The Opitz syndrome gene product, MID1, associates with microtubules

Schweiger, Susann; Foerster, John; Lehmann, Tanja; Suckow, Vanessa; Muller, Yves A.; Walter, Gerhard; Davies, Tim; Porter, Hunter; Bokhoven, Hans van; Lunt, Peter; Traub, Peter; Ropers, Hans‐Hilger

doi:10.1073/pnas.96.6.2794

Cited by 116 publications

(151 citation statements)

References 34 publications

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“…To date, 79 OS male index cases have been published that carry mutations in the MID1 gene [Cho et al, 2006;Cox et al, 2000;De Falco et al, 2003;Ferrentino et al, 2007;Gaudenz et al, 1998;Mnayer et al, 2006;Pinson et al, 2004;Quaderi et al, 1997;Schweiger et al, 1999;Shaw et al, 2006;So et al, 2005;Winter et al, 2003] and three additional OS patients are reported here [Tania Attié-Bitach, personal communication; and our unpublished results] for a total of 82 OS index cases who carry mutations in the MID1 gene. Table 1 lists all the mutations found in the MID1 gene, their position and their putative effect on the protein product or on the transcript.…”

Section: Mid1 Mutations In Os Patientsmentioning

confidence: 99%

“…MID1 associates with the microtubules through the COS domain during the entire cell cycle: it is located on the interphase microtubular apparatus as well as on the mitotic spindle [Cainarca et al, 1999;Schweiger et al, 1999;Short and Cox, 2006]. The association with the microtubules is dynamic and regulated by phosphorylation [Liu et al, 2001].…”

Section: Introductionmentioning

confidence: 99%

“…The association with the microtubules is dynamic and regulated by phosphorylation [Liu et al, 2001]. MID1 mutant forms reproducing C-terminal mutations found in OS patients show a reduced affinity for the microtubules and are often found in cytoplasmic bodies [Cainarca et al, 1999;Schweiger et al, 1999]. Along the microtubules, MID1 exerts the role of RING finger E3 ubiquitin ligase that regulates phosphatase 2A (PP2A) catalytic subunit degradation [Trockenbacher et al, 2001].…”

Section: Introductionmentioning

confidence: 99%

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MID1 mutations in patients with X-linked Opitz G/BBB syndrome

2008

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Communicated by Arnold MunnichMutations in the MID1 gene are responsible for the X-linked form of Opitz G/BBB syndrome (OS), a disorder that affects the development of midline structures. OS is characterized by hypertelorism, hypospadias, laryngotracheo-esophageal (LTE) abnormalities, and additional midline defects. Cardiac, anal, and neurological defects are also present. The expressivity of OS is highly variable, even within the same family. We reviewed all the MID1 mutations reported so far, in both familial and sporadic cases. The mutations are scattered along the entire length of the gene and consist of missense and nonsense mutations, insertions and deletions, either inframe or causing frameshifts, and deletions of either single exons or the entire MID1 coding region. The variety of described mutations and the lack of a strict genotype-phenotype correlation confirm the previous suggestion of the OS phenotype being caused by a loss-of-function mechanism. However, although a specific mutation cannot entirely account for the observed phenotype, we observed preferential association between some types of mutation and specific clinical manifestations, e.g., brain anatomical defects and truncating mutations. This may suggest that the pathogenetic mechanism underlying the OS phenotype is more complex and may vary among the affected organs. Hum Mutat 29(5), [584][585][586][587][588][589][590][591][592][593][594] 2008.

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Section: Mid1 Mutations In Os Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MID1 mutations in patients with X-linked Opitz G/BBB syndrome

2008

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“…The OS associated missense, nonsense, and frame shift mutations that have been reproduced in vitro cause a different localization of the protein within the cell, i.e. low affinity for the microtubular apparatus Cox, et al, 2000;Schweiger, et al, 1999), indicating that the absence of MID1 E3 ubiquitin ligase function on the cytoskeleton, either caused by point mutations or complete deletion of the gene, is detrimental during development of the midline structures.No genotype/phenotype correlation is evident and all the patients present with a selection of clinical manifestations which is independent from the kind and position of the mutation they carry, with the possible exception of a recently reported correlation of a mild phenotype associated with mutations in the Fibronectin type III domain of the protein (Mnayer, et al, 2006). All MID1-mutated patients present at least two of the most frequent clinical manifestations, i.e.…”

