Structural and functional implications of SLC13A3 and SLC9A6 mutations: an in silico approach to understanding intellectual disability.

BACKGROUND: Intellectual disability (ID) is a condition that varies widely in both its clinical presentation and its genetic underpinnings. It significantly impacts patients' learning capacities and lowers their IQ below 70. The solute carrier (SLC) family is the most abundant class of transmembrane transporters and is responsible for the translocation of various substances across cell membranes, including nutrients, ions, metabolites, and medicines. The SLC13A3 gene encodes a plasma membrane-localized Na+/dicarboxylate cotransporter 3 (NaDC3) primarily expressed in the kidney, astrocytes, and the choroid plexus. In addition to three Na + ions, it brings four to six carbon dicarboxylates into the cytosol. Recently, it was discovered that patients with acute reversible leukoencephalopathy and a-ketoglutarate accumulation (ARLIAK) carry pathogenic mutations in the SLC13A3 gene, and the X-linked neurodevelopmental condition Christianson Syndrome is caused by mutations in the SLC9A6 gene, which encodes the recycling endosomal alkali cation/proton exchanger NHE6, also called sodium-hydrogen exchanger-6. As a result, there are severe impairments in the patient's mental capacity, physical skills, and adaptive behavior. METHODS AND RESULTS: Two Pakistani families (A and B) with autosomal recessive and X-linked intellectual disorders were clinically evaluated, and two novel disease-causing variants in the SLC13A3 gene (NM 022829.5) and the SLC9A6 gene (NM 001042537.2) were identified using whole exome sequencing. Family-A segregated a novel homozygous missense variant (c.1478 C > T; p. Pro493Leu) in the exon-11 of the SLC13A3 gene. At the same time, family-B segregated a novel missense variant (c.1342G > A; p.Gly448Arg) in the exon-10 of the SLC9A6 gene. By integrating computational approaches, our findings provided insights into the molecular mechanisms underlying the development of ID in individuals with SLC13A3 and SLC9A6 mutations. CONCLUSION: We have utilized in-silico tools in the current study to examine the deleterious effects of the identified variants, which carry the potential to understand the genotype-phenotype relationships in neurodevelopmental disorders.

Mutation screening of multiple Pakistani MCPH families revealed novel and recurrent protein-truncating mutations of ASPM.

Autosomal primary microcephaly (MCPH) is a heterogenetic disorder that affects brain's cerebral cortex size and leads to a reduction in the cranial vault. Along with the hallmark feature of reduced head circumference, microcephalic patients also exhibit a variable degree of intellectual disability as well. Genetic studies have reported 28 MCPH genes, most of which produce microtubule-associated proteins and are involved in cell division. Herein this study, 14 patients from seven Pashtun origin Pakistani families of primary microcephaly were analyzed. Mutation analysis was performed through targeted Sanger DNA sequencing on the basis of phenotype-linked genetic makeup. Genetic analysis in one family found a novel pathogenic DNA change in the abnormal spindle microtubule assembly (ASPM) gene (NM_018136.4:c.3871dupGA), while the rest of the families revealed recurrent nonsense mutation c.3978G>A (p.Trp1326*) in the same gene. The novel reported frameshift insertion presumably truncates the protein p.(Lys1291Glyfs*14) and deletes the N-terminus domains. Identification of novel ASPM-truncating mutation expands the mutational spectrum of the ASPM gene, while mapping of recurrent mutation c.3978G>A (p.Trp1326*) will aid in establishing its founder effect in the Khyber Pakhtunkhwa (KPK) inhabitant population of Pakistan and should be suggestively screened for premarital counseling of MCPH susceptible families. Most of the recruited families are related to first-degree consanguinity. Hence, all the family elders were counseled to avoid intrafamilial marriages.

Variants in HCFC1 and MN1 genes causing intellectual disability in two Pakistani families.

