• 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)

Dosage ID:
ISCA-6632
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
08/23/2021

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
HI Evidence:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
HI Evidence Comments:
Loss of function mutations in MID1 are responsible for the X-linked form of Opitz Syndrome (OS) in males. Several types of loss of function variants have been reported, including whole and partial gene deletions, splicing, nonsense, and frameshift variants. Three major signs of OS include hypertelorism, hypospadias in males or genital abnormalities in females, and defects of the larynx extending towards the trachea and esophagus. See GeneReviews. The expressivity of the OS symptoms is highly variable. Analysis of MID1-mutated patients highlighted the presence of some consistent clinical manifestations present in almost all patients (hypertelorism, LTE defects and hypospadias) and other less frequent signs such as cleft lip and/or palate, cardiac and anal defect. Female MID1 variant carriers had milder phenotypes compared to male MID1 variant carriers, with the most common manifestation being hypertelorism in both sexes. Functional studies: MID1 is a microtubule-associated protein that influences microtubule dynamics. MID1 proteins harboring variants as described in OS patients lack the capability to associate with microtubules, forming cytoplasmic clumps (PMIDs: 10077590, 32283114). Additional papers: Several smaller case series have been described with disease-causing loss of function variants reports in MID1 scattered along the entire length of the gene (PMID: 15121778 Pinson et al 2004 in JMG, PMID: 15558842 in AJMG, So et al. 2004 PMID: 18360914 Hum Mut, Fontanella et al. 2008 PMID: 21326312 J. Hum Genet 2011). Case series also includes two recent prenatal exome studies (Normand et al PMID: 30266093, Genome Medicine 2018 and Fang et al 2020; Prenatal Diagnosis PMID: 32386258 ). In the first prenatal case, a hemizygous nonsense variant (p.S225*) was detected in a male fetus inherited from a mildly affected mother. And in the second prenatal case, a likely pathogenic hemizygous nonsense variant (p.Glu408*) with unknown inheritance was detected in a male by WES. To date 105 mutations have been reported in the human gene mutation database (HGMD June 2021). pLI = 0.98/HI = 5.12 (loss of function prediction scores in agreement)
NOTE:

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

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
Focal duplications involving MID1 have not been described to date. Triplosensitivity not a known mechanism.
NOTE:

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.

Genomic View

Select assembly: (NC_000023.10) (NC_000023.11)