MID1 — Mediated Wiki

{{Short description|Protein-coding gene in humans}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox_gene}} '''MID1''' is a protein that belongs to the Tripartite motif family (TRIM) and is also known as TRIM18.<ref name="Quaderi 1997">{{cite journal | vauthors = Quaderi NA, Schweiger S, Gaudenz K, Franco B, Rugarli EI, Berger W, Feldman GJ, Volta M, Andolfi G, Gilgenkrantz S, Marion RW, Hennekam RC, Opitz JM, Muenke M, Ropers HH, Ballabio A | title = Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22 | journal = Nature Genetics | volume = 17 | issue = 3 | pages = 285–91 | date = November 1997 | pmid = 9354791 | doi = 10.1038/ng1197-285 | hdl = 2066/24575 | s2cid = 5832037 | hdl-access = free }}</ref><ref name="Reymond 2001">{{cite journal | vauthors = Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L, Riganelli D, Zanaria E, Messali S, Cainarca S, Guffanti A, Minucci S, Pelicci PG, Ballabio A | title = The tripartite motif family identifies cell compartments | journal = The EMBO Journal | volume = 20 | issue = 9 | pages = 2140–51 | date = May 2001 | pmid = 11331580 | pmc = 125245 | doi = 10.1093/emboj/20.9.2140 }}</ref> The ''MID1'' gene is located on the short arm of the X chromosome and loss-of-function mutations in this gene are causative of the X-linked form of a rare developmental disease, Opitz G/BBB Syndrome.<ref name="Quaderi 1997" /><ref>{{cite journal | vauthors = Opitz JM | title = G syndrome (hypertelorism with esophageal abnormality and hypospadias, or hypospadias-dysphagia, or "Opitz-Frias" or "Opitz-G" syndrome)--perspective in 1987 and bibliography | journal = American Journal of Medical Genetics | volume = 28 | issue = 2 | pages = 275–85 | date = October 1987 | pmid = 3322001 | doi = 10.1002/ajmg.1320280203 }}</ref>

== The ''MID1'' gene and its product == The human ''MID1'' gene is located on the short arm of the X chromosome (Xp22.2) and includes 9 coding exons, spanning approximately 400 kb of the genome.<ref name="Quaderi 1997" /><ref name="Van den Veyver 1998">{{cite journal | vauthors = Van den Veyver IB, Cormier TA, Jurecic V, Baldini A, Zoghbi HY | title = Characterization and physical mapping in human and mouse of a novel RING finger gene in Xp22 | journal = Genomics | volume = 51 | issue = 2 | pages = 251–61 | date = July 1998 | pmid = 9722948 | doi = 10.1006/geno.1998.5350 }}</ref> Upstream to the first coding exon, the ''MID1'' gene employs alternative 5' untranslated exons and at least five alternative promoters that drive the transcription of the gene, resulting in several ''MID1'' transcript isoforms.<ref name="Landry 2002">{{cite journal | vauthors = Landry JR, Mager DL | title = Widely spaced alternative promoters, conserved between human and rodent, control expression of the Opitz syndrome gene MID1 | journal = Genomics | volume = 80 | issue = 5 | pages = 499–508 | date = November 2002 | pmid = 12408967 | doi = 10.1006/geno.2002.6863 }}</ref> The ''MID1'' gene encodes a 667 amino acid protein that belongs to the TRIM family. MID1 protein consists of a conserved N-terminal tripartite module composed of a RING domain, 2 B-Box domains (B-box 1 and B-box 2) and a coiled-coil region.<ref name="Quaderi 1997" /><ref name="Reymond 2001" /> Within the TRIM family, MID1 belongs to the C-I subgroup characterised by the presence, downstream to the tripartite motif, of a COS domain, a Fibronectin type III (FN3) repeat and a PRY-SPRY domain.<ref>{{cite journal | vauthors = Short KM, Cox TC | title = Subclassification of the RBCC/TRIM superfamily reveals a novel motif necessary for microtubule binding | journal = The Journal of Biological Chemistry | volume = 281 | issue = 13 | pages = 8970–80 | date = March 2006 | pmid = 16434393 | doi = 10.1074/jbc.M512755200 | doi-access = free }}</ref>

