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. 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. 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. 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.
Aminoacyl‐tRNA synthetases (ARSs) are essential enzymes for faithful assignment of amino acids to their cognate tRNA. Variants in ARS genes are frequently associated with clinically heterogeneous ...phenotypes in humans and follow both autosomal dominant or recessive inheritance patterns in many instances. Variants in tryptophanyl‐tRNA synthetase 1 (WARS1) cause autosomal dominantly inherited distal hereditary motor neuropathy and Charcot‐Marie‐Tooth disease. Presently, only one family with biallelic WARS1 variants has been described. We present three affected individuals from two families with biallelic variants (p.Met1? and p.(Asp419Asn)) in WARS1, showing varying severities of developmental delay and intellectual disability. Hearing impairment and microcephaly, as well as abnormalities of the brain, skeletal system, movement/gait, and behavior were variable features. Phenotyping of knocked down wars‐1 in a Caenorhabditis elegans model showed depletion is associated with defects in germ cell development. A wars1 knockout vertebrate model recapitulates the human clinical phenotypes, confirms variant pathogenicity, and uncovers evidence implicating the p.Met1? variant as potentially impacting an exon critical for normal hearing. Together, our findings provide consolidating evidence for biallelic disruption of WARS1 as causal for an autosomal recessive neurodevelopmental syndrome and present a vertebrate model that recapitulates key phenotypes observed in patients.
Homozygous WARS1 variants have been identified in individuals with syndromic neurodevelopmental and hearing phenotypes. Here, we performed functional studies in Caenorhabditis elegans and zebrafish.
Background
Congenital ichthyosis is a diverse group of keratinization disorders associated with generalized scaling of skin of varying severity. The non‐syndromic forms of congenital ichthyosis are ...further grouped into common ichthyosis (ichthyosis vulgaris and X‐linked ichthyosis), autosomal recessive congenital ichthyosis, and keratopathic ichthyosis.
Objective
To identify sequence variants involved in different forms of hereditary ichthyoses.
Methods
We studied eight families with different types of ichthyosis including four families with autosomal recessive congenital ichthyosis and four families with common ichthyosis. Whole exome sequencing and PCR based genotyping was carried out to find out the molecular basis of disease.
Results
In one family, a novel duplication sequence variant NM_002016.2:c.2767dupT; NP_002007.1:p.Ser923PhefsTer2 was identified in FLG gene; in four families a previously reported nonsense sequence variant NM_000359.3:c.232C>T; NP_002007.1:p.Arg78Ter was identified in TGM1 gene, while, in three families of X‐linked recessive ichthyosis, the whole STS gene (NM_001320752.2; NP_001307681.2) regions were deleted.
Study limitation
Gene expression studies have not been performed that would have strengthened the findings of computational analysis.
Conclusion
This study highlights the significance of the c.232C>T variant in the TGM1 gene as a possible founder mutation, complete STS gene deletion as reported previously in Pakistani population, while novel sequence variant in the FLG gene expands the spectrum of variations in this gene. These findings may be used for genetic counseling of the studied families.
Abstract
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.
Intellectual disability (ID) is a clinically and genetically heterogeneous disorder. It drastically affects the learning capabilities of patients and eventually reduces their IQ level below 70.
The ...current genetic study ascertained two consanguineous Pakistani families suffering from autosomal recessive intellectual developmental disorder-5 (MRT5). We have used exome sequencing followed by Sanger sequencing to identify the disease-causing variants.
Genetic analysis using whole exome sequencing in these families identified two novel mutations in the
(NM_017755.5). Family-A segregated a novel missense variant c.953A>C; p.Tyr318Ser in exon-9 of the
. The variant substituted an amino acid Tyr318, highly conserved among different animal species and located in the functional domain of
known as "SAM-dependent methyltransferase RsmB/NOP2-type". Whereas in family B, we identified a novel splice site variant c.97-1G>C that affects the splice acceptor site of
. The identified splice variant (c.97-1G>C) was predicted to result in the skipping of exon-2, which would lead to a frameshift followed by a premature stop codon (p. His86Profs
16). Furthermore, it could result in the termination of translation and synthesis of dysfunctional protein, most likely leading to nonsense-mediated decay. The dynamic consequences of
missense variant was further explored together with wildtype through molecular dynamic simulations, which uncovered the disruption of
function due to a gain in structural flexibility. The present molecular genetic study further extends the mutational spectrum of
to be involved in ID and its genetic heterogeneity in the Pakistani population.
Amelogenesis imperfecta (AI) is a highly heterogeneous group of hereditary developmental abnormalities which mainly affects the dental enamel during tooth development in terms of its thickness, ...structure, and composition. It appears both in syndromic as well as non-syndromic forms. In the affected individuals, the enamel is usually thin, soft, rough, brittle, pitted, chipped, and abraded, having reduced functional ability and aesthetics. It leads to severe complications in the patient, like early tooth loss, severe discomfort, pain, dental caries, chewing difficulties, and discoloration of teeth from yellow to yellowish-brown or creamy type. The study aimed to identify the disease-causing variant in a consanguineous family.
