PMC:64779 / 1890-5933 JSONTXT

{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/64779","sourcedb":"PMC","sourceid":"64779","source_url":"https://www.ncbi.nlm.nih.gov/pmc/64779","text":"Background\nOpitz GBBB syndrome (OS; Opitz syndrome) is a genetically and phenotypically complex disorder defined by characteristic facial anomalies (hypertelorism and variably labiopalatine and laryngotracheo-esophageal (LTE) clefting), structural heart defects, as well as anal and genital anomalies [1,2]. Recently, we and others identified the MID1 gene (also called FXY) as the underlying cause of the X-linked form of the disease [3-5]. Defects in MID1 have been found in ~50% of OS cases consistent with evidence from genetic linkage and cytogenetic studies that at least one autosomal form of the disorder, at chromosome position 22q11.2, also exists [6-8]. The deletion of the same interval produces the 22q11 deletion syndrome, which encompasses a group of disorders (eg. DiGeorge and velocardiofacial syndromes) showing some phenotypic overlap with OS [6,9]. Collectively, 22q11 anomalies represent one of the most common genetic causes of malformations (estimated 1 in 5000 live births) [10]. Although progress has recently been made towards elucidating the genes contributing to the 22q11 deletion phenotype [11-14], a specific autosomal OS gene has not yet been identified.\nThe MID1 gene encodes the defining member of a new subclass of the RBCC (RING, B-box, Coiled-Coil) family of proteins. This subclass is characterised by the combination of both a fibronectin type III motif and a B30.2-like (or SPRY) domain positioned C-terminal to the RBCC domain [15,16]. As in other members of the RBCC protein family, MID1 forms multiprotein complexes of between 250 and 450 kDa [17]. The MID1 protein, presumably as part of these complexes, has been shown to associate with cytoplasmic microtubules along their length and throughout the cell cycle using immunofluorescence detection of endogenous MID1, transient expression of GFP-MID1 fusion proteins, and cellular fractionation [5,18]. Most mutations in MID1 that cause OS are truncating mutations with many, but not all, directly affecting the C-terminal half of the protein [5]. Interestingly, all examined MID1 mutations disrupt the normal microtubule-associated distribution and this has been demonstrated to occur in vivo with endogenous mutant protein and in transient transfection studies using GFP fusion proteins [5,17,18].\nAn intriguing aspect of OS is the marked intrafamilial variability seen even among related males with the same X-linked mutation. This observation may be explained by the fact that other proteins, such as the highly related MID2 protein that is expressed in some of the same tissues and also associates with the microtubule network [15,19], could at least partially compensate for the loss of MID1 [5]. Such a mechanism has also been proposed for other microtubule-associated proteins, such as tau [20]. Alternatively, variations in the level or action of other factors in the same molecular pathway (for example, a factor encoded by the 22q11.2 locus and/or another component of the MID1 macromolecular complex) could contribute to this variability. Both explanations are consistent with the conclusion that OS is caused by loss of function of MID1 [5].\nIn this paper we report the identification of Alpha 4 as an interacting partner of both the Opitz syndrome protein, MID1, and the highly related MID2 protein. Alpha 4 is a unique and highly conserved regulatory subunit of PP2-type phosphatases, such as PP2A [21-24], and an integral component of the rapamycin-sensitive signaling pathway [25]. Our finding that both MID1 and MID2, either as homo- or hetero-dimers, are able to tether a key regulator of intracellular signaling to microtubules has significant implications for our understanding of the pathophysiological basis of OS and provides additional support for the hypothesis that MID2 could act as a modifier of the OS phenotype. Furthermore, as the Alpha 4 gene maps to Xq13 [26], our results identify it as a candidate for other X-linked disorders such as FG (Opitz-Kaveggia) syndrome that overlaps clinically with Opitz GBBB 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