== MID1 main cellular functions ==

=== MID1 as an E3 ubiquitin ligase === MID1 is a microtubular protein<ref>{{cite journal | vauthors = Schweiger S, Foerster J, Lehmann T, Suckow V, Muller YA, Walter G, Davies T, Porter H, van Bokhoven H, Lunt PW, Traub P, Ropers HH | title = The Opitz syndrome gene product, MID1, associates with microtubules | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 6 | pages = 2794–9 | date = March 1999 | pmid = 10077590 | pmc = 15848 | doi = 10.1073/pnas.96.6.2794 | bibcode = 1999PNAS...96.2794S | doi-access = free }}</ref><ref>{{cite journal | vauthors = Cainarca S, Messali S, Ballabio A, Meroni G | title = Functional characterization of the Opitz syndrome gene product (midin): evidence for homodimerization and association with microtubules throughout the cell cycle | journal = Human Molecular Genetics | volume = 8 | issue = 8 | pages = 1387–96 | date = August 1999 | pmid = 10400985 | doi = 10.1093/hmg/8.8.1387 | doi-access = }}</ref> that acts as an ubiquitin E3 ligase ''in vitro'' and in cells. Ubiquitination is a type of post-translational modification in which the transfer of one or several ubiquitin peptide molecules to substrates determines their stability and/or activity.<ref>{{cite journal | vauthors = Hershko A, Ciechanover A | title = The ubiquitin system | journal = Annual Review of Biochemistry | volume = 67 | pages = 425–79 | date = 1998 | pmid = 9759494 | doi = 10.1146/annurev.biochem.67.1.425 }}</ref> The MID1 E3 ubiquitin ligase activity is catalysed by the RING domain, a hallmark of one of the main classes of E3 ubiquitin ligases that, within the ubiquitination cascade, facilitate the transfer of the ubiquitin peptide to specific substrates.<ref name="troc 2001">{{cite journal | vauthors = Trockenbacher A, Suckow V, Foerster J, Winter J, Krauss S, Ropers HH, Schneider R, Schweiger S | title = MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation | journal = Nature Genetics | volume = 29 | issue = 3 | pages = 287–94 | date = November 2001 | pmid = 11685209 | doi = 10.1038/ng762 | s2cid = 34834612 }}</ref><ref>{{cite journal | vauthors = Han X, Du H, Massiah MA | title = Detection and characterization of the in vitro e3 ligase activity of the human MID1 protein | journal = Journal of Molecular Biology | volume = 407 | issue = 4 | pages = 505–20 | date = April 2011 | pmid = 21296087 | doi = 10.1016/j.jmb.2011.01.048 }}</ref><ref>{{cite journal | vauthors = Napolitano LM, Jaffray EG, Hay RT, Meroni G | title = Functional interactions between ubiquitin E2 enzymes and TRIM proteins | journal = The Biochemical Journal | volume = 434 | issue = 2 | pages = 309–19 | date = March 2011 | pmid = 21143188 | doi = 10.1042/BJ20101487 | s2cid = 5932399 | url = https://hal.archives-ouvertes.fr/hal-00565906/file/PEER_stage2_10.1042%252FBJ20101487.pdf }}</ref> Several MID1 E3 ubiquitin ligase targets have been reported: Alpha4 (α4) and its associated phosphatase, PP2A,<ref name="troc 2001" /> Fu,<ref name="Schweiger 2014">{{cite journal | vauthors = Schweiger S, Dorn S, Fuchs M, Köhler A, Matthes F, Müller EC, Wanker E, Schneider R, Krauß S | title = The E3 ubiquitin ligase MID1 catalyzes ubiquitination and cleavage of Fu | journal = The Journal of Biological Chemistry | volume = 289 | issue = 46 | pages = 31805–17 | date = November 2014 | pmid = 25278022 | pmc = 4231658 | doi = 10.1074/jbc.M113.541219 | doi-access = free }}</ref> Pax6<ref name="Pfi2016">{{cite journal | vauthors = Pfirrmann T, Jandt E, Ranft S, Lokapally A, Neuhaus H, Perron M, Hollemann T | title = Hedgehog-dependent E3-ligase Midline1 regulates ubiquitin-mediated proteasomal degradation of Pax6 during visual system development | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 36 | pages = 10103–8 | date = September 2016 | pmid = 27555585 | pmc = 5018744 | doi = 10.1073/pnas.1600770113 | bibcode = 2016PNAS..11310103P | doi-access = free }}</ref> and BRAF35.<ref>{{cite journal | vauthors = Zanchetta ME, Napolitano LM, Maddalo D, Meroni G | title = The E3 ubiquitin ligase MID1/TRIM18 promotes atypical ubiquitination of the BRCA2-associated factor 35, BRAF35 | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research| volume = 1864 | issue = 10 | pages = 1844–1854 | date = October 2017 | pmid = 28760657 | doi = 10.1016/j.bbamcr.2017.07.014 | doi-access = }}</ref>

