Hirschsprung disease (HSCR) is sometimes associated with a set of characteristics including mental retardation, microcephaly, and distinct facial features, but the gene mutated in this condition has not yet been identified. Here we report that mutations in SIP1, encoding Smad interacting protein-1, cause disease in a series of cases. SIP1 is located in the deleted segment at 2q22 from a patient with a de novo t(2;13)(q22;q22) translocation. SIP1 seems to have crucial roles in normal embryonic neural and neural crest development.

Exposure to bisphenol A is associated with recurrent miscarriage.

The amino-terminal enhancer of split (AES) encodes a 197-amino acid protein that is homologous to the NH 2 -terminal domain of the Drosophila Groucho protein but lacks COOH-terminal WD40 repeats. Although the Drosophila Groucho protein and its mammalian homologs, transducin-like enhancer of split proteins, are known to act as non-DNA binding corepressors, the role of the AES protein remains unclarified. Using the yeast twohybrid system, we have identified the protein-protein interaction between AES and the p65 (RelA) subunit of the transcription factor nuclear factor B (NF-B), which activates various target genes involved in inflammation, apoptosis, and embryonic development. The interaction between AES and p65 was confirmed by in vitro glutathione S-transferase pull down assay and by in vivo co-immunoprecipitation study. In transient transfection assays, AES repressed p65-driven gene expression. AES also inhibited NF-B-dependent gene expression induced by tumor necrosis factor ␣, interleukin-1␤, and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1, which is an upstream kinase for NF-B activation. These data indicate that AES acts as a corepressor for NF-B and suggest that AES may play a pivotal role in the regulation of NF-B target genes.Nuclear factor B (NF-B) 1 is an inducible cellular transcription factor that regulates a wide variety of cellular and viral genes including several cytokines, cell adhesion molecules, and human immunodeficiency virus (HIV) (1-4). The members of the NF-B family in mammalian cells include the proto-oncogene c-Rel, Rel A (p65), Rel B, NF B1 (p50/105), and NF B2 (p52/p100). These proteins share a conserved 300-amino acids region known as the Rel homology domain, which is responsible for DNA binding, dimerization, and nuclear translocation of NF-B (1-4). In most cells, Rel family members form heteroand homodimers with distinct specificities in various combinations. p65, Rel B, and c-Rel are transcriptionally active members of the NF-B family, whereas p50 and p52 primarily serve as mere DNA binding subunits (1-4). The transactivation domains of p65, Rel B, and c-Rel have been mapped in their unique COOH-terminal regions. p65 was shown to contain at least two independent transactivation domains within its COOH-terminal 120 amino acids (5-8). One p65 activation domain, TA1, is confined to the COOH-terminal 30 amino acids of p65. The second domain TA2 is contained within the NH 2 -terminally adjacent 90 amino acids.A common feature of the regulation of NF-B family is their sequestration in the cytoplasm as inactive complexes with a class of inhibitory molecules known as I Bs (1-4). Treatment of cells with a variety of inducers such as phorbol esters, interleukin-1, and tumor necrosis factor (TNF) results in phosphorylation, ubiquitination, and degradation of the I B proteins (4, 9, 10). The degradation of I B proteins exposes the nuclear localization sequence in the remaining NF-B dimers, leading to nuclear translocation and subsequent binding of NF...

Mutations in ZFHX1B, encoding Smad-interacting protein 1 (SIP1), have been recently reported to cause a form of Hirschsprung disease (HSCR). Patients with ZFHX1B deficiency typically show mental retardation, delayed motor development, epilepsy, microcephaly, distinct facial features, and/or congenital heart disease, in addition to the cardinal form of HSCR. To investigate the breadth of clinical variation, we studied DNA samples from six patients with clinical profiles quite similar to those described elsewhere for ZFHX1B deficiency, except that they did not have HSCR. The results showed the previously reported R695X mutation to be present in three cases, with three novel mutations-a 2-bp insertion (760insCA resulting in 254fs262X), a single-base deletion (270delG resulting in 91fs107X), and a 2-bp deletion (2178delTT resulting in 727fs754X)-newly identified in the other three. All mutations occurred in one allele and were de novo events. These results demonstrate that ZFHX1B deficiency is an autosomal dominant complex developmental disorder and that individuals with functional null mutations present with mental retardation, delayed motor development, epilepsy, and a wide spectrum of clinically heterogeneous features suggestive of neurocristopathies at the cephalic, cardiac, and vagal levels.

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