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A p.D116G mutation in CREB1 leads to novel multiple malformation syndrome resembling CrebA knockout mouse

We evaluated an autopsy case with severe neonatal respiratory distress, hypoplasia of thymus, thyroid gland and cerebellum, and agenesis of the corpus callosum displaying striking phenotypic similarity to the CrebA knockout mouse. On the assumption that comparable genetic alterations must be present, we checked the whole genomic DNA sequence of cyclic adenosine monophosphate (cAMP) response element binding protein 1 (CREB1), the human counterpart of mouse CrebA, and found a missense c.347A>G mutation corresponding to p.D116G within the kinase‐inducible domain (KID) of CREB1. When transcribed in vitro, while Ser‐133 phosphorylation of KID was maintained upon forskolin treatment, mutated CREB1 protein failed to associate with the KIX domain of co‐activator CREBBP/EP300, and thereby, interrupted cAMP‐dependent protein kinase A signal transduction as the dominant‐negative form. This is the first report of a sporadic CREB1‐related multiple malformation syndrome that, in light of accumulated knowledge of phenotypic features in gene‐targeted animals, clearly emphasizes the importance of cross‐species translational research. Hum Mutat 33:651–654, 2012. © 2012 Wiley Periodicals, Inc.