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confidence: 99%

MID1 mutation screening in a large cohort of Opitz G/BBB syndrome patients: twenty-nine novel mutations identified

et al. 2007

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Opitz G/BBB Syndrome (OS) is a multiple congenital anomaly disorder characterized by defects along the body midline. The disease is characterized by variable expressivity of signs that include hypertelorism, cleft lip and/or palate, laryngo-tracheo-esophageal abnormalities, cardiac defects, and hypospadias. OS patients also present with mental retardation and brain anatomical abnormalities. An autosomal dominant form mapping to chromosome 22 and an X-linked form of OS are known. The gene responsible for the Xlinked form of OS, MID1, codes for a member of the Tripartite Motif family of E3 ubiquitin ligases. Here we report 29 novel mutations in 29 unrelated patients of a cohort of 140 male OS cases. These mutations are found in both familial and sporadic cases. They are scattered along the entire length of the gene and are represented by missense and nonsense mutations, insertions and deletions causing frame shift mutations, and deletion of either single exons or the entire gene. The variety of the mutations found confirms that loss-of-function is the mechanism underlying the OS phenotype. Moreover, the low percentage of MID1-mutated OS patients, 47% of the familial and 13% of the sporadic cases, suggests a wider genetic heterogeneity underlying the OS phenotype. © 2007 Wiley-Liss, Inc. KEY WORDS: X-linked Opitz syndrome; MID1; midline defects INTRODUCTIONOpitz G/BBB Syndrome (OS; MIM# 300000) is characterized by multiple congenital midline structure anomalies (Opitz, et al., 1969a;Opitz, et al., 1969b laryngo-tracheo-esophageal (LTE) abnormalities; cardiac and anal defects and hypospadias (De Falco, et al., 2003;Robin, et al., 1996). OS patients often show mental retardation and brain anatomical midline defects (De Falco, et al., 2003;Pinson, et al., 2004). OS is genetically heterogeneous with an autosomal dominant and an X-linked form (Robin, et al., 1995). The autosomal dominant form is linked to a large region of 22q11.2 but the gene(s) responsible has not been identified yet (Robin, et al., 1995). Conversely, the gene implicated in the X-linked form of OS, MID1, has been identified on the short arm of the X chromosome (Xp22.3) (Quaderi, et al., 1997). The MID1 gene encodes a member of the Tripartite Motif family (Meroni and Diez-Roux, 2005;Reymond, et al., 2001). MID1 acts as an E3 ubiquitin ligase associated to the microtubules and is implicated in the control of Phosphatase 2A protein levels Schweiger, et al., 1999;Short, et al., 2002;Trockenbacher, et al., 2001). Approximately 40 mutations have been found along the entire length of the MID1 gene in both sporadic and familial cases of OS (Cox, et al., 2000;De Falco, et al., 2003;Gaudenz, et al., 1998;Mnayer, et al., 2006;Pinson, et al., 2004;So, et al., 2005;. The expressivity of the OS symptoms is highly variable and analysis of MID1-mutated patients highlighted the presence of 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 ana...

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“…22 A microtubule co-assembly assay revealed that, the MID1 protein from OS fetal fibroblasts with the mutation in C-terminal exon lacks microtubule-binding ability. 23 In another study conducted on avian embryos, the mutated MID1 construct without C-terminus portion failed to affect the left-right axis pattern, suggesting that the mutated construct is a loss-of-function construct. 24,25 Therefore, it is likely that the nonsense mutation found in our two patients leads to the loss of function of MID1, which may be the underlying mechanism of hypospadias.…”

Section: Discussionmentioning

confidence: 97%

Hypospadias associated with hypertelorism, the mildest phenotype of Opitz syndrome

et al. 2011

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Hypospadias is a common congenital malformation in boys in which the urethral meatus opens on the underside of the penis. It is considered a complex disorder with several genes involved and the molecular etiology is just beginning to be revealed. As more than 85% of Opitz G/BBB syndrome (OS) patients with MID1 mutations are manifested with hypospadias, we have investigated the association between the MID1 gene and hypospadias. DNA from 114 hypospadias cases was analyzed with direct sequencing of the MID1 gene. Genotyping analysis was performed for the single-nucleotide polymorphism (SNP) c.1230G4A in 370 individuals with varying degrees of hypospadias and compared with 759 healthy controls. We identified one nonsense mutation c.712G4T (p.E238X), one missense mutation c.1679A4G (p.K560R) and two synonymous variants c.1230G4A (p.S410S) and c.1284T4G (p.V428V). We also detected a significant difference in the rare allele frequency of SNP c.1230G4A in hypospadias patients as compared with controls (P¼0.016). Our finding suggests that hypospadias associated with hypertelorism is the mildest phenotype in OS caused by MID1 mutations.

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The Opitz syndrome gene product, MID1, associates with microtubules

Cited by 116 publications

References 34 publications

MID1 mutations in patients with X-linked Opitz G/BBB syndrome

MID1 mutations in patients with X-linked Opitz G/BBB syndrome

MID1 mutation screening in a large cohort of Opitz G/BBB syndrome patients: twenty-nine novel mutations identified

Hypospadias associated with hypertelorism, the mildest phenotype of Opitz syndrome

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