Carpenter syndrome is a pleiotropic disorder with autosomal recessive inheritance, the cardinal features of which include craniosynostosis, polysyndactyly, obesity, and cardiac defects. Using homozygosity mapping, we found linkage to chromosome 6p12.1-q12 and, in 15 independent families, identified five different mutations (four truncating and one missense) in RAB23, which encodes a member of the RAB guanosine triphosphatase (GTPase) family of vesicle transport proteins and acts as a negative regulator of hedgehog (HH) signaling. In 10 patients, the disease was caused by homozygosity for the same nonsense mutation, L145X, that resides on a common haplotype, indicative of a founder effect in patients of northern European descent. Surprisingly, nonsense mutations of Rab23 in open brain mice cause recessive embryonic lethality with neural-tube defects, suggesting a species difference in the requirement for RAB23 during early development. The discovery of RAB23 mutations in patients with Carpenter syndrome implicates HH signaling in cranial-suture biogenesis—an unexpected finding, given that craniosynostosis is not usually associated with mutations of other HH-pathway components—and provides a new molecular target for studies of obesity.

https://www.cell.com/ajhg/pdf/S0002-9297(07)61033-7.pdf

RAB23 Mutations in Carpenter Syndrome Imply an Unexpected Role for Hedgehog Signaling in Cranial-Suture Development and Obesity

Although motor deficits are gaining attention in autism research much less attention has been paid to the physical activity patterns in this group of children. The participants in this study were a group of children with autism spectrum disorder (N = 72) between the ages of 9-18 years. This cross-sectional study explored the physical activity patterns of seventy-two children with autism spectrum disorder as they aged. Results indicated significant differences between the mean time spent in moderate to vigorous physical activity and the mean time spent in sedentary activity. Older children with autism spectrum disorder are significantly more physically inactive, compared to younger children. Physical activity programs and interventions need to address this deficit, in physical activity. Children with autism have a similar trend in physical activity patterns compared to their peers without autism; associated benefits and future research will be discussed.

/pdf/the-physical-activity-patterns-of-children-with-autism-3gm6jyfvrr.pdf

The physical activity patterns of children with autism

Rab GTPases and their roles in brain neurons and glia

Polycystin-2 (also called TRPP2), an integral membrane protein mutated in patients with cystic kidney disease, is located in the primary cilium where it is thought to transmit mechanical stimuli into the cell interior. After studying a series of polycystin-2 deletion mutants we identified two amino acids in loop 4 that were essential for the trafficking of polycystin-2 to the somatic (nonciliary) plasma membrane. However, polycystin-2 mutant proteins in which these two residues were replaced by alanine were still sorted into the cilium, thus indicating that the trafficking routes to the somatic and ciliary plasma membrane compartments are distinct. We also observed that the introduction of dominant-negative Sar1 mutant proteins and treatment of cells with brefeldin A prevented the transport into the ciliary plasma membrane compartment, whereas metabolic labeling experiments, light microscopical imaging, and high-resolution electron microscopy revealed that full-length polycystin-2 did not traverse the Golgi apparatus on its way to the cilium. These data argue that the transport of polycystin-2 to the ciliary and to the somatic plasma membrane compartments originates in a COPII-dependent fashion at the endoplasmic reticulum, that polycystin-2 reaches the cis side of the Golgi apparatus in either case, but that the trafficking to the somatic plasma membrane goes through the Golgi apparatus whereas transport vesicles to the cilium leave the Golgi apparatus at the cis compartment. Such an interpretation is supported by the finding that mycophenolic acid treatment resulted in the colocalization of polycystin-2 with GM130, a marker of the cis-Golgi apparatus. Remarkably, we also observed that wild-type Smoothened, an integral membrane protein involved in hedgehog signaling that under resting conditions resides in the somatic plasma membrane, passed through the Golgi apparatus, but the M2 mutant of Smoothened, which is constitutively located in the ciliary but not in the somatic plasma membrane, does not. Finally, a dominant-negative form of Rab8a, a BBSome-associated monomeric GTPase, prevented the delivery of polycystin-2 to the primary cilium whereas a dominant-negative form of Rab23 showed no inhibitory effect, which is consistent with the view that the ciliary trafficking of polycystin-2 is regulated by the BBSome.

