Alternative titles; symbols
HGNC Approved Gene Symbol: MID1
SNOMEDCT: 81771002;
Cytogenetic location: Xp22.2 Genomic coordinates (GRCh38) : X:10,445,310-10,833,683 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp22.2 | Opitz GBBB syndrome | 300000 | X-linked recessive | 3 |
MID1 plays a role in the ubiquitin-specific regulation of the microtubule-associated catalytic subunit of protein phosphatase 2Ac (PP2AC; see 176915), and a MID1/alpha-4 (IGBP1; 300139) complex is the core of a microtubule-associated mRNP complex that links cytoskeleton-associated mRNA transport and translation control factors with members of the mTOR (601231)/PP2A signaling cascade (summary by Aranda-Orgilles et al., 2008)
The study of a family in which the Opitz syndrome (300000) segregated with an X-chromosome inversion permitted Quaderi et al. (1997) to refine the position of the disease locus on Xp22, which they referred to as OSX (for Opitz syndrome, X-linked). By use of a positional cloning strategy within the OSX critical region, Quaderi et al. (1997) identified a novel gene, designated MID1 (midline-1), containing a RING finger motif. During their efforts to construct a transcription map of the Xp22 region, Quaderi et al. (1997) performed exon-trapping experiments on the cosmids contained in a previously described contig. One of the exon-trapping products was derived from the MID1 gene, which spans the Opitz syndrome inversion breakpoint. The MID1 protein belongs to a family of transcriptional regulators that contain protein-protein interaction domains and have been implicated in fundamental processes such as body axis patterning and cell transformation. The MID1 gene is ubiquitously expressed in both fetal and adult tissues and displays a transcript of approximately 7 kb that encodes a 667-amino acid protein.
Dal Zotto et al. (1998) cloned the murine homolog of MID1. Mid1 expression in undifferentiated cells in the central nervous, gastrointestinal, and urogenital systems suggested that abnormal cell proliferation may underlie the defect in midline development characteristic of Opitz syndrome. Dal Zotto et al. (1998) found that Mid1 is located within the mouse pseudoautosomal region in Mus musculus, whereas it seems to be X-specific in Mus spretus. Therefore, Mid1 is likely to be a recent acquisition of the M. musculus PAR. Genetic and fluorescence in situ hybridization analyses also demonstrated a high frequency of unequal crossovers in the murine PAR, creating spontaneous deletion/duplication events involving Mid1. These data provided evidence that genetic instability of the PAR may affect functionally important genes. MID1 is the first example of a gene subject to X inactivation in man while escaping it in mouse.
Perry et al. (1998) identified the 10-exon human FXY gene as a member of the RING finger family, characterized by the presence of an N-terminal zinc-binding domain. FXY also contains 4 additional domains: 2 potential zinc binding B box domains, a leucine coiled-coil domain characteristic of the 'RING B-box coiled-coil' (RBCC) subgroup of RING finger proteins, and a C-terminal domain conserved in several other RBCC proteins. Perry et al. (1998) determined that the human FXY cDNA encodes a 667-amino acid protein with 95% identity to the protein encoded by the mouse Fxy gene. A major RNA species of 7.4 kb and 2 minor RNAs of 4.3 and 2.6 kb were detected by Northern blot analysis in all adult human tissues tested. RT-PCR analysis demonstrated FXY expression in several 8- and 9-week human fetal tissues.
Pinson et al. (2004) used in situ hybridization on human embryo sections to study MID1 expression during development. They found strong expression in the central nervous system, particularly the hindbrain, as well as in gastrointestinal and respiratory tract epithelium, metanephros, anal folds, and a small area of the interventricular septum of the heart.
The MID1 gene contains 3 exons (Perry et al., 1998). Cox et al. (2000) showed that the MID1 gene spans at least 400 kb, almost twice the distance originally reported, and has a minimum of 6 mRNA isoforms as a result of the alternative use of 5-prime untranslated exons.
Dal Zotto et al. (1998) refined the cytogenetic localization of the human MID1 gene to Xp22.3.
