Succinic Semialdehyde Dehydrogenase Deficiency: In Vitro and In Silico Characterization of a Novel Pathogenic Missense Variant and Analysis of the Mutational Spectrum of ALDH5A1

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare, monogenic disorder affecting the degradation of the main inhibitory neurotransmitter γ-amino butyric acid (GABA). Pathogenic variants in the ALDH5A1 gene that cause an enzymatic dysfunction of succinic semialdehyde dehydrogenase (SSADH) lead to an accumulation of potentially toxic metabolites, including γ-hydroxybutyrate (GHB). Here, we present a patient with a severe phenotype of SSADHD caused by a novel genetic variant c.728T > C that leads to an exchange of leucine to proline at residue 243, located within the highly conserved nicotinamide adenine dinucleotide (NAD)⁺ binding domain of SSADH. Proline harbors a pyrrolidine within its side chain known for its conformational rigidity and disruption of protein secondary structures. We investigate the effect of this novel variant in vivo, in vitro, and in silico. We furthermore examine the mutational spectrum of all previously described disease-causing variants and computationally assess all biologically possible missense variants of ALDH5A1 to identify mutational hotspots.     

中国北方结晶基底区合金岩体的地球物理、地球化学、遥感特征及其定量评价

本文从物、化探及遥感资料的角度,论述了我国北方结晶基底区含金岩体的分类、特征标志及评价方法。按岩体所表现的物、化、遥特征,将中酸性侵人体分为继承型和非继承型两类。不同类型岩体对矿床有不同控制作用。论述了隐伏区岩体的物、化、遥特征及评价。此外,还以晋东北地区为例,说明了利用物化探、遥感资料研究和评价含金岩体的效果。     

Usher Syndrome: Genetics of a Human Ciliopathy

Usher syndrome (USH) is an autosomal recessive syndromic ciliopathy characterized by sensorineural hearing loss, retinitis pigmentosa and, sometimes, vestibular dysfunction. There are three clinical types depending on the severity and age of onset of the symptoms; in addition, ten genes are reported to be causative of USH, and six more related to the disease. These genes encode proteins of a diverse nature, which interact and form a dynamic protein network called the “Usher interactome”. In the organ of Corti, the USH proteins are essential for the correct development and maintenance of the structure and cohesion of the stereocilia. In the retina, the USH protein network is principally located in the periciliary region of the photoreceptors, and plays an important role in the maintenance of the periciliary structure and the trafficking of molecules between the inner and the outer segments of photoreceptors. Even though some genes are clearly involved in the syndrome, others are controversial. Moreover, expression of some USH genes has been detected in other tissues, which could explain their involvement in additional mild comorbidities. In this paper, we review the genetics of Usher syndrome and the spectrum of mutations in USH genes. The aim is to identify possible mutation associations with the disease and provide an updated genotype–phenotype correlation.     

甲玛铜多金属矿床锆石微量元素基本特征及成因意义

甲玛铜多金属矿四个斑岩岩体中锆石阴极发光形态显示多数为岩浆锆石,少数为热液锆石和继承锆石核。稀土配分型式均呈现重稀土元素相对富集而轻稀土元素相对亏损,少数配分型式分散且轻稀土元素含量较高的为热液锆石。Ti、Ce、(Sm/La)N、Nb/Hf等元素含量及比值范围均位于岩浆区域。所研究的锆石主要为岩浆成因,但受到热液流体作用影响。锆石特征可为判断同类型斑岩矿床的成矿潜力提供理论依据,并指导找矿。     

西藏甲玛铜多金属矿斑岩锆石成因矿物学研究

阴极发光技术已经成为研究矿物化学分带及内部生长结构的重要手段之一。本文通过对甲玛铜多金属矿四个主要斑岩岩体中锆石的阴极发光形态和微量元素的研究,讨论锆石成因及其对找矿的指导意义。锆石阴极发光形态显示多数为岩浆锆石,少数为热液锆石和继承锆石核;稀土配分型式均呈现重稀土元素相对富集而轻稀土元素相对亏损,强Ce正异常和弱Eu负异常的岩浆锆石特征,其中少数配分型式分散且轻稀土元素含量较高的为热液锆石;Ti、Ce、(Sm/La)_N、Nb/Hf等元素含量及比值范围均位于区域。甲玛矿床4个斑岩岩体中的锆石主要为岩浆成因,同时受热液流体作用的影响。因而,利用锆石特征可为判断同类型斑岩矿床的成矿潜力提供了理论依据,同时可指导找矿。     

Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia: A Translational Perspective for the Clinician-Scientist

