[Chylomicron retention disease caused by SAR1B gene variations in 2 cases and literatures review].

Objective: To summarize the genotype and clinical characteristics of chylomicron retention disease (CMRD) caused by secretion associated Ras related GTPase 1B (SAR1B) gene variations. Methods: Clinical data and genetic testing results of 2 children with CMRD treated at Children's Hospital of Fudan University and Jiangxi Provincial Children's Hospital from May 2022 to July 2023 were summarized. To provide an overview of the clinical and genetic characteristics of CMRD caused by SAR1B gene variations, all of the literature was searched and reviewed from China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, China VIP database, China Biology Medicine disc and PubMed database (up to January 2024) with "chylomicron retention disease" "Anderson disease" or "Anderson syndrome" as the search terms. All relevant literatures were reviewed to summarize the clinical and genetic features of CMRD caused by SAR1B gene variations. Results: One 11-year-old boy and one 4-month-old girl with CMRD. Both patients had lipid malabsorption, failure to thrive, decreased cholesterol, elevated transaminase and creatine kinase, and Vitamin E deficiency, with homozygous variations (c.224A>G) and compound heterozygous variations (c.224A>G and c.554G>T) in SAR1B gene, respectively. Case 1 was followed up for over a month, and he still occasionally experienced lower limb muscle pain. Case 2 was followed up for more than a year, and her had caught up to normal levels. Both patients had no other significant discomfort. Literature search retrieved 0 Chinese literature and 22 English literatures. In addition to the 2 cases reported in this study, a total of 51 patients were identified as CMRD caused by SAR1B gene variations. Twenty-one types of SAR1B variants 10 missense, 4 nonsense, 3 frameshift, 1 in-frame deletion, 1 splice, 1 gross deletion, and 1 gross insertion-deletion were found among the 51 CMRD cases. Among all the patients, 49 cases had lipid malabsorption (43 cases had diarrhea or fatty diarrhea, 17 cases had vomiting, and 12 cases had abdominal distension), 45 cases had lipid soluble Vitamin deficiency (43 cases had Vitamin E deficiency, 10 cases had Vitamin A deficiency, 9 case had Vitamin D deficiency, and 5 cases had Vitamin K deficiency), 35 cases had failure to thrive, 32 cases had liver involvement (32 cases had elevated transaminases, 5 cases had fatty liver, and 3 cases had hepatomegaly), 29 cases had white small intestinal mucosa under endoscopy, and 17 cases had elevated creatine kinase, 14 cases had neuropathy, 5 cases had ocular lesions, 2 cases had acanthocytosis, 1 case had decreased cardiac ejection fraction, and 1 case was symptom-free. Conclusions: Early infancy failure to thrive and lipid malabsorption are common issues for CMRD patients. The laboratory tests are characterized by hypocholesterolemia with or without fat-soluble Vitamin deficiency, elevated liver enzymes and (or) creatine kinase. Currently, missense variations are frequent among the primarily homozygous SAR1B genotypes that have been described.

The adenosine deaminase acting on RNA 1 p150 isoform is involved in the pathogenesis of dyschromatosis symmetrica hereditaria.

BACKGROUND: Dyschromatosis symmetrica hereditaria (DSH) is characterized by the presence of hyperpigmented and hypopigmented macules mostly on the dorsal aspects of the extremities. Mutations in the adenosine deaminase acting on RNA1 (ADAR1) gene have been revealed as the cause of DSH. ADAR1 is known to give rise to two protein isoforms (p150 and p110) that differ by the 295 N-terminal amino acids, but the specific roles of its two isoforms in the pathogenesis of DSH are poorly understood. OBJECTIVES: A Chinese family with typical DSH was screened for mutation of ADAR1, and we aimed to investigate the functional significance of the identified mutation. METHODS: All exons and adjacent exon-intron sequences were amplified and sequenced. The possible influence of the identified mutation on the functionality of p150 and p110 was analysed using the minigene strategy and dual-luciferase reporter assay, respectively. RESULTS: We identified a novel two-base-pair deletion of AG (c.271_272delAG) in exon 2 of ADAR1. The AG deletion caused a frameshift mutation in the p150 isoform, and the mutant p150 transcripts were subjected to nonsense-mediated mRNA decay. However, the deletion mutation did not alter the encoded amino acid sequence of the p110 protein due its position in the 5'-untranslated region of the p110 isoform, and had no significant influence on the expression of p110. CONCLUSIONS: The results represent the first evidence that the ADAR1 p150 isoform is the determinant of DSH and may give insight into the currently unknown mechanisms involved in the development of DSH.

Polymorphisms in microRNA target sites influence susceptibility to schizophrenia by altering the binding of miRNAs to their targets.

Single nucleotide polymorphisms (SNPs) in 3' untranslated regions (3' UTRs) of genes may affect miRNA binding to messenger RNA and contribute to the risk of disease. Whether the SNPs that modify miRNA binding in the 3' UTR are involved in schizophrenia-related genes remains unclear. We selected 803 SNPs from the 3' UTRs of 425 candidate genes for schizophrenia. The potential target SNPs were recognized by Gibbs free energy of miRNA binding. Some SNPs were associated in the literature with schizophrenia or other related neurological diseases. A case-control study of nine SNPs not previously reported as significant in any disease was carried out in a Chinese-Han cohort. We found that rs3219151 (C>T, GABRA6) showed significant decreased risk for schizophrenia (OR=0.8121, p=0.008, p(adjust)=0.03). Further, two putative target SNPs, rs165599 (COMT) and rs10759 (RGS4) reported in several references previously, were selected for analysis by luciferase assay to determine their modification to miRNA binding. We found that miR-124 showed significantly repressed 3' UTR binding to RGS4 mRNA from the rs10759-C allele (p<0.05). Our results suggest that rs3219151 of GABRA6 was associated significantly to decrease the risk of schizophrenia, rs10759 (RGS4) was possible to increase the risk of schizophrenia by miRNA altering the binding of miRNAs to their targets influencing susceptibility to schizophrenia.