Perry et al. (1998) demonstrated that the human FXY gene is located within Xp22.3, proximal to the human pseudoautosomal boundary. This finding provided further evidence for the addition-attrition theory (Graves, 1995), which proposes that divergence of the mammalian X and Y chromosomes has occurred through cyclical addition of autosomal segments onto the PAR of either the X or Y chromosome. The autosomal addition is then recombined onto its partner, resulting in an enlarged PAR. Meanwhile, the male-determining Y chromosome undergoes a series of rearrangements and deletions, reducing its homology with the X chromosome and gradually decreasing the size of the PAR as genes within this region lose their homologous Y-chromosome partner and become X-unique. The change in location of the STS gene from its presumed original PAR location to Xp22, proximal to the PAR, in humans has been presented as evidence for the addition-attrition theory. Southern blot hybridization analysis of male and female human genomic DNA demonstrated that FXY is probably X-linked; this was suggested by comparison of the signal obtained from DNA derived from the 2 sexes. To locate the gene more precisely, PCR primers derived from exon 2 were used to screen the Genebridge 4 radiation hybrid mapping panel. The localization to Xp22.3 was confirmed by mapping of an EST present in the Unigene database encompassing the 3-prime end of FXY. FXY was also mapped against 2 YAC contigs. They showed that the gene is flanked by 2 previously characterized genes, AMELX and CLCN4 (302910).
Cainarca et al. (1999) referred to the protein encoded by the MID1 gene as midin. They stated that the putative 667-amino acid protein contains a so-called tripartite motif (a RING motif, 2 B-boxes, and a coiled-coil motif) and an RFP-like domain. The tripartite motif is characteristic of a family of proteins, named the B-box family, involved in cell proliferation and development. Since the subcellular compartment and the ability to form multiprotein structures both appear to be crucial for the function of this family of proteins, Cainarca et al. (1999) studied these properties on the wildtype and mutated forms of midin. They found that endogenous midin is associated with microtubules throughout the cell cycle, colocalizing with cytoplasmic fibers in interphase and with mitotic spindle and midbodies during mitosis and cytokinesis. Immunoprecipitation experiments demonstrated the ability of the tripartite motif to mediate midin homodimerization, consistent with the evidence, obtained by gel filtration analysis, that midin exists in the form of large protein complexes. Functional characterization of altered forms of midin, resulting from mutations found in Opitz syndrome patients, revealed that association with microtubules is compromised, while the ability to homodimerize and form multiprotein complexes is retained. Thus, Cainarca et al. (1999) suggested that midin is involved in the formation of multiprotein structures acting as anchor points to microtubules and that impaired association with these cytoskeletal structures causes the developmental defects of Opitz syndrome. (The RFP-like domain was first described in the RET finger protein (RFP; 602165).)
By using GFP as a tag, Schweiger et al. (1999) showed that MID1 is a microtubule-associated protein that influences microtubule dynamics in MID1-overexpressing cells. They confirmed this observation by demonstrating a colocalization of MID1 and tubulin (see 191130) in subcellular fractions and the association of endogenous MID1 with microtubules after in vitro assembly. Furthermore, overexpressed MID1 proteins harboring mutations described in Opitz syndrome patients lack the capability to associate with microtubules, forming cytoplasmic clumps instead. These data gave an idea of the possible molecular pathomechanism underlying the Opitz syndrome phenotype.
Wildtype Mid1 colocalizes predominantly with microtubules, in contrast to mutant versions of Mid1 that appear clustered in the cytosol. Using yeast 2-hybrid screening, Liu et al. (2001) found that the alpha-4 subunit (IGBP1; 300139) of protein phosphatases-2A, -4, and -6 bound Mid1. Localization of Mid1 and the alpha-4 subunit was influenced by one another in transiently transfected cells. Mid1 could recruit the alpha-4 subunit onto microtubules, and high levels of the alpha-4 subunit could displace Mid1 into the cytosol. Metabolic (32)P labeling of cells revealed Mid1 to be a phosphoprotein, and coexpression of the full-length alpha-4 subunit decreased Mid1 phosphorylation, indicative of a functional interaction. Association of GFP-Mid1 with microtubules in living cells was perturbed by inhibitors of MAP kinase activation. Liu et al. (2001) concluded that Mid1 association with microtubules, which seems important for normal midline development, is regulated by dynamic phosphorylation involving MAP kinase and protein phosphatase that is targeted specifically to Mid1 by the alpha-4 subunit. Human birth defects may result from environmental or genetic disruption of this regulatory cycle.