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and potentially lethal inherited arrhythmia disease characterized by exercise or emotion-induced bidirectional or polymorphic ventricular tachyarrhythmias. The median age of disease onset is reported to be approximately 10 years of age. The majority of CPVT patients have pathogenic variants in the gene encoding the cardiac ryanodine receptor, or calsequestrin 2. These lead to mishandling of calcium in cardiomyocytes resulting in after-depolarizations, and ventricular arrhythmias. Disease severity is particularly pronounced in younger individuals who usually present with cardiac arrest and arrhythmic syncope. Risk stratification is imprecise and long-term prognosis on therapy is unknown despite decades of research focused on pediatric CPVT populations. The purpose of this review is to summarize contemporary data on pediatric CPVT, highlight knowledge gaps and present future research directions for the clinician-scientist to address.     

Deletion of POMT2 in Zebrafish Causes Degeneration of Photoreceptors

Mutations in the extracellular matrix protein eyes shut homolog (EYS) are a common cause of retinitis pigmentosa, a blinding disease characterized by photoreceptor degeneration. EYS binds to matriglycan, a carbohydrate modification on O-mannosyl glycan substitutions of the cell-surface glycoprotein α-dystroglycan. Patients with mutations in enzymes required for the biosynthesis of matriglycan exhibit syndromic retinal atrophy, along with brain malformations and congenital muscular dystrophy. Protein O-mannosyltransferase 2 (POMT2) is an enzyme required for the synthesis of O-mannosyl glycans. To evaluate the roles of O-mannosyl glycans in photoreceptor health, we generated protein O-mannosyltransferase 2 (pomt2) mutant zebrafish by CRISPR. pomt2 mutation resulted in a loss of matriglycan and abolished binding of EYS protein to α-dystroglycan. Mutant zebrafish presented with hydrocephalus and hypoplasia of the cerebellum, as well as muscular dystrophy. EYS protein was enriched near photoreceptor connecting cilia in the wild-type, but its presence and proper localization was significantly reduced in mutant animals. The mutant retina exhibited mis-localization of opsins and increased apoptosis in both rod and cone photoreceptors. Immunofluorescence intensity of G protein subunit alpha transducin 2 (GNAT2) antibody (a general cone marker) and 1D4 antibody (a long double cone marker) in mutant retinas did not differ from wild-type retinas at 1-month post fertilization, but was reduced at 6 months post fertilization, indicating significant cone degeneration. These data suggest that POMT2-mediated O-mannosyl glycosylation is required for EYS protein localization to the connecting cilium region and photoreceptor survival.     

Signal Peptide Variants in Inherited Retinal Diseases: A Multi-Institutional Case Series

Signal peptide (SP) mutations are an infrequent cause of inherited retinal diseases (IRDs). We report the genes currently associated with an IRD that possess an SP sequence and assess the prevalence of these variants in a multi-institutional retrospective review of clinical genetic testing records. The online databases, RetNet and UniProt, were used to determine which IRD genes possess a SP. A multicenter retrospective review was performed to retrieve cases of patients with a confirmed diagnosis of an IRD and a concurrent SP variant. In silico evaluations were performed with MutPred, MutationTaster, and the signal peptide prediction tool, SignalP 6.0. SignalP 6.0 was further used to determine the locations of the three SP regions in each gene: the N-terminal region, hydrophobic core, and C-terminal region. Fifty-six (56) genes currently associated with an IRD possess a SP sequence. Based on the records review, a total of 505 variants were present in the 56 SP-possessing genes. Six (1.18%) of these variants were within the SP sequence and likely associated with the patients’ disease based on in silico predictions and clinical correlation. These six SP variants were in the CRB1 (early-onset retinal dystrophy), NDP (familial exudative vitreoretinopathy) (FEVR), FZD4 (FEVR), EYS (retinitis pigmentosa), and RS1 (X-linked juvenile retinoschisis) genes. It is important to be aware of SP mutations as an exceedingly rare cause of IRDs. Future studies will help refine our understanding of their role in each disease process and assess therapeutic approaches.     

基于遗传算法的黄河疏浚系统优化计算

黄河标准化堤防建设中使用的LQS两相流潜水泵系统是由3个两相流潜水泵并联加2个泥浆泵串联组成复杂的串并联系统。笔者利用改进的遗传算法对系统进行了优化计算。结果表明,应用遗传算法可以有效地解决LQS疏浚系统的性能优化问题,无论是讣算速度还是计算结果都令人满意,同时可比传统运行方式节约大量能源。该成果已应用于黄河清淤固堤工程中,效果十分明显。