MID1 |
- 3
Haplo
Score - 0
Triplo
Score
Gene Facts External Data Attribution
- HGNC Symbol
- MID1 (HGNC:7095) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
- HGNC Name
- midline 1
- Gene type
- protein-coding gene
- Locus type
- gene with protein product
- Previous symbols
- No previous names found
- Alias symbols
- OS, FXY, TRIM18, RNF59
- %HI
- 5.13(Read more about the DECIPHER Haploinsufficiency Index)
- pLI
- 0.98(Read more about gnomAD pLI score)
- LOEUF
- 0.3(Read more about gnomAD LOEUF score)
- Cytoband
- Xp22
- Genomic Coordinates
-
GRCh37/hg19: chrX:10413350-10851802 NCBI Ensembl UCSC GRCh38/hg38: chrX:10445310-10833683 NCBI Ensembl UCSC - MANE Select Transcript
- NM_000381.4 ENST00000317552.9 (Read more about MANE Select)
- Function
- Has E3 ubiquitin ligase activity towards IGBP1, promoting its monoubiquitination, which results in deprotection of the catalytic subunit of protein phosphatase PP2A, and its subsequent degradation by polyubiquitination. {ECO:0000269|PubMed:10400985, ECO:0000269|PubMed:11685209, ECO:0000269|PubMed:22613722}. (Source: Uniprot)
Dosage Sensitivity Summary (Gene)
Haploinsufficiency (HI) Score Details
- X-linked Opitz G/BBB syndrome Monarch
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PUBMED:
23791568
Migliore et al 2013 (Eur J Med Genet): In 12 patients, the authors report missense, nonsense, small insertions and deletions in MID1 (Table 2; 3 de novo). Further, exonic deletions were also detected by MLPA. The affected individuals have the following MID1 variants: 2 missense variants, 2 maternally inherited nonsense variants, one de novo nonsense variant, one maternally inherited frameshift variant, one frameshift variant with unknown inheritance, one de novo deletion that extends upstream of MID1, two deletions with unknown inheritance, one deletion that is maternally inherited, and a maternally inherited duplication that leads to a frameshift and premature truncation.
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PUBMED:
29456483
Maia et al (2017 Mol Syndromology) reported two loss of function pathogenic frameshift MID1 variants. One of the variants was maternally inherited c.1656del and the other was de novo (c.1215_1228dup). This was observed in 2 unrelated families by sanger sequencing in a total of 4 males. Of note, authors mentioned that X-chromosome inactivation patterns in the blood of unaffected carrier females were not skewed. This is in concordance with previously published data by Pinson et al., 2004.
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PUBMED:
32656166
In a recent 2020 study (Front Pediatr), a frameshift loss of function pathogenic variant was identified p.(Lys444Glnfs*32) in MID1. This frameshift variant was found to occur de novo and the parents of the proband were healthy at the time of recruitment. As the family was lost to follow-up, clinical re-evaluation was not possible.
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PUBMED:
9354791
Quaderi et al. (Nat Gen, 1997) used Sanger sequence analysis to detect and describe some of the earliest variants in MID1 (predicted to be loss of function events). These variants include a 3-bp deletion involving a methionine codon, a 24-bp duplication causing the addition of 8 amino acids, and a 1-bp insertion resulting in a frameshift. The 3-bp deletion was found to segregate in the 5 affected members of the family but not in the 6 unaffected members and functional studies were not performed. Prior to this, evidence for an X-linked form of Optiz syndrome (OS) was provided by a large French family in which the disease appeared to co-segregate with a pericentric inversion of the X chromosome (inv(X)(p22.3q26)), possibly disrupting an important gene/locus. In one of the affected males with the inversion, Quaderi et al. investigated MID1 expression and RT-PCR analysis showed absence of MID1 expression in this affected male relative to a control locus.
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PUBMED:
11030761
Cox et al., (Human Mol Gen, 2000) identified thirteen males and two females exhibiting features consistent with X-linked Opitz syndrome. A de novo nonsense variant was identified (E115*) in MID1 in one participant. This variant is predicted to truncate the protein before the B-box motifs. An additional 2 nonsense variants of unknown inheritance were detected in this study, 1102C→T (R368*) in family OSP3 and 1483C→T (R495*) in family OSP9.
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PUBMED:
17221865
Ferrentino et al 2007 (Human Mutation) by Sanger Sequencing found 29 novel variants in 29 unrelated male patients in a cohort of 140 individuals with OS. Five nonsense variants led to the creation of stop codons in MID1 and were predicted to lead to premature protein truncation. Two of these variants (c.430G>T-p.Glu144* and c.561T>A-p.Cys187*) are predicted to produce a very short N-terminal portion of the protein. One of these variants was maternally inherited and the other four have unknown inheritance. The other MID1 variants reported include 9 missense, 3 maternally inherited splice site variants, one de novo frameshift, one paternally inherited frameshift, 3 maternally inherited frameshift variants, 2 frameshift variants of unknown inheritance, 2 paternally inherited deletions, and 3 deletions of unknown inheritance. All of the paternally inherited variants came from affected fathers.
The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.
Triplosensitivity (TS) Score Details
The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.