Using yeast 2-hybrid and coimmunoprecipitation analyses, Berti et al. (2004) found that mouse Mid1 interacted with Mig12 (MID1IP1; 300961). When coexpressed in mammalian cells, the 2 proteins colocalized and induced formation of microtubule bundles containing acetylated tubulin. Mig12 and Mid1 protected microtubules against depolymerizing agents, but neither protein stabilized microtubules when expressed alone. Interaction of Mig12 with Mid1 required the coiled-coil domain of Mid1. Both Mig12 and Mid1 also self-associated.
Aranda-Orgilles et al. (2008) found that MID1 associated with elongation factor-1-alpha (EF1A, or EEF1A1; 130590) and several other proteins involved in mRNA transport and translation, including RACK1 (GNB2L1; 176981), annexin A2 (ANXA2; 151740), nucleophosmin (NPM1; 164040), and proteins of the small ribosomal subunits. The cytoskeleton-bound MID1/translation factor complex, which also included alpha-4, specifically associated with G- and U-rich RNAs and incorporated MID1 mRNA, thus forming a microtubule-associated ribonucleoprotein complex. Mutant MID1 proteins found in Opitz syndrome patients lost the ability to interact with EF1A.
By knockdown and overexpression experiments in HEK293T cells, Chen et al. (2021) found that MID1 promoted viral infection. MID1 inhibited type I interferon (IFNI; see 147640) production during viral infection and thereby negatively regulated the IFNI antiviral response. As a ubiquitin E3 ligase, MID1 induced K48-linked polyubiquitination of IRF3 (603734) at lys313, which downregulated IRF3 through proteasome-dependent degradation and restricted IFNI production and the cellular antiviral response.
Palmer et al. (1997) identified a gene, which they symbolized Fxy for 'finger on X and Y,' that spans the mouse pseudoautosomal boundary on the X chromosome. The first 3 exons of the gene are located on the X chromosome, whereas the 3-prime exons of the gene are located on both the X and Y chromosomes. They proposed that the gene is at an intermediate stage in evolving from a pseudoautosomal location to one that is X-unique. The Fxy gene is identical to the Mid1 gene.
Perry and Ashworth (1999) reported that in humans, the rat, and the wild mouse species Mus spretus, the FXY (MID1) gene is entirely X-unique. They found that the rate of sequence divergence of the 3-prime end of the Fxy gene is much higher when pseudoautosomal than when X-unique. They therefore suggested that chromosomal position can directly affect the rate of evolution of a gene.
Quaderi et al. (1997) identified mutations in the MID1 gene in 3 Opitz syndrome families: a 3-bp deletion involving a methionine codon (300552.0001), a 24-bp duplication causing addition of 8 amino acids (300552.0002), and a 1-bp insertion resulting in a frameshift and loss of 101 amino acid residues (300552.0003). All these mutations were in the C-terminal region of the MID1 gene.
Among 15 patients with Opitz syndrome, Cox et al. (2000) identified 7 novel mutations in the MID1 gene, 2 of which disrupt the N terminus of the protein. The most severe of these, glu115 to ter (E115X; 300552.0005), is predicted to truncate the protein before the B-box motifs. Another mutation, leu626 to pro (L626P; 300552.0004), represented the most C-terminal alteration reported to date. Green fluorescent protein (GFP) fusion constructs of 2 N-terminal mutants showed no evidence of cytoplasmic aggregation, suggesting that this feature is not pathognomonic for X-linked Opitz syndrome.
