A family with X-linked Cornelia de Lange syndrome due to a novel SMC1A missense mutation identified by multi-gene panel sequencing

Cornelia de Lange syndrome (CdLS) is a rare, clinically and genetically heterogeneous, multi-system developmental disorder caused by mutations in genes that encode components of the cohesin complex. X-linked CdLS caused by an SMC1A mutation is an extremely rare disease characterized by phenotypes milder than those of classic CdLS. In the Republic of Korea, based on a literature review, one family with SMC1A-related CdLS with mild phenotypes has been genetically confirmed to date. In this study, we describe the clinical features of a Korean boy with a hemizygous novel missense mutation and his mother with a heterozygous mutation, i.e., c.2447G>A (p.Arg816His) in SMC1A, identified by multi-gene panel sequencing. The proband had a mild phenotype with typical facial features and his mother exhibited a mild, subclinical phenotype. This study expands the clinical spectrum of patients with X-linked CdLS caused by SMC1A variants. Moreover, these findings reinforce the notion that a dominant negative effect in a carrier female with a heterozygous mutation in SMC1A results in a phenotype milder than that in a male patient with the same mutation.

Altered Expression of Aquaporin 4 (AQP4) in Hippocampal Formation after Systemic Hyponatremia / 대한해부학회지

The expression of aquaporin-4 (AQP4) protein, bi-directional water channel, in the blood-brain barrier of the hippocampal formation (HF) was studied in the rat to determine the role of AQP4 in the pathophysiology of systemic hyponatremia. Systemic hyponatremia was induced by coadministration of 30 ml (~12% body weight) dextrose solution (140 mM) intraperitoneally and a 3-microg subcutaneous dose of 1-deamino-8-D-arginine vasopressin (dDAVP). Two and six hours after the drug administration, there were significant reductions in the serum osmolarity (252+/-5.1 and 252+/-6.4 mOsm/L) and in Na+/- concentration (117+/-1.7 and 97.2 mM) from the control values (296+/-5.2 mOsm/L, 140+/-4.7 mM). Brain injury in the HF and the expression of AQP4 were determined by using TUNEL, immunohistochemistry and quantitative immunoblotting. TUNEL revealed apoptotic cell death in the dentate gyrus (DG), presumably resulting from brain edema and a subsequent elevation of intracranial pressure after 2 h of systemic hyponatremia. However, AQP4 expression was decreased by 82%+/-6% after 2 h of systemic hyponatremia and then normalized after 6 h (108%+/-9%) compared with that of the control. Therefore, apoptotic cell death in the DG from brain swelling in this systemic hyponatremic model is likely associated with decrease of excessive brain water elimination because reincreased AQP4 expression/function accelerates the elimination of apoptotic cells from the DG.

The Effect of Transient Global Ischemia on the Rat Dentate Gyrus: Apoptosis in the Granular Zone and Neurogenesis in the Subgranular Zone / 대한해부학회지

It has been known that granule neurons of the dentate gyrus (DG) are born in adulthood as well as during development. Apoptotic cell death also occurs normally throughout the life of the rat brain. The present study was designed to determine the effect of transient global ischemia on the apoptosis and/or neurogenesis of granule cells in the dentate gyrus. TUNEL study revealed that the ischemia produced an significant increase in apoptosis mainly in the granular zone (GZ) of the DG. The percentage of TUNEL-positive cells in the DG was maximal (37.3+/-2.5%) 8 hr after ischemia and declined thereafter. However, immunocytochemical studies showed that there was an increase in neurogenesis mainly in the subgranular zone (SGZ) although the induction of neurogenesis took longer than the apoptosis. As a neurogenesis marker, proliferating cell nuclear antigen (PCNA)-positive cells, possibly progenitor cells, were significantly increased by 34.1+/-2.2%(n=3, p<0.05) mainly in the dentate SGZ 4 days after ischemia. In addition, the gradual increase in Bcl-2 expression was only paralleled with the neurogenesis in the SGZ, but not with the apoptosis in the GZ of the DG. The expression level of Bcl-2 in the SGZ was increased significantly (optical density 43.7+/-3.4; n = 3, p<0.05) 4 days after the ischemic insult. Furthermore, the ischemia-induced neurogenesis in the SGZ was also indirectly supported by the observation that the expression of synapsin-alpha was significantly increased (176%; n=3 p<0.05) in the CA3 region 4 days after the ischemia. Taken together, these results strongly suggest that the transient global ischemia induces the apoptosis in the GZ, whereas the cell proliferation in the SCZ of the DG. In situ hybridization using the antisense probes to the NR2A and NR2B subunits of NMDA receptors revealed that the ischemia produced a more profound effect on the mRNA expression of NR2A (61.9% reduction) than NR2B (20.5% reduction). Thus, we also suggest a possibility that ischemia could induce the neurogenesis in the SGZ of the DG through downregulation of the number of functional NMDA receptors.

Organization of Direct Hippocampal Projections to the Different Regions of the Ventral Striatum in primate / 대한해부학회지

The organization of the striatal projection fibers from the hippocampal formation (HF) was studied in the monkey with particular emphasis on specific projections of the ventral striatum. Retrograde tracers were injected into the five different regions of the ventral striatum such as the ventromedial caudate nucleus, ventral shell, central shell, and dorsal core of the nucleus accumbens (NA), and ventrolateral putamen. The ventromedial caudate nucleus and the shell of the NA received dense projections from the HF. Although the ventromedial caudate nucleus and the shell of the NA are both innervated by the HF, the shell receives the larger of these projections. This suggests that the HF is more strongly connected with the shell of the NA than with the ventromedial caudate nucleus. There are no differences between the ventral shell and central shell of the NA. Labeled neurons were mainly observed in the rostral parts of the dorsomedial CA1 and adjacent subicular complex (prosubiculum, subiculum, presubiculum, and parasubiculum) of the HF. These results suggest that the shell of the NA is the main converging site receiving hippocampal projections primarily related to integrating visuospatial and limbic information.

AMPA Receptor-Induced Neuronal Cell Death in Rat Hippocampus Following Transient Global Ischemia: Relationship to Calpain and Caspase-3 Expression / 대한해부학회지

A central challenge in ischemia-induced neuronal death research is understanding the mechanisms by which apoptotic or necrotic cascades are initiated and affected. We tested potential roles for AMPA and NMDA receptor protein levels and activation of calpain, caspase-3 in the hippocampus at times after transient global ischemia when detectable necrotic or apoptotic cell damage was observed by neurofilament 200 (NF200) degradation, TUNEL, and H & E. We determined that the decrease in the AMPA receptor subunit, GluR2, in response to the transient global ischemia plays a major role in triggering the neuronal cell death in hippocampus. We also examined potential roles for calpain and caspase-3 in ischemic cell death and found that (1) calpain is activated at a time following caspase-3 activation and paralleled degradation of NR2A, NR2B, and GluR2 and irreversible necrotic neuronal changes, (2) caspase-3 is has their maximal expression at the time of highest apoptosis, (3) the NF200 degradation, one of the neuronal deathinducing factors was correlated well with the calpain activation and necrotic changes in the hippocampal CA1 neurons. These results suggest that the significant degradation of GluR2 subunits of AMPA receptor and calpain activation are possibly involved in NF 200 degradation-mediated necrotic hippocampal cell death after transient global ischemia.