=== MID1-α4-PP2A complex === Together with α4 and PP2A, MID1 can form a ternary complex in which α4 acts as an adaptor protein.<ref name="troc 2001" /> The data so far indicate that MID1 promotes α4 mono-ubiquitination, leading to its calpain-dependent cleavage<ref>{{cite journal | vauthors = Watkins GR, Wang N, Mazalouskas MD, Gomez RJ, Guthrie CR, Kraemer BC, Schweiger S, Spiller BW, Wadzinski BE | title = Monoubiquitination promotes calpain cleavage of the protein phosphatase 2A (PP2A) regulatory subunit α4, altering PP2A stability and microtubule-associated protein phosphorylation | journal = The Journal of Biological Chemistry | volume = 287 | issue = 29 | pages = 24207–15 | date = July 2012 | pmid = 22613722 | pmc = 3397847 | doi = 10.1074/jbc.M112.368613 | doi-access = free }}</ref> that in turn causes PP2A catalytic subunit (PP2Ac) polyubiquitination and proteasomal degradation.<ref name="troc 2001" /> Since PP2A is involved in many cellular processes,<ref>{{cite journal | vauthors = Sontag E | title = Protein phosphatase 2A: the Trojan Horse of cellular signaling | journal = Cellular Signalling | volume = 13 | issue = 1 | pages = 7–16 | date = January 2001 | pmid = 11257442 | doi = 10.1016/s0898-6568(00)00123-6 }}</ref> the MID1-α4-PP2A ternary complex may be involved in the regulation of several of them, mainly on microtubules. The complex can modulate mTORC1 signalling; indeed PP2A attenuates mTORC1 activity through dephosphorylation. By lowering PP2Ac levels, MID1 leads to increase mTORC1 signalling.<ref>{{cite journal | vauthors = Liu E, Knutzen CA, Krauss S, Schweiger S, Chiang GG | title = Control of mTORC1 signaling by the Opitz syndrome protein MID1 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 21 | pages = 8680–5 | date = May 2011 | pmid = 21555591 | pmc = 3102420 | doi = 10.1073/pnas.1100131108 | bibcode = 2011PNAS..108.8680L | doi-access = free }}</ref> Conversely, the lack or loss-of-function mutations of MID1 lead to increased levels of PP2A and, as a consequence, to a general hypo-phosphorylation of PP2A targets, included mTORC1. The signalling of mTORC1 is implicated in cytoskeletal dynamics, intracellular transport, cell migration, autophagy, protein synthesis, cell metabolism, so it is possible that MID1, by controlling PP2Ac, is ultimately implicated in some of these cellular processes.

