Clinical and molecular characteristics of autosomal recessive congenital ichthyosis in Thailand.

BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) is a heterogenous group of rare keratinization disorders. To date, more than 13 causative genes have been identified. However, data on clinical and molecular characteristics including genotype-phenotype correlation are lacking in Thailand. OBJECTIVE: We collected cases diagnosed with non-syndromic ARCI and syndromic recessive congenital ichthyosis at the Institute of Dermatology from 2011 to 2021 and performed genetic testing with next-generation sequencing and assessed clinical details. METHODS: Baseline demographic data, birth history, family history, skin manifestations at birth, current cutaneous manifestations, comorbidities, and response to treatments were assessed. DNA was screened for mutations using targeted gene sequencing of 45 genes related to congenital ichthyosis. RESULTS: A total of 33 patients were analyzed with an average age of 23.8 ± 13.9 years. Congenital ichthyosiform erythroderma (CIE) was most common (60.6%), followed by lamellar ichthyosis (18.2%), self-improving congenital ichthyosis (6.1%), Netherton syndrome (6.1%), ichthyosis prematurity syndrome (3%), Sjögren-Larsson syndrome (3%) and bathing suit ichthyosis (3%). Eight genes were found with pathogenic variants in our cohort as follows: ABCA12 42.4% (14/33), NIPAL4 24.2% (8/33), TGM1 15.2% (5/33), SPINK5 6.1% (2/33), ALDH3A2 3% (1/33), SLC27A4 3% (1/33), CYP4F22 3% (1/33), and ST14 3% (1/33). Clinically, 79% of patients with ABCA12 pathogenic variants in this study had CIE, 79% of w had novel biallelic pathogenic compound heterozygous variants, whereas 21% had homozygous missense variants. CONCLUSIONS: This is the first study to describe clinical and molecular findings of ARCI in a cohort from Thailand. Our findings demonstrate the clinical spectrum of the diseases and expand the molecular findings in a Southeast Asian population.

Interaction of dengue virus nonstructural protein 5 with Daxx modulates RANTES production.

Dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS), caused by dengue virus (DENV) infection, are important public health problems in the tropical and subtropical regions. Abnormal hemostasis and plasma leakage are the main patho-physiological changes in DHF/DSS. A remarkably increased production of cytokines, the so called 'cytokine storm', is observed in the patients with DHF/DSS. A complex interaction between DENV proteins and the host immune response contributes to cytokine production. However, the molecular mechanism(s) by which DENV nonstructural protein 5 (NS5) mediates these responses has not been fully elucidated. In the present study, yeast two-hybrid assay was performed to identify host proteins interacting with DENV NS5 and a death-domain-associate protein (Daxx) was identified. The in vivo relevance of this interaction was suggested by co-immunoprecipitation and nuclear co-localization of these two proteins in HEK293 cells expressing DENV NS5. HEK293 cells expressing DENV NS5-K/A, which were mutated at the nuclear localization sequences (NLS), were created to assess its functional roles in nuclear translocation, Daxx interaction, and cytokine production. In the absence of NLS, DENV NS5 could neither translocate into the nucleus nor interact with Daxx to increase the DHF-associated cytokine, RANTES (CCL5) production. This work demonstrates the interaction between DENV NS5 and Daxx and the role of the interaction on the modulation of RANTES production.

Disseminated Autochthonous Dermal Leishmaniasis Caused by Leishmania siamensis (PCM2 Trang) in a Patient from Central Thailand Infected with Human Immunodeficiency Virus.

AbstractSeveral case reports of autochthonous leishmaniasis in Thailand have been published since 1996. Most of the previous cases presented with visceral leishmaniasis (VL) and were mostly reported in southern part of Thailand. Recently, it has been evident that Leishmania martiniquensis is the main cause of Leishmania infection in Thailand. However, Leishmania siamensis (PCM2 Trang isolate) was found to be of a separate lineage with restricted distribution in southern Thailand and also a cause of disseminated dermal and visceral leishmaniasis in one published case. Here we report the first patient from central Thailand with human immunodeficiency virus infection presenting with disseminated dermal leishmaniasis. Polymerase chain reaction and DNA sequencing analysis (large subunit of RNA polymerase II and 18S ribosomal RNA internal transcribed spacer 1) from the tissue biopsy sample revealed the pathogen sequences to be highly homologous to PCM2 Trang strain previously reported from southern Thailand.

Generation of human single-chain variable fragment antibodies specific to dengue virus non-structural protein 1 that interfere with the virus infectious cycle.

Severe forms of dengue virus (DENV) infection frequently cause high case fatality rate. Currently, there is no effective vaccine against the infection. Clinical cases are given only palliative treatment as specific anti-DENV immunotherapy is not available and it is urgently required. In this study, human single-chain variable fragment (HuScFv) antibodies that bound specifically to the conserved non-structural protein-1 (NS1) of DENV and interfered with the virus replication cycle were produced by using phage display technology. Recombinant NS1 (rNS1) of DENV serotype 2 (DENV2) was used as antigen in phage bio-panning to select phage clones that displayed HuScFv from antibody phage display library. HuScFv from two phagemid transformed E. coli clones, i.e., clones 11 and 13, bound to the rNS1 as well as native NS1 in both secreted and intracellular forms. Culture fluids of the HuScFv11/HuScFv13 exposed DENV2 infected cells had significant reduction of the infectious viral particles, implying that the antibody fragments affected the virus morphogenesis or release. HuScFv epitope mapping by phage mimotope searching revealed that HuScFv11 bound to amino acids 1-14 of NS1, while the HuScFv13 bound to conformational epitope at the C-terminal portion of the NS1. Although the functions of the epitopes and the molecular mechanism of the HuScFv11 and HuScFv13 require further investigations, these small antibodies have high potential for development as anti-DENV biomolecules.