A two-method meta-analysis of Neuregulin 1(NRG1) association and heterogeneity in schizophrenia.

NRG1 is one of the most researched genes associated with schizophrenia. Although three meta-analyses in this area have been published, the results have been inconclusive and even conflicting. Family based studies can be problematical due to the difficulty of synthesizing them with case-control studies. Heterogeneity is another persistently difficult problem which tends to be side-stepped in genetic studies. To deal with these points, we performed a meta-analysis of 26 published case-control and family-based association studies up to September 2008 covering 8049 cases, 8869 controls and 1515 families. The matrix of coancestry coefficient was also calculated using population genetics. Across these studies, the conclusions are as follows: Firstly, only SNP8NRG221132, 420M9-1395(0) and 478B14-848(0) showed significant association in the relatively small sample size. Secondly, we applied both Kazeem's and Lohmueller's methods for synthesizing family and case control studies and there was no statistically significant difference between the results from the two methods, suggesting that either method can be used. In addition, the association analysis of case-control studies was statistically consistent with that of family studies. Finally, the matrix of coancestry coefficient suggested obvious population stratification. The study reveals that one SNP of the NRG1 gene does not contribute significantly to schizophrenia and that population stratification is evident. In future genetic association analysis on complex psychic diseases, haplotype blocks and population structure should be given greater consideration.

Genetic analysis, molecular tagging and mapping of the thermo-sensitive genic male-sterile gene (wtms1) in wheat.

A thermo-sensitive genic male-sterile (TGMS) wheat line ( Triticum aestivum L.) BNY-S was obtained from the spontaneous mutant of BNY-F. Its fertility was decided by the temperature during the differentiation stage of the spikelets. BNY-S was completely sterile when the temperature was lower than 10 degrees C during the differentiation stage of the spikelets, but fertile when the temperature was higher than 10 degrees C. Genetic analysis indicated that the sterility of BNY-S was controlled by a single recessive gene, which was named as wtms1. An F(2) population, consisting of 3,000 individuals from the cross between BNY-S and Lankao 52-24, was used for genetic analysis and statistical analysis of the TGMS and, out of them, 158 sterile and 93 fertile extremes were present for molecular tagging and mapping of the wtms1 gene. SSR (simple sequence repeat) and AFLP (amplified fragment length polymorphism) techniques combined with BSA (bulked segregant analysis) were used to screen markers linked to the target gene. As a result, wtms1 was preliminarily mapped on chromosome 2B according to SSR analysis. In AFLP analysis, 14 polymorphic AFLP loci were identified with a linkage relation to the wtms1 gene. Then linkage analysis using the F(2) population showed that three of them, E: AAG/M: CTA(163), E: AGG/M: CTC(220) and E: ACA/M: CTA(160), were linked to the wtms1 gene relatively close to a genetic distance of 6.9 cM, 6.9 cM and 13.9 cM, respectively. Finally, the wtms1 gene was mapped between the SSR marker Xgwm 374 and the AFLP marker E: AAG/M: CTA(163) with the distance of 4.8 cM and 6.9 cM, respectively. A partial linkage map was constructed according the SSR and AFLP data.

Fine mapping of the rice thermo-sensitive genic male-sterile gene tms5.

AnnongS-1, a thermo-sensitive genic male-sterile (TGMS) rice line, has a new TGMS gene. Genetic analysis indicated that the sterility of AnnongS-1 was controlled by a single resessive gene named tms5. In our previous studies based on an F(2) population from the cross between AnnongS-1 and Nanjing11, tms5 was mapped on chromosome 2. Recently, a RIL (recombinant inbred line) population from the same cross was developed and used for the fine mapping of the tms5 gene. Molecular marker techniques combined with BSA (bulked segregant analysis) were used. As a result, two AFLP markers (AF10, AF8), one RAPD marker (RA4), one STS marker (C365-1), one CAPs marker (G227-1) and four SSR markers (RM279, RM492, RM327, RM324) were found to be closely linked to tms5 gene. The DNA sequences of the RFLP marker of C365 and G227 were found in GenBank, and on the basis of these sequences, many primers were designed to amplify the two parents and their RIL population plants. Finally, the tms5 gene was mapped between STS marker C365-1 and CAPs marker G227-1 at a distance of 1.04 cM from C365-1 and 2.08 cM from G227-1.

Tagging and mapping of rice sheath blight resistant gene.

Sheath blight (Rhizoctonia solani Kühn) is one of the severe rice diseases worldwide. In this study, an F(2) population from a cross between "4011" and "Xiangzaoxian19" is used to identify molecular markers linked with the resistant trait. "4011" was a transgenic rice cultivar carrying a resistant gene to sheath blight, while "Xiangzaoxian19" is a highly susceptible one. As a result, five molecular markers, including three RFLP markers converted from RAPD and AFLP markers, and two SSR markers were identified to link with the sheath blight resistant gene. This dominant resistant gene was named as R sb 1 and mapped on rice chromosome 5. The linkage distance between the markers (E-AT:M-CAC(120), E-AT:M-CTA(230), OPN-16(2000), RM164(320) and RM39(300)) and R sb 1 was 1.6 cM, 9.9 cM, 1.6 cM, 15.2 cM and 1.6 cM, respectively.