https://rupress.org/jcb/article-pdf/192/4/631/1349719/jcb_201007050.pdf

Polycystin-2 takes different routes to the somatic and ciliary plasma membrane

https://onlinelibrary.wiley.com/doi/pdf/10.1042/BC20100150

Rabs and other small GTPases in ciliary transport.

The gene mutated in the mouse open brain (opb) phenotype antagonizes sonic hedgehog-mediated signaling and encodes a small GTPase of the Rab family, Rab23. To date, the brain expression profile and exact mechanism of function of the Rab23 protein has remained unknown. Specific antibodies generated against Rab23 showed that the protein is highly enriched in the adult rodent brain and present in low levels in multiple tissues of the adult rodent. Rab23 is found in the cytosol as well as being associated with the plasma and endosomal membranes. In the adult mouse brain, Rab23 is found in βIII tubulin (TuJ) positive neuronal cell bodies and are most prominent in the cortex, hypothalamus and the cerebellum. It is, however, absent from glial fibrillary acidic protein (GFAP) positive astrocytes or CNPase positive oligodendrocytes. Despite the plasma membrane/endosomal membrane localization of Rab23, neither overexpression of the GTP-restricted nor the GDP-bound mutant forms affect internalization of transferrin or epidermal growth factor. Exogenous overexpression of Rab23 or its mutants also did not affect the morphological differentiation of thalamic neurons in culture. Expression of Rab23 in the adult brain is suggestive, however, of having a postnatal function beyond its role in embryonic development. © 2006 Wiley-Liss, Inc.

Open brain gene product Rab23: expression pattern in the adult mouse brain and functional characterization.

Abstract This study investigated the effects of trichloroisocyanuric acid (TCCA) on the bleaching and morphology of melanin-containing pathological sections. The pathological sections of 27 patients with high melanin content were bleached with 0.5% potassium permanganate, 10% hydrogen peroxide, and different concentrations of TCCA. Significant differences were found among the blank control group, 1% TCCA group ( P &lt; 0.0001). The hematoxylin–eosin (HE) score of the "recovery pH" HE staining group after treatment with 1% TCCA was similar to that of the "Conventional HE" scheme group ( P &gt; 0.05). The morphological diagnostic scores of 50 cases of pathological sections with different melanin content before and after TCCA bleaching were compared. The results showed a significant difference in the diagnostic score between the middle- and high-melanin content groups before and after 1% TCCA bleaching ( P &lt; 0.05). Immunohistochemical staining was performed on meningeal melanoma tissue. For this, 8% TCCA solution was used to remove melanin after Ki67, S100, and β-catenin immunohistochemical staining. After bleaching with TCCA, the staining and positioning of each marker with different localization were accurate and the background was clear. The same results were also shown with EBER-ISH. This study concluded that 1% TCCA could be used for HE staining of pathological sections containing melanin, and "restore pH" HE scheme as the staining method after TCCA melanin removal. Further, 8% TCCA was used for bleaching after immunohistochemical DAB staining. Melanin can be completely removed, and sections can meet diagnostic needs. 

/pdf/construction-of-hematoxylin-eosin-immunohistochemistry-and-ujd7mzfe.pdf

Construction of hematoxylin–eosin, immunohistochemistry, and EBER-ISH methodology after trichloroisocyanuric acid treatment in melanin-containing tissues

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Open brain gene product Rab23: expression pattern in the adult mouse brain and functional characterization.

Construction of hematoxylin–eosin, immunohistochemistry, and EBER-ISH methodology after trichloroisocyanuric acid treatment in melanin-containing tissues