Pinson et al. (2004) identified 1 previously reported and 5 novel mutations in the MID1 gene in 14 patients with Opitz syndrome.
Among 63 male individuals referred to De Falco et al. (2003) as instances of sporadic or familial X-linked Opitz syndrome, they found novel mutations of the MID1 gene in 11. The mutations were scattered throughout the gene, although more were represented in the 3-prime region. The low frequency of mutations in MID1 and the high variability of the phenotype suggested the involvement of other genes in the OS phenotype.
So et al. (2005) identified 10 novel mutations in the MID1 gene in 70 patients with Opitz syndrome.
In a family with X-linked Opitz syndrome (300000), Quaderi et al. (1997, 1997) identified a 3-bp deletion in the MID1 gene involving a methionine codon.
In a family with X-linked Opitz syndrome (300000), Quaderi et al. (1997, 1997) identified a 24-bp duplication in the MID1 gene causing the addition of 8 amino acids to the protein product.
In a family with X-linked Opitz syndrome (300000), Quaderi et al. (1997, 1997) identified a 1-bp insertion in the MID1 gene, resulting in a frameshift and loss of 101 amino acid residues in the protein product.
In an isolated patient, Cox et al. (2000) identified a 1877T-C transition in MID1, resulting in a leu626-to-pro substitution in the carboxyl B30.2 domain of the protein.
In an isolated patient, Cox et al. (2000) identified a 343G-T transversion in MID1, resulting in a glu115-to-ter substitution in the N terminus and truncation of the protein C-terminal to the B-box motifs. Unlike wildtype MID1, cells transiently transfected with this mutant construct in the form of a GFP fusion protein did not colocalize with microtubules.
In a patient with Opitz syndrome (300000), Winter et al. (2003) identified a duplication of the first exon of the MID1 gene. The diagnosis of Opitz syndrome was made soon after birth on the basis of a combination of characteristic symptoms. Anal atresia, a rectourethral fistula, and a bifid scrotum were found. In addition, he had a complex heart defect (coarctation of the aorta, patent ductus arteriosus and atrial septal defect secundum type, and abnormal venous return) and a tracheoesophageal cleft. Facial abnormalities comprised hypertelorism, mild downslanting of palpebral fissures, and posteriorly rotated ears. The mother was heterozygous for the duplication and showed mild hypertelorism, a tracheoesophageal cleft, and esophageal stenosis, which was surgically corrected.
In a carrier mother and 2 affected sons with Opitz syndrome (300000), So et al. (2005) identified an 884T-C transition in exon 4 of the MID1 gene, predicting a leu295-to-pro substitution (L295P). At the age of 2 years, the older son had evident hypertelorism, cleft lip and palate, hypospadias, a small midline epigastric defect, ureteral dilatation, and, in infancy, he had an enlarged fontanel. The younger son, examined at age 4.5 months, had hypertelorism, hypospadias, and an enlarged fontanel. The mother had hypertelorism, a small midline epigastric defect, and lacked an incisor.
In an Opitz syndrome (300000) family with affected members in 3 generations, So et al. (2005) found a 2-bp deletion in exon 8 of the MID1 gene (1545delGA), resulting in a frameshift. A grandfather had hypertelorism, a history of swallowing difficulties as an infant, tracheoesophageal fistula, and anal atresia. A carrier daughter had telecanthus and epicanthic folds. Her son was noted at birth to have hypertelorism, cleft lip, laryngotracheal cleft, septal defect, and hypospadias.
In a patient with Opitz syndrome (300000), Ferrentino et al. (2007) identified a 712G-T transversion in exon 2 of the MID1 gene, resulting in a glu238-to-ter (E238X) substitution. The mutant protein would lack the whole C-terminal region, resulting in a loss of function.
Zhang et al. (2011) identified the E238X mutation in 2 Swedish brothers with hypospadias and hypertelorism, but no other features of Opitz syndrome. These authors suggested that hypospadias associated with hypertelorism is the mildest phenotype in Opitz syndrome caused by MID1 mutations. The mutation was not found in 95 controls.
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