Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22

Quaderi, Nandita; Schweiger, Susann; Gaudenz, Karin; Franco, Brunella; Rugarli, Elena I.; Berger, Wolfgang; Feldman, George J.; Volta, Manuela; Andolfi, Grazia; Gilgenkrantz, Simone; Marion, Robert W.; Hennekam, Raoul C. M.; Opitz, John M.; Muenke, Maximilian; Ropers, H.-H.; Ballabio, Andrea

doi:10.1038/ng1197-285

Cited by 330 publications

(338 citation statements)

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“…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).…”

Section: Introductionmentioning

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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Section: Introductionmentioning

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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“…T he Opitz G͞BBB syndrome (OS), also known as the hypospadias-dysphagia syndrome or telecanthus with associated abnormalities, is associated with midline abnormalities such as cleft lip, laryngeal cleft, heart defects, hypertelorism, hypospadias, imperforate anus, agenesis of the corpus callosum, and developmental delay (1). It was demonstrated that OS is a heterogeneous disorder, with X linked and autosomal forms.…”

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confidence: 99%

Phosphorylation and microtubule association of the Opitz syndrome protein mid-1 is regulated by protein phosphatase 2A via binding to the regulatory subunit α4

Prickett

Elliott

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

115

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Opitz syndrome (OS) is a human genetic disease characterized by deformities such as cleft palate that are attributable to defects in embryonic development at the midline. Gene mapping has identified OS mutations within a protein called Mid1. Wild-type Mid1 predominantly colocalizes with microtubules, in contrast to mutant versions of Mid1 that appear clustered in the cytosol. Using yeast two-hybrid screening, we found that the ␣4-subunit of protein phosphatases 2A͞4͞6 binds Mid1. Epitope-tagged ␣4 coimmunoprecipitated endogenous or coexpressed Mid1 from COS7 cells, and this required only the conserved C-terminal region of ␣4. Localization of Mid1 and ␣4 was influenced by one another in transiently transfected cells. Mid1 could recruit ␣4 onto microtubules, and high levels of ␣4 could displace Mid1 into the cytosol. Metabolic 32 P labeling of cells showed that Mid1 is a phosphoprotein, and coexpression of full-length ␣4 decreased Mid1 phosphorylation, indicative of a functional interaction. Association of green fluorescent protein-Mid1 with microtubules in living cells was perturbed by inhibitors of MAP kinase activation. The conclusion is 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 ␣4. Human birth defects may result from environmental or genetic disruption of this regulatory cycle.

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“…As hypospadias forms part of OS, 8 we hypothesized that the gene responsible for the X-linked form of OS, the MID1 gene, might be involved in the development of hypospadias as a mild form of OS. 9,10 We identified one nonsense mutation, one missense mutation and two synonymous variants. We also found there was significant difference between the rare allele frequency of SNP c.1230G4A in cases as compared with controls.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in the MID1 gene cause the X-linked form of Opitz G/BBB syndrome (OS, characterized by midline abnormalities such as hypertelorism, cleft lip/palate, tracheo-esophageal abnormalities, cardiac defects and hypospadias). [8][9][10] The function of MID1 is highly conserved in vertebrates, and experiments conducted in mice and chicken showed that MID1 expression correlated well with the tissues affected in OS. 11,12 In situ hybridization studies on human embryos showed that the expression of MID1 was localized in undifferentiated cells of midline structures including the urogenital system.…”

Section: Introductionmentioning

confidence: 99%

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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Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22

Cited by 330 publications

References 56 publications

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

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

Phosphorylation and microtubule association of the Opitz syndrome protein mid-1 is regulated by protein phosphatase 2A via binding to the regulatory subunit α4

Hypospadias associated with hypertelorism, the mildest phenotype of Opitz syndrome

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