We recruited a consanguineous Pashtun family of Pakistani origin. Exome sequencing analysis was followed by Sanger sequencing to identify the pathogenic variant in this family.
Clinical analysis revealed hypomaturation AI having generalized yellow-brown or creamy type of discoloration in affected members. We identified a novel nonsense sequence variant c.1192C > T (p.Gln398*) in exon-12 of SLC24A4 by using exome sequencing. Later, its co-segregation within the family was confirmed by Sanger sequencing. The human gene mutation database (HGMD, 2019) has a record of five pathogenic variants in SLC24A4, causing AI phenotype.
This nonsense sequence variant c.1192C > T (p.Gln398*) is the sixth disease-causing variant in SLC24A4, which extends its mutation spectrum and confirms the role of this gene in the morphogenesis of human tooth enamel. The identified variant highlights the critical role of SLC24A4 in causing a rare AI type in humans.
Bardet-Biedl syndrome (BBS) is a rare clinically and genetically heterogeneous autosomal recessive multi-systemic disorder with 22 known genes. The primary clinical and diagnostic features include ...six different hallmarks, such as rod-cone dystrophy, learning difficulties, renal abnormalities, male hypogonadism, post-axial polydactyly, and obesity. Here, we report nine consanguineous families and a non-consanguineous family with several affected individuals presenting typical clinical features of BBS. In the present study, 10 BBS Pakistani families were subjected to whole exome sequencing (WES), which revealed novel/recurrent gene variants, including a homozygous nonsense mutation (c.94C>T; p.Gln32Ter) in the
(NM_006860.5) gene in family A, a homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the
(NM_001195306.1) gene in family B, a homozygous nonsense variant (c.720C>A; p.Cys240Ter) in the
(NM_015910.7) in family C, a homozygous nonsense variant (c.505A>T; p.Lys169Ter) in the
(NM_020347.4) in family D, pathogenic homozygous 1 bp deletion (c.775delA; p.Thr259Leufs*21) in the
/
(NM_170784.3) gene in family E, a pathogenic homozygous missense variant (c.1339G>A; p.Ala447Thr) in
(NM_024649.4) in families F and G, a pathogenic homozygous donor splice site variant (c.951+1G>A; p?) in
(NM_024649.4) in family H, a pathogenic bi-allelic nonsense variant in
(NM_170784.3) (c.119C>G; p.Ser40*) in family I, and homozygous pathogenic frameshift variants (c.196delA; p.Arg66Glufs*12) in
(NM_152384.3) in family J. Our findings extend the mutation and phenotypic spectrum of four different types of ciliopathies causing BBS and also support the importance of these genes in the development of multi-systemic human genetic disorders.
Achai is a small size cattle breed, resilient to harsh and cold environment. Cryopreservation of Achai bull semen may help to improve its genetics and preserve the germplasm. Reactive oxygen species ...(ROS) affects the structural and functional integrity of the spermatozoa. During freezing and thawing processes, the ROS make changes in the spermatozoa quality parameters and reduce total antioxidant capacity (T-AOC) of semen that is considered as marker of oxidative stress. This study was designed to determine the effect of glycine along with vitamin E on post-thawed spermatozoa quality and total antioxidant capacity in Achai cattle. The semen collection was done twice a week from four mature fertile Achai cattle bulls (n=4). The glycine was utilized as 0 mM, 5 mM, 10 mM, 15 mM, and 20 mM along with vitamin E @ 2.3 mM added constantly in each concentration. The control group contained all extenders except glycine. The results revealed that post-thawed spermatozoa motility was found significantly higher (P<0.05) at 10 mM as compared to 5 mM, 15 mM, and 20 mM. Compared with control group, glycine concentration at 10 mM and other concentrations increased progressive and fast motility (%), curvilinear, straight line, and average path velocity (μm/s). Moreover, beat cross frequency (Hz) was higher (P<0.05), and post-thaw viability (%), plasma membrane integrity, and mitochondrial membrane potential were significantly higher (P<0.05) at 10 mM of glycine concentration in comparison to control and other glycine concentrations. Besides, acrosome integrity (%) and DNA integrity (%) as well as post-thawed T-AOC were also significantly higher (P<0.05) at 10 mM of glycine concentration as compared to other glycine concentrations and control group. It is concluded that 10 mM of glycine along with vitamin E @ 2.3 mM improved cryopreserved semen quality of Achai bull.
Metallic implants have been used widely in orthopaedic field of area. Materials such as titanium, ceramic, stainless steel, and other metal alloys are commonly used to be attached on bones. Those ...material have higher stiffness than cortical bone significantly in reducing compression at the fracture site and cause the "stress-shielding" phenomenon. The materials can lead to subsequent bone loss upon healing. Besides, these materials also have limitations involving corrosion and release of ions. This study aimed to investigate the bamboo and glass fibre hybrid laminated composite for orthopaedic applications for tibia fracture fixation. This study involve the uses of bamboo and glass fibre hybrid laminas and cold pressed using epoxy resin to produce layered bamboo epoxy composite laminates with glass fibre. The mechanical properties of layered bamboo epoxy composite laminates including tensile strength and flexