The combinatory phenotype of thrombocytopenia and developmental delay has been described for two genetic conditions: a chromosome 11q deletion that is referred to as Jacobsen syndrome, and a 21q22 microdeletion syndrome. Herein, we report a young girl who presented with persistent macrothrombocytopenia and a developmental delay. Whole exome sequencing revealed a de novo amino acid substitution in CDC42, a critical regulator of the cytoskeleton. Our observation recapitulates observations in mice lacking Cdc42. We suggest that this CDC42 mutation may represent yet another mechanism leading to the combinatory phenotype of persistent macrothrombocytopenia and developmental delay.
We generated an ORF65 deletion mutant by using a cosmid system constructed from the genome of a low-passage clinical isolate (P-Oka). Using the SCID-hu mouse model, we demonstrated that the ORF65 protein is dispensable for viral replication in skin and T cells, which are critical host cell targets during primary varicella-zoster virus infection.Varicella-zoster virus (VZV) is a human herpesvirus that causes varicella (chickenpox) as the primary infection, establishes latency in sensory nerve ganglia, and may reactivate as herpes zoster (shingles) (1, 2). Open reading frame (ORF) 65 of VZV is one of four genes located in the short unique region of the genome and is homologous to Us9 in herpes simplex virus type 1 and the other alphaherpesviruses (3, 4, 7-9, 12, 16, 18). VZV ORF65 is predicted to encode an 11-kDa protein with 20% serine and threonine residues and a hydrophobic carboxyl terminus (6). Cohen et al. demonstrated that a partial deletion of ORF65 in a recombinant vaccine Oka strain was dispensable for viral replication in melanoma cells (5). The role of VZV ORF65 protein in vivo has not been reported.In previous work, Moffat et al. found that the vaccine Oka strain was attenuated in its growth in skin xenografts compared with the low-passage clinical isolate P-Oka (15). P-Oka was isolated from a varicella lesion and used to develop the attenuated vaccine Oka strain (17). To introduce mutations into a VZV genome from a wild-type virus, we made a cosmid system for VZV by using DNA derived from the P-Oka clinical isolate. This cosmid system was used to construct a complete deletion of ORF65. We evaluated the effects of the complete FIG. 1. Construction of P-Oka cosmid vectors with full deletion of VZV ORF65. Line 1 shows a schematic diagram of the P-Oka VZV genome and the location of ORF65 in the unique short region. Line 2 depicts the overlapping segments of the VZV genome used to construct the P-Oka VZV cosmids. Line 3 shows the AatII fragment which includes ORF65. Line 4 indicates the deleted region (open box), resulting in cosmid pvSpe23⌬65.
Norovirus causes acute gastroenteritis in all age groups. Afebrile convulsion is an occasional neurologic complication in norovirus infection, but encephalitis is rare. We report the case of a previously healthy 15-month-old girl with norovirus encephalopathy who had a poor neurologic outcome. Norovirus (genogroup II) was detected in plasma and stool by real-time reverse transcription polymerase chain reaction, but the cerebrospinal fluid showed negative result for genome. Elevated concentrations of cerebrospinal fluid interleukin-6, interleukin-10, interferon-γ, and tumor necrosis factor-α were observed on the third day of illness. The encephalopathy in our patient may be related to hypercytokinemia rather than to direct viral invasion.
Approximately 1 percent of healthy individuals carry human herpesvirus-6 within a host chromosome. This is referred to as chromosomally integrated herpesvirus-6 (CIHHV-6). In this study, we investigated the chromosomal integration site in six individuals harboring CIHHV-6B. Using FISH, we found that HHV-6B signals are consistently located at the telomeric region. The proximal endpoints of the integrated virus were mapped at one of two telomere-repeat-like sequences (TRSs) within the DR-R in all cases. In two cases, we isolated junction fragments between the viral TRS and human telomere repeats. The distal endpoints were mapped at the distal TRS in all cases. The size of the distal TRS was found to be ~5 kb which is sufficient to fulfill cellular telomeric functions. We conclude that the viral TRS in the DR regions fulfill dual functions for CIHHV-6: homology-mediated integration into the telomeric region of the chromosome and neo-telomere formation that is then stably transmitted.
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