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MID1
midline 1
The MID1 gene provides instructions for the midline-1 protein, which is crucial for cellular structure, division, and the recycling of other vital proteins. MID1 is part of the tripartite motif (TRIM) family of genes, involved in numerous cellular activities, particularly the recycling of unwanted proteins.
MID1 is located on the short (p) arm of chromosome X, at band Xp22.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The MID1 gene encodes the midline-1 protein, a member of the tripartite motif (TRIM) family. TRIM proteins participate in many cellular processes, especially the ubiquitin-proteasome system, which tags and recycles proteins that are no longer needed. The midline-1 protein specifically interacts with microtubules, key components of the cell's internal scaffolding, influencing cell shape, division, and migration.
What the gene does
The MID1 gene produces the midline-1 protein, which plays a critical role in cellular maintenance and organisation. This protein attaches to microtubules, which are rigid, hollow structures forming the cell's cytoskeleton. Microtubules are fundamental for cells to maintain their shape, undergo division, and move effectively. Midline-1 is also responsible for recycling specific proteins, such as protein phosphatase 2A (PP2A), integrin alpha-4 (ITGA4), and serine/threonine-protein kinase 36 (STK36). This recycling process ensures these crucial proteins can be reused rather than broken down, which is essential for normal cellular functioning.
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Chromosome location
The MID1 gene is located on the short (p) arm of the X chromosome at position 22.2, specifically Xp22.2. This location is significant for its inheritance patterns.
Protein structure
The midline-1 protein is composed of 667 amino acids and features several distinct domains. These include an N-terminal RING-type (Zinc finger) domain spanning amino acids 10-60, followed by two B box-type 1 (Zinc finger) and B box-type 2 (Zinc finger) domains at positions 116-165 and 172-212 respectively. A Coiled coil domain is found between amino acids 205-264. Further along the protein, there is a COS domain (amino acids 320-379), a Fibronectin type-III domain (amino acids 381-484), and a B30.2/SPRY domain (amino acids 482-659). A Disordered region is also present between amino acids 471-524.
Key variants
Variants within the MID1 gene can lead to changes in the midline-1 protein, impacting its ability to function correctly. These genetic alterations can disrupt protein recycling processes and microtubule interactions, potentially leading to developmental conditions. The spectrum of variants can vary, from single nucleotide changes to larger deletions or duplications.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1102C>T | p.Arg368Ter | Pathogenic | ★★☆☆ | X-linked Opitz G/BBB syndrome |
c.1444_1447dup | p.Ser483fs | Pathogenic | ★★☆☆ | X-linked Opitz G/BBB syndrome |
c.1483C>T | p.Arg495Ter | Pathogenic | ★★☆☆ | X-linked Opitz G/BBB syndrome |
c.1554_1555del | p.Thr518_Pro519insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.388G>A | p.Ala130Thr | Pathogenic/Likely pathogenic | ★★☆☆ | X-linked Opitz G/BBB syndrome |
c.829C>T | p.Arg277Ter | Pathogenic | ★★☆☆ | X-linked Opitz G/BBB syndrome |
g.10474749CT[1] | - | Pathogenic | ★☆☆☆ | not provided |
c.1141+1G>A | - | Pathogenic | ★☆☆☆ | X-linked Opitz G/BBB syndrome |
c.1141+2T>C | - | Pathogenic | ★☆☆☆ | not provided |
c.865-2A>G | - | Pathogenic | ★☆☆☆ | not provided |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Changes in the MID1 gene are associated with Opitz G/BBB syndrome, a condition characterised by abnormalities affecting midline structures of the body. This can include features such as widely spaced eyes, difficulties with breathing or swallowing, specific facial characteristics, brain malformations, and genital abnormalities, particularly in males.
No disease links recorded for this gene in our reference set.
UK clinical status
The MID1 gene is included in several NHS Genomic Medicine Service panels, indicating its recognised clinical importance within the UK. These panels cover conditions such as Clefting, Developmental Disorders Gene (DDG2P), Foetal Anomalies (under R21), Intellectual Disability, and Non-syndromic familial congenital anorectal malformations.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the MID1 gene?
The MID1 gene encodes the midline-1 protein, which binds to microtubules to support cellular structure and division. It also plays a key role in recycling essential proteins, ensuring normal cellular function.
Which condition is linked to variants in the MID1 gene?
Variants in the MID1 gene are primarily associated with Opitz G/BBB syndrome, a genetic disorder characterised by developmental abnormalities along the body's midline.
Is the MID1 gene relevant for UK clinical testing?
Yes, the MID1 gene is part of several NHS Genomic Medicine Service panels in the UK, including those for Clefting, Developmental Disorders, Foetal Anomalies, Intellectual Disability, and Non-syndromic familial congenital anorectal malformations.
References
- Du H, Wu K, Didoronkute A. MID1 catalyzes the ubiquitination of protein phosphatase 2A and mutations within its Bbox1 domain disrupt polyubiquitination of alpha4 but not of PP2Ac. PloS one. 2014. PMID: 25207814
- Du H, Huang Y, Zaghlula M. The MID1 E3 ligase catalyzes the polyubiquitination of Alpha4 (α4), a regulatory subunit of protein phosphatase 2A (PP2A): novel insights into MID1-mediated regulation of PP2A. The Journal of biological chemistry. 2013. PMID: 23740247
- Han X, Du H, Massiah MA. Detection and characterization of the in vitro e3 ligase activity of the human MID1 protein. Journal of molecular biology. 2011. PMID: 21296087
- Fontanella B, Russolillo G, Meroni G. MID1 mutations in patients with X-linked Opitz G/BBB syndrome. Human mutation. 2008. PMID: 18360914
- Ferrentino R, Bassi MT, Chitayat D. MID1 mutation screening in a large cohort of Opitz G/BBB syndrome patients: twenty-nine novel mutations identified. Human mutation. 2007. PMID: 17221865
- Mnayer L, Khuri S, Merheby HA. A structure-function study of MID1 mutations associated with a mild Opitz phenotype. Molecular genetics and metabolism. 2006. PMID: 16378742
- Schweiger S, Schneider R. The MID1/PP2A complex: a key to the pathogenesis of Opitz BBB/G syndrome. BioEssays : news and reviews in molecular, cellular and developmental biology. 2003. PMID: 12655643
- De Falco F, Cainarca S, Andolfi G. X-linked Opitz syndrome: novel mutations in the MID1 gene and redefinition of the clinical spectrum. American journal of medical genetics. Part A. 2003. PMID: 12833403
- Liu J, Prickett TD, Elliott E. Phosphorylation and microtubule association of the Opitz syndrome protein mid-1 is regulated by protein phosphatase 2A via binding to the regulatory subunit alpha 4. Proceedings of the National Academy of Sciences of the United States of America. 2001. PMID: 11371618
- Trockenbacher A, Suckow V, Foerster J. MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation. Nature genetics. 2001. PMID: 11685209
- Quaderi NA, Schweiger S, Gaudenz K. Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22. Nature genetics. 1997. PMID: 9354791