=== MID1 and Sonic Hedgehog === MID1 is also involved is the Sonic Hedgehog (Shh) pathway.<ref>{{cite journal | vauthors = Ingham PW, McMahon AP | title = Hedgehog signaling in animal development: paradigms and principles | journal = Genes & Development | volume = 15 | issue = 23 | pages = 3059–87 | date = December 2001 | pmid = 11731473 | doi = 10.1101/gad.938601 | doi-access = free }}</ref> MID1 catalyses the ubiquitination and proteasomal-dependent cleavage of Fu, a kinase involved in Hedgehog signalling pathway.<ref name="Schweiger 2014" /> The cleavage of the kinase domain of Fu favours the translocation of the transcription factor GLI3A (activator form) in the nucleus.<ref name="Schweiger 2014" /><ref name="Krauss 2008">{{cite journal | vauthors = Krauss S, Foerster J, Schneider R, Schweiger S | title = Protein phosphatase 2A and rapamycin regulate the nuclear localization and activity of the transcription factor GLI3 | journal = Cancer Research | volume = 68 | issue = 12 | pages = 4658–65 | date = June 2008 | pmid = 18559511 | doi = 10.1158/0008-5472.CAN-07-6174 | doi-access = free }}</ref> In this way, GLI3A activates the expression of Shh target genes, leading to an increase of Shh signalling. The cross talk between MID1 and the Shh pathway is also supported by experimental evidence in model organisms.<ref name="Pfi2016" /><ref>{{cite journal | vauthors = Granata A, Quaderi NA | title = The Opitz syndrome gene MID1 is essential for establishing asymmetric gene expression in Hensen's node | journal = Developmental Biology | volume = 258 | issue = 2 | pages = 397–405 | date = June 2003 | pmid = 12798296 | doi = 10.1016/s0012-1606(03)00131-3 | doi-access = }}</ref>

== Role and expression during embryonic development == ''MID1'' is nearly ubiquitously expressed in all embryonic tissues, having an important function during development. Several model organisms have been used to study the expression pattern of ''MID1'' transcript at different times of gestation: mouse,<ref>{{cite journal | vauthors = Dal Zotto L, Quaderi NA, Elliott R, Lingerfelter PA, Carrel L, Valsecchi V, Montini E, Yen CH, Chapman V, Kalcheva I, Arrigo G, Zuffardi O, Thomas S, Willard HF, Ballabio A, Disteche CM, Rugarli EI | title = The mouse Mid1 gene: implications for the pathogenesis of Opitz syndrome and the evolution of the mammalian pseudoautosomal region | journal = Human Molecular Genetics | volume = 7 | issue = 3 | pages = 489–99 | date = March 1998 | pmid = 9467009 | doi = 10.1093/hmg/7.3.489 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Lancioni A, Pizzo M, Fontanella B, Ferrentino R, Napolitano LM, De Leonibus E, Meroni G | title = Lack of Mid1, the mouse ortholog of the Opitz syndrome gene, causes abnormal development of the anterior cerebellar vermis | journal = The Journal of Neuroscience | volume = 30 | issue = 8 | pages = 2880–7 | date = February 2010 | pmid = 20181585 | pmc = 6633954 | doi = 10.1523/JNEUROSCI.4196-09.2010 }}</ref> chicken,<ref>{{cite journal | vauthors = Richman JM, Fu KK, Cox LL, Sibbons JP, Cox TC | title = Isolation and characterisation of the chick orthologue of the Opitz syndrome gene, Mid1, supports a conserved role in vertebrate development | journal = The International Journal of Developmental Biology | volume = 46 | issue = 4 | pages = 441–8 | date = 2002 | pmid = 12141430 }}</ref><ref>{{cite journal | vauthors = Latta EJ, Golding JP | title = Regulation of PP2A activity by Mid1 controls cranial neural crest speed and gangliogenesis | journal = Mechanisms of Development | volume = 128 | issue = 11–12 | pages = 560–76 | date = 2011 | pmid = 22285438 | doi = 10.1016/j.mod.2012.01.002 | doi-access = free }}</ref> xenopus<ref name="Pfi2016" /><ref>{{cite journal | vauthors = Suzuki M, Hara Y, Takagi C, Yamamoto TS, Ueno N | title = MID1 and MID2 are required for Xenopus neural tube closure through the regulation of microtubule organization | journal = Development| volume = 137 | issue = 14 | pages = 2329–39 | date = July 2010 | pmid = 20534674 | doi = 10.1242/dev.048769 | doi-access = free }}</ref> and also human embryos.<ref>{{cite journal | vauthors = Pinson L, Augé J, Audollent S, Mattéi G, Etchevers H, Gigarel N, Razavi F, Lacombe D, Odent S, Le Merrer M, Amiel J, Munnich A, Meroni G, Lyonnet S, Vekemans M, Attié-Bitach T | title = Embryonic expression of the human MID1 gene and its mutations in Opitz syndrome | journal = Journal of Medical Genetics | volume = 41 | issue = 5 | pages = 381–6 | date = May 2004 | pmid = 15121778 | pmc = 1735763 | doi = 10.1136/jmg.2003.014829 }}</ref> At the very early stage of embryonic development, ''MID1'' is expressed in the primitive node where MID1 plays a pivotal role in establishing the molecular asymmetry at the node, which is crucial for the early definition of the laterality as embryonic development progresses. Later in embryogenesis, at the neurulation stage, ''MID1'' transcript is mainly observed in the cranial region of the developing neural folds. Starting from midgestation, the highest levels of ''MID1'' transcript are observed in the proliferating compartments of the central nervous system and in the epithelia of the developing branchial arches, craniofacial processes, optic vesicle, in the heart and in the gastrointestinal and urogenital system.