BACKGROUND: Intellectual disability (ID) is a neurodevelopmental condition affecting around 2% of children and young adults worldwide, characterized by deficits in intellectual functioning and adaptive behavior. Genetic factors contribute to the development of ID phenotypes, including mutations and structural changes in chromosomes. Pathogenic variants in the HCFC1 gene cause X-linked mental retardation syndrome, also known as Siderius type X-linked mental retardation. The MN1 gene is necessary for palate development, and mutations in this gene result in a genetic condition called CEBALID syndrome. METHODS: Exome sequencing was used to identify the disease-causing variants in two affected families, A and B, from various regions of Pakistan. Affected individuals in these two families presented ID, developmental delay, and behavioral abnormalities. The validation and co-segregation analysis of the filtered variant was carried out using Sanger sequencing. RESULTS: In an X-linked family A, a novel hemizygous missense variant (c.5705G > A; p.Ser1902Asn) in the HCFC1 gene (NM_005334.3) was identified, while in family B exome sequencing revealed a heterozygous nonsense variant (c.3680 G > A; p. Trp1227Ter) in exon-1 of the MN1 gene (NM_032581.4). Sanger sequencing confirmed the segregation of these variants with ID in each family. CONCLUSIONS: The investigation of two Pakistani families revealed pathogenic genetic variants in the HCFC1 and MN1 genes, which cause ID and expand the mutational spectrum of these genes.

Optimum Choice of Randomly Oriented Carbon Nanotube Networks for UV-Assisted Gas Sensing Applications.

We investigated the noise and photoresponse characteristics of various optical transparencies of nanotube networks to identify an optimal randomly oriented network of carbon nanotube (CNT)-based devices for UV-assisted gas sensing applications. Our investigation reveals that all of the studied devices demonstrate negative photoconductivity upon exposure to UV light. Our studies confirm the effect of UV irradiation on the electrical properties of CNT networks and the increased photoresponse with decreasing UV light wavelength. We also extend our analysis to explore the low-frequency noise properties of different nanotube network transparencies. Our findings indicate that devices with higher nanotube network transparencies exhibit lower noise levels. We conduct additional measurements of noise and resistance in an ethanol and acetone gas environment, demonstrating the high sensitivity of higher-transparent (lower-density) nanotube networks. Overall, our results indicate that lower-density nanotube networks hold significant promise as a viable choice for UV-assisted gas sensing applications.

Nature of the 1/f noise in graphene-direct evidence for the mobility fluctuation mechanism.

The nature of the low-frequency 1/f noise in electronic materials and devices is one of the oldest unsolved physical problems (f is the frequency). The fundamental question of the noise source-fluctuations in the mobility vs. number of charge carriers-is still debated. While there are several pieces of evidence to prove that the 1/f noise in semiconductors is due to the fluctuations in the number of the charge carriers, there is no direct evidence of the mobility fluctuations as the source of 1/f noise in any material. Herein, we measured noise in an h-BN encapsulated graphene transistor under the conditions of geometrical magnetoresistance to directly assess the mechanism of low-frequency electronic current fluctuations. It was found that the relative noise spectral density of the graphene resistance fluctuations depends non-monotonically on the magnetic field (B) with a minimum at approximately µ0B ≅ 1 (µ0 is the electron mobility). This observation proves unambiguously that mobility fluctuations are the dominant mechanism of electronic noise in high-quality graphene. Our results are important for all proposed applications of graphene in electronics and add to the fundamental understanding of the 1/f noise origin in any electronic device.

Electrical Gating of the Charge-Density-Wave Phases in Two-Dimensional h-BN/1T-TaS2 Devices.

