,ensgenes,rna,genes[85323889.04%3A85363310.96]-r&QSTR=55863[gene_id]&QUERY=uid%2816330121%29&ZOOM=0.0584}}

• DLG2: A member of the membrane-associated guanylate kinase family.
• TMEM126A: A paralog of TMEM126B expressed in the mitochondria.{{cite web | title = Entrez Gene: TMEM126A transmembrane protein 126A| url = https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&list_uids=84233}}
• CREBZF: Also known as the Zhangfei protein, a protein that interacts with herpes simplex virus.{{cite web | title = OMIM Zhangfei protein| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=omim&DbFrom=gene&Cmd=Link&LinkName=gene_omim&LinkReadableName=OMIM&IdsFromResult=58487}}

A conceptual translation of the TMEM126B protein, including a projection of the secondary structure,{{cite journal | vauthors = Burgess AW, Ponnuswamy PK, Sheraga HA |title=Analysis of conformations of amino acid residues and prediction of backbone topography in proteins. |journal=Israel Journal of Chemistry |volume=12 |issue= 1–2|pages= 239–286 |year= 1974 |doi= 10.1002/ijch.197400022}} predictions of transmembrane regions,{{cite journal | vauthors = Persson B, Argos P | title = Prediction of transmembrane segments in proteins utilising multiple sequence alignments | journal = Journal of Molecular Biology | volume = 237 | issue = 2 | pages = 182–92 | date = March 1994 | pmid = 8126732 | doi = 10.1006/jmbi.1994.1220 }} and putative phosphorylation{{cite web | title = NetPhos 2.0 predictions for TMEM126B| url = http://www.cbs.dtu.dk/cgi-bin/nph-webface?jobid=netphos,4BE2123100D1705A&opt=none}} and glycation sites{{cite web | title = NetGlycate 1.0 predictions for TMEM126B| url = http://www.cbs.dtu.dk/cgi-bin/nph-webface?jobid=netglycate,4BE2122A00D191C1&opt=none}} is included below:

File:Human proteins - Conceptual translation of TMEM126B.png

TMEM126B is expressed in most tissue types, with the notable exceptions of adipose tissue, ear tissue, the larynx, lymph tissue, nerve tissue, pituitary gland, spleen, thymus, thyroid, trachea, and umbilical cord.{{cite web | title = EST profile - Hs.525063| url = https://www.ncbi.nlm.nih.gov/UniGene/ESTProfileViewer.cgi?uglist=Hs.525063 }} It also appears to be highly expressed in parathyroid, bone marrow, and urinary bladder tissue. There is also evidence that one of the isoforms of TMEM126B is expressed in the cell membrane of memory B cells of the adaptive immune system.{{Cite web |title=WIPO - Search International and National Patent Collections - WO2009081254 - CELLS BELONGING TO THE ADAPTIVE IMMUNE SYSTEM THAT EXPRESS PAQ ISOFORM OF TMEM126B |url=https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009081254 |access-date=2025-05-23 |website=patentscope.wipo.int}}

File:Tmem126B expression.png

The following properties of TMEM126B were predicted using bioinformatic analysis:

• Molecular Weight: 22.7 KDal {{cite journal | vauthors = Brendel V, Bucher P, Nourbakhsh IR, Blaisdell BE, Karlin S | title = Methods and algorithms for statistical analysis of protein sequences | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 6 | pages = 2002–6 | date = March 1992 | pmid = 1549558 | pmc = 48584 | doi = 10.1073/pnas.89.6.2002 | bibcode = 1992PNAS...89.2002B | doi-access = free }}
• Isoelectric point: 9.02{{cite web |title= PI Program (Isoelectric Point Prediction) |url= http://www.embl-heidelberg.de/cgi/pi-wrapper.pl |url-status= dead |archive-url= https://web.archive.org/web/20081026062821/http://www.embl-heidelberg.de/cgi/pi-wrapper.pl |archive-date= 2008-10-26 }}
• TMEM126B orthologs have highly variable isoelectric points.
• Post-translational modification: several possible phosphorylation sites were detected, and a pair of possible glycation sites were predicted
• No signal peptide has been predicted.{{cite journal | vauthors = Bendtsen JD, Nielsen H, von Heijne G, Brunak S | title = Improved prediction of signal peptides: SignalP 3.0 | journal = Journal of Molecular Biology | volume = 340 | issue = 4 | pages = 783–95 | date = July 2004 | pmid = 15223320 | doi = 10.1016/j.jmb.2004.05.028 | citeseerx = 10.1.1.165.2784 }}

In addition to co-subunits for complex I, TMEM126B has protein-protein interactions with ECSIT, NDUFAF1, NDUFC2, NDUFA13, and others.

{{reflist}}

{{refbegin | 2}}

• {{cite journal | vauthors = Kiel DP, Demissie S, Dupuis J, Lunetta KL, Murabito JM, Karasik D | title = Genome-wide association with bone mass and geometry in the Framingham Heart Study | journal = BMC Medical Genetics | volume = 8 | pages = S14 | date = September 2007 | issue = Suppl 1 | pmid = 17903296 | pmc = 1995606 | doi = 10.1186/1471-2350-8-S1-S14 | doi-access = free }}
• {{cite journal | vauthors = Estrada K, Krawczak M, Schreiber S, van Duijn K, Stolk L, van Meurs JB, Liu F, Penninx BW, Smit JH, Vogelzangs N, Hottenga JJ, Willemsen G, de Geus EJ, Lorentzon M, von Eller-Eberstein H, Lips P, Schoor N, Pop V, de Keijzer J, Hofman A, Aulchenko YS, Oostra BA, Ohlsson C, Boomsma DI, Uitterlinden AG, van Duijn CM, Rivadeneira F, Kayser M | title = A genome-wide association study of northwestern Europeans involves the C-type natriuretic peptide signaling pathway in the etiology of human height variation | journal = Human Molecular Genetics | volume = 18 | issue = 18 | pages = 3516–24 | date = September 2009 | pmid = 19570815 | pmc = 2729669 | doi = 10.1093/hmg/ddp296 }}

{{refend}}