NEDD8 is a ubiquitin (Ub)-like protein.Here we report a novel ubiquitinylation-related pathway for modification by NEDD8. NEDD8 was activated by an E1 (Ub-activating enzyme)-like complex, consisting of APP-BP1 and hUba3 with high respective homologies to the aminoand carboxy-terminal regions of E1 and then linked to hUbc12 (a human homolog of yeast Ub-conjugating enzyme Ubc12p). The major target protein modified by NEDD8 was found to be Hs-cullin-4A (Cul-4A), a member of the family of human cullin/Cdc53 proteins functioning as an essential component of a multifunctional Ub-protein ligase E3 complex that has a critical role in Ub-mediated proteolysis.

This study concerns the significance of nuclear/cytoplasmic expression of beta-catenin and mutation of the beta-catenin gene in craniopharyngiomas. Fourteen adamantinomatous type and one squamous papillary type craniopharyngiomas were studied. Histologically, 13 of 14 adamantinomatous type craniopharyngiomas showed typical features, ie mixtures of 'palisading cells', 'stellate cells', and 'ghost cells'. In addition, 'whorl-like arrays' of epithelial cells were frequently observed in the areas of stellate cells. On immunohistochemistry, all typical adamantinomatous type craniopharyngiomas showed nuclear/cytoplasmic expression of beta-catenin predominantly in cohesive cells within the whorl-like arrays and in cells transitional towards ghost cells, where immunoreactivity for Ki-67 was almost absent. The cohesive cells in the whorl-like arrays also demonstrated loss of cytokeratin isoform expression. Using direct sequencing of amplified nucleic acids, nine of the 13 typical adamantinomatous type craniopharyngiomas with nuclear beta-catenin accumulation showed heterozygous one-base substitution mutation of the beta-catenin gene. The other unusual adamantinomatous type and squamous papillary type craniopharyngiomas showed no obvious nuclear/cytoplasmic beta-catenin immunoreactivity and no mutation of the beta-catenin gene, suggesting molecular heterogeneity. These findings suggest that the pathogenesis of typical adamantinomatous type craniopharyngioma is associated with abnormalities of Wnt signalling that act as a morphogenetic signal towards whorl-like arrays and ghost cells rather than as simple proliferation stimuli.

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Cerebellar and/or vermis atrophy is recognized in various types of childhood disorders with clinical and genetic heterogeneity. Although careful evaluation of clinical features and neuroimaging can lead to correct diagnosis of disorders, their diagnosis is sometimes difficult because clinical features can overlap with each other. In this study, we performed family-based whole exome sequencing of 23 families including 25 patients with cerebellar and/or vermis atrophy in childhood, who were unable to be diagnosed solely by clinical examination. Pathological mutations of seven genes were found in ten patients from nine families (9/23, 39.1 %): compound heterozygous mutations in FOLR1, C5orf42, POLG, TPP1, PEX16, and de novo mutations in CACNA1A, and ITPR1. Patient 1A with FOLR1 mutations showed extremely low concentration of 5-methyltetrahydrofolate in the cerebrospinal fluid and serum, and Patient 6 with TPP1 mutations demonstrated markedly lowered tripeptidyl peptidase 1 activity in leukocytes. Furthermore, Patient 8 with PEX16 mutations presented a mild increase of very long chain fatty acids in the serum as supportive data for genetic diagnosis. The main clinical features of these ten patients were nonspecific and mixed, and included developmental delay, intellectual disability, ataxia, hypotonia, and epilepsy. Brain MRI revealed both cerebellar and vermis atrophy in eight patients (8/10, 80 %), vermis atrophy/hypoplasia in two patients (2/10, 20 %), and brainstem atrophy in one patient (1/10, 10 %). Our data clearly demonstrate the utility of whole exome sequencing for genetic diagnosis of childhood cerebellar and/or vermis atrophy.

Use of the International Society for the Study of Vascular Anomalies (ISSVA) classification system has been strongly recommended in recent years because of the need for separate therapeutic measures for patients with vascular tumors and malformations. In the ISSVA classification system, vascular tumors, which are neoplastic, are distinguished from vascular malformations, which are caused by vascular structural anomalies and are not neoplastic, on the basis of the presence or absence of neoplastic proliferation of vascular endothelial cells. It is important that radiologists be familiar with the development, diagnosis, and treatment of vascular tumors and malformations, especially the imaging features of low- and high-flow vascular malformations. Some vascular tumors and malformations develop in isolation, whereas others develop within the phenotype of a syndrome. Syndromes that are associated with vascular tumors include PHACE syndrome. Syndromes that are associated with vascular malformations include Sturge-Weber, Klippel-Trénaunay, Proteus, blue rubber bleb nevus, Maffucci, and Gorham-Stout syndromes, all of which demonstrate low flow, and Rendu-Osler-Weber, Cobb, Wyburn-Mason, and Parkes Weber syndromes, all of which demonstrate high flow. Because imaging findings may help identify such syndromes as systemic, it is important that radiologists familiarize themselves with these conditions.

Lesions in the corona radiata above the posterior limb of the internal capsule on a coronal view by term MRI were useful for predicting motor prognosis in preterm infants with periventricular leukomalacia.

We suggest that hypogonadism, GH deficiency, and hypothyroidism could be possible endocrinological defects in patients with CHD7 mutations and that olfactory bulb hypoplasia as well as semicircular canal aplasia should be considered as a major sign for CHARGE syndrome and recommend a computed tomography scan of the temporal bone and magnetic resonance imaging study of the olfactory bulb region.

None of our patients showed evidence of transition from favorable to unfavorable prognosis, a finding that points to a reduction in the significance of screening as a public health measure. Until results of ongoing screening trials involving older patients have been evaluated, the observation program can be used as a temporary measure to avoid, with little risk, unnecessary surgical intervention.