MID1 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that belongs to the
Tripartite motif family The tripartite motif family (TRIM) is a protein family.
Function
Many TRIM proteins are induced by interferons, which are important component of resistance to pathogens and several TRIM proteins are known to be required for the restriction of infe ...
(TRIM) and is also known as TRIM18.
The ''MID1''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
is located on the short arm of the
X chromosome
The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex-d ...
and loss-of-function mutations in this gene are causative of the X-linked form of a rare developmental disease,
Opitz G/BBB Syndrome.
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.
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.
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.
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.
MID1 main cellular functions
MID1 as an E3 ubiquitin ligase
MID1 is a microtubular protein that acts as an ubiquitin E3 ligase ''in vitro'' and in cells.
Ubiquitination
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
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. 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.
Several MID1 E3 ubiquitin ligase targets have been reported: Alpha4 (α4) and its associated phosphatase, PP2A,
Fu,
Pax6
and BRAF35.
MID1-α4-PP2A complex
Together with α4 and
PP2A
Protein phosphatase 2 (PP2), also known as PP2A, is an enzyme that in humans is encoded by the ''PPP2CA'' gene. The PP2A heterotrimeric protein phosphatase is ubiquitously expressed, accounting for a large fraction of phosphatase activity in eu ...
, MID1 can form a ternary complex in which α4 acts as an adaptor protein.
The data so far indicate that MID1 promotes α4 mono-ubiquitination, leading to its calpain-dependent cleavage that in turn causes PP2A catalytic subunit (PP2Ac) polyubiquitination and proteasomal degradation.
Since PP2A is involved in many cellular processes, the MID1-α4-PP2A ternary complex may be involved in the regulation of several of them, mainly on
microtubules
Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nm and have an inner diameter between 11 an ...
. The complex can modulate mTORC1 signalling; indeed PP2A attenuates
mTORC1
mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.
mTOR Complex 1 (mTORC1) is compo ...
activity through dephosphorylation. By lowering PP2Ac levels, MID1 leads to increase mTORC1 signalling. 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
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular dire ...
,
autophagy
Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...
, 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
Sonic hedgehog protein (SHH) is encoded for by the ''SHH'' gene. The protein is named after the character ''Sonic the Hedgehog''.
This signaling molecule is key in regulating embryonic morphogenesis in all animals. SHH controls organogenesis and ...
(Shh) pathway. MID1 catalyses the ubiquitination and proteasomal-dependent cleavage of Fu, a kinase involved in Hedgehog signalling pathway.
The cleavage of the kinase domain of Fu favours the translocation of the transcription factor GLI3A (activator form) in the nucleus.
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.
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, chicken, xenopus
and also human embryos.
At the very early stage of embryonic development, ''MID1'' is expressed in the
primitive node
The primitive node (or primitive knot) is the organizer for gastrulation in most amniote embryos. In birds it is known as Hensen's node, and in amphibians it is known as the Spemann-Mangold organizer. It is induced by the Nieuwkoop center in am ...
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
Neurulation refers to the folding process in vertebrate embryos, which includes the transformation of the neural plate into the neural tube. The embryo at this stage is termed the neurula.
The process begins when the notochord induces the formati ...
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
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
and in the epithelia of the developing branchial arches, craniofacial processes,
optic vesicle
The eyes begin to develop as a pair of diverticula (pouches) from the lateral aspects of the forebrain. These diverticula make their appearance before the closure of the anterior end of the neural tube; after the closure of the tube around the 4th ...
, in the heart and in the gastrointestinal and
urogenital system
The genitourinary system, or urogenital system, are the organs of the reproductive system and the urinary system. These are grouped together because of their proximity to each other, their common embryological origin and the use of common pathw ...
.
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).
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
Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits (eyes), or orbital hypertelorism. In this condition the distance between the inner eye corners as ...
often associated with
cleft lip and palate
A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The ...
, 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
Hypospadias is a common variation in fetal development of the penis in which the urethra does not open from its usual location in the head of the penis. It is the second-most common birth abnormality of the male reproductive system, affecting abou ...
.
In addition, XLOS patients can present cardiac abnormalities and anal defects.
XLOS also shows a neurological component represented by
cerebellar vermis
The cerebellar vermis (from Latin ''vermis,'' "worm") is located in the medial, cortico-nuclear zone of the cerebellum, which is in the posterior fossa of the cranium. The primary fissure in the vermis curves ventrolaterally to the superior ...
hypoplasia
Hypoplasia (from Ancient Greek ὑπo- ''hypo-'' 'under' + πλάσις ''plasis'' 'formation'; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.agenesis In medicine, agenesis () refers to the failure of an organ to develop during embryonic growth and development due to the absence of primordial tissue. Many forms of agenesis are referred to by individual names, depending on the organ affected:
* A ...
or hypoplasia of the
corpus callosum
The corpus callosum (Latin for "tough body"), also callosal commissure, is a wide, thick nerve tract, consisting of a flat bundle of commissural fibers, beneath the cerebral cortex in the brain. The corpus callosum is only found in placental mam ...
accompanied by intellectual disabilities and developmental delays.
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
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
,
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
, and
neurodegeneration
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
relevant pathways has been reported.
Notes
References
Further reading
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{{PDB Gallery, geneid=4281