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BMC Cell Biology 2002
MID1 and MID2 homo- and heterodimerise to tether the rapamycin-sensitive PP2A regulatory subunit, Alpha 4, to microtubules: implications for the clinical variability of X-linked Opitz GBBB syndrome and other developmental disordersAbstract: To identify protein partners of MID1 and MID2 we undertook two separate yeast two-hybrid screens. Using this system we identified Alpha 4, a regulatory subunit of PP2-type phosphatases and a key component of the rapamycin-sensitive signaling pathway, as a strong interactor of both proteins. Analysis of domain-specific deletions has shown that the B-boxes of both MID1 and MID2 mediate the interaction with Alpha 4, the first demonstration in an RBCC protein of a specific role for the B-box region. In addition, we show that the MID1/2 coiled-coil motifs mediate both homo- and hetero-dimerisation, and that dimerisation is a prerequisite for association of the MID-Alpha 4 complex with microtubules.Our findings not only implicate Alpha 4 in the pathogenesis of Opitz GBBB syndrome but also support our earlier hypothesis that MID2 is a modifier of the X-linked phenotype. Of further note is the observation that Alpha 4 maps to Xq13 within the region showing linkage to FG (Opitz-Kaveggia) syndrome. Overlap in the clinical features of FG and Opitz GBBB syndromes warrants investigation of Alpha 4 as a candidate for causing FG syndrome.Opitz 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]. C
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