We report on the electrical gating of the charge-density-wave phases and current in h-BN-capped three-terminal 1T-TaS2 heterostructure devices. It is demonstrated that the application of a gate bias can shift the source-drain current-voltage hysteresis associated with the transition between the nearly commensurate and incommensurate charge-density-wave phases. The evolution of the hysteresis and the presence of abrupt spikes in the current while sweeping the gate voltage suggest that the effect is electrical rather than self-heating. We attribute the gating to an electric-field effect on the commensurate charge-density-wave domains in the atomic planes near the gate dielectric. The transition between the nearly commensurate and incommensurate charge-density-wave phases can be induced by both the source-drain current and the electrostatic gate. Since the charge-density-wave phases are persistent in 1T-TaS2 at room temperature, one can envision memory applications of such devices when scaled down to the dimensions of individual commensurate domains and few-atomic plane thicknesses.

The Expansion of the Spectrum in Stuttering Disorders to a Novel ARMC Gene Family (ARMC3).

Stuttering is a common neurodevelopment speech disorder that negatively affects the socio-psychological dimensions of people with disability. It displays many attributes of a complex genetic trait, and a few genetic loci have been identified through linkage studies. Stuttering is highly variable regarding its phenotypes and molecular etiology. However, all stutters have some common features, including blocks in speech, prolongation, and repetition of sounds, syllables, and words. The involuntary actions associated with stuttering often involve increased eye blinking, tremors of the lips or jaws, head jerks, clenched fists, perspiration, and cardiovascular changes. In the present study, we recruited a consanguineous Pakistani family showing an autosomal recessive mode of inheritance. The exome sequencing identified a homozygous splice site variant in ARMC3 (Armadillo Repeat Containing 3) in a consanguineous Pashtun family of Pakistani origin as the underlying genetic cause of non-syndromic stuttering. The homozygous splice site variant (NM_173081.5:c.916 + 1G > A) segregated with the stuttering phenotype in this family. The splice change leading to the skipping of exon-8 is a loss of function (LoF) variant, which is predicted to undergo NMD (Nonsense mediated decay). Here, we report ARMC3 as a novel candidate gene causing the stuttering phenotype. ARMC3 may lead to neurodevelopmental disorders, including stuttering in humans.

Organic Vapor Sensing Mechanisms by Large-Area Graphene Back-Gated Field-Effect Transistors under UV Irradiation.

The gas sensing properties of graphene back-gated field-effect transistor (GFET) sensors toward acetonitrile, tetrahydrofuran, and chloroform vapors were investigated with the focus on unfolding possible gas detection mechanisms. The FET configuration of the sensor device enabled gate voltage tuning for enhanced measurements of changes in DC electrical characteristics. Electrical measurements were combined with a fluctuation-enhanced sensing methodology and intermittent UV irradiation. Distinctly different features in 1/f noise spectra for the organic gases measured under UV irradiation and in the dark were observed. The most intense response observed for tetrahydrofuran prompted the decomposition of the DC characteristic, revealing the photoconductive and photogating effect occurring in the graphene channel with the dominance of the latter. Our observations shed light on understanding surface processes at the interface between graphene and volatile organic compounds for graphene-based sensors in ambient conditions that yield enhanced sensitivity and selectivity.

Graphene Epoxy-Based Composites as Efficient Electromagnetic Absorbers in the Extremely High-Frequency Band.

We report on the synthesis of the epoxy-based composites with graphene fillers and test their electromagnetic shielding efficiency by the quasi-optic free-space method in the extremely high-frequency (EHF) band (220-325 GHz). The curing adhesive composites were produced by a scalable technique with a mixture of single-layer and few-layer graphene layers of few-micrometer lateral dimensions. It was found that the electromagnetic transmission, T, is low even at small concentrations of graphene fillers: T<1% at a frequency of 300 GHz for a composite with only ϕ = 1 wt% graphene. The main shielding mechanism in composites with the low graphene loading is absorption. The composites of 1 mm in thickness and a graphene loading of 8 wt% provide an excellent electromagnetic shielding of 70 dB in the sub-terahertz EHF frequency band with negligible energy reflection to the environment. The developed lightweight adhesive composites with graphene fillers can be used as electromagnetic absorbers in the high-frequency microwave radio relays, microwave remote sensors, millimeter wave scanners, and wireless local area networks.