== Clinical significance == The ''MID1'' gene was identified concomitantly with the discovery that it was causatively mutated in patients with a rare genetic disease, the X-linked form of Opitz G/BBB syndrome (XLOS) (OMIM #300000).<ref name="Quaderi 1997" /> XLOS is a congenital malformative disorder characterised by defects in the embryonic development of midline structures. XLOS is characterised by high variability of the clinical signs and, being X-linked, males are generally affected. The most frequently observed signs are: dysmorphic features, mainly represented by hypertelorism often associated with cleft lip and palate, frontal bossing, large nasal bridge, and low-set ears. Laryngo-tracheo-esophageal abnormalities are also frequently observed in XLOS patients as well as external genitalia abnormalities that are predominantly represented by various-degree-hypospadias.<ref name="Fontanella 2008">{{cite journal | vauthors = Fontanella B, Russolillo G, Meroni G | title = MID1 mutations in patients with X-linked Opitz G/BBB syndrome | journal = Human Mutation | volume = 29 | issue = 5 | pages = 584–94 | date = May 2008 | pmid = 18360914 | doi = 10.1002/humu.20706 | doi-access = free }}</ref> In addition, XLOS patients can present cardiac abnormalities and anal defects.<ref name="Fontanella 2008" /> XLOS also shows a neurological component represented by cerebellar vermis hypoplasia and agenesis or hypoplasia of the corpus callosum accompanied by intellectual disabilities and developmental delays.<ref name="Fontanella 2008" /> Since its discovery as the causative gene for XLOS, approximately one hundred different pathogenetic mutations have been described in the ''MID1'' gene. Even though the type and the distribution of mutations suggested a loss-of-function mechanism in the pathogenesis of Opitz syndrome, the aetiology of the disease remains still unclear. Additional clinical conditions are described to be associated with alterations of ''MID1'', given also its implication in a wide variety of cellular mechanisms. In fact, involvement of ''MID1'' in asthma, cancer, and neurodegeneration relevant pathways has been reported.

==Notes== {{Academic-written review|Q=Q91863888}}

== References == {{reflist}}

== Further reading == {{refbegin | 2}} * {{cite book |last1=Meroni |first1=Germana |title=X-Linked Opitz G/BBB Syndrome |chapter=MID1-Related Opitz G/BBB Syndrome |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK1327/ |website=GeneReviews® |publisher=University of Washington, Seattle |date=1993|pmid=20301502 }} {{refend}}