http://repub.eur.nl/res/aut/33332/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/37716/ 2012-09-07T00:00:00Z Polymicrogyria is a malformation of the developing cerebral cortex caused by abnormal organization and characterized by many small gyri and fusion of the outer molecular layer. We have identified autosomal-recessive mutations in RTTN, encoding Rotatin, in individuals with bilateral diffuse polymicrogyria from two separate families. Rotatin determines early embryonic axial rotation, as well as anteroposterior and dorsoventral patterning in the mouse. Human Rotatin has recently been identified as a centrosome-associated protein. The Drosophila melanogaster homolog of Rotatin, Ana3, is needed for structural integrity of centrioles and basal bodies and maintenance of sensory neurons. We show that Rotatin colocalizes with the basal bodies at the primary cilium. Cultured fibroblasts from affected individuals have structural abnormalities of the cilia and exhibit downregulation of BMP4, WNT5A, and WNT2B, which are key regulators of cortical patterning and are expressed at the cortical hem, the cortex-organizing center that gives rise to Cajal-Retzius (CR) neurons. Interestingly, we have shown that in mouse embryos, Rotatin colocalizes with CR neurons at the subpial marginal zone. Knockdown experiments in human fibroblasts and neural stem cells confirm a role for RTTN in cilia structure and function. RTTN mutations therefore link aberrant ciliary function to abnormal development and organization of the cortex in human individuals. http://repub.eur.nl/res/pub/25006/ 2009-01-01T00:00:00Z Objective: To report the presence of intracerebral hemorrhage and porencephaly, both present at birth, in two preterm infants with a mutation in the collagen 4 A1 gene. Methods: Two preterm infants with antenatal intracerebral hemorrhage and established porencephaly, as well as their affected mother and grandfather, underwent neurological and ophthalmological examination and magnetic resonance imaging of the brain. Mutation analysis of the COL4A1 gene was performed in the infants and in their mother. Results: Both infants had a novel G1580R mutation in the COL4A1 gene, encoding procollagen type IV α1. A history of mild antenatal trauma was present in the first but not in the second infant. Both preterm infants were asymptomatic at birth. The intracerebral hemorrhage and porencephaly were diagnosed with cranial ultrasound examination and were subsequently confirmed with magnetic resonance imaging. Leukoencephalopathy was present in the mother and in her father. Interpretation: Mutation of the COL4A1 gene appears to be a risk factor of antenatal intracerebral hemorrhage followed by porencephaly in the preterm newborn.