The mouse Mid1 gene: implications for the pathogenesis of Opitz syndrome and the evolution of the mammalian pseudoautosomal region

Abstract

We have recently reported isolation of the gene responsible for X-linked Opitz G/BBB syndrome, a defect of midline development. MID1 is located on the distal short arm of the human X chromosome (Xp22. 3) and encodes a novel member of the B box family of zinc finger proteins. We have now cloned the murine homolog of MID1 and performed preliminary expression studies during development. Mid1 expression in undifferentiated cells in the central nervous, gastrointestinal and urogenital systems suggests that abnormal cell proliferation may underlie the defect in midline development characteristic of Opitz syndrome. We have also found that Mid1 is located within the mouse pseudoautosomal region (PAR) in Mus musculus , while it seems to be X-specific in Mus spretus. Therefore, Mid1 is likely to be a recent acquisition of the M. musculus PAR. Genetic and FISH analyses also demonstrated a high frequency of unequal crossovers in the murine PAR, creating spontaneous deletion/duplication events involving Mid1. These data provide evidence for the first time that genetic instability of the PAR may affect functionally important genes. In addition, we show that MID1 is the first example of a gene subject to X-inactivation in man while escaping it in mouse. These data contribute to a better understanding of the molecular content and evolution of the rodent PAR.

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

“…The developmental pattern of expression in mouse and chicken is very similar. The MID1 gene in these species is almost ubiquitously expressed but more abundant in undifferentiated cells of the central nervous system, the developing branchial arches, and the gastrointestinal and urogenital systems [Dal Zotto et al, 1998;Richman et al, 2002]. Analysis in the chicken revealed expression in the neural crest cells [Richman et al, 2002].…”

X-linked microtubule-associated protein, Mid1, regulates axon development

“…Mid1 encodes a 667-amino acid protein of the RBCC/TRIM family and has been shown to exhibit E3 ligase activity (3). The Mid1 protein is highly conserved between rodents and human (4), and its transcript is expressed ubiquitously in embryonic tissues, with the highest levels observed in the progenitor cells of the central nervous system and where cell proliferation is active (4,5). Full-length Mid1 protein is associated with microtubules (6,7), and the most frequently reported cases of mutations in Mid1 occur at its C terminus (8), which is known to disrupt its association with microtubules, leading to the clustering of truncated Mid1 (6).…”

Hypospadias associated with hypertelorism, the mildest phenotype of Opitz syndrome

“…[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. 13 Hypospadias is one common finding in OS cases (485%) with MID1 mutations, thus MID1 is a strong candidate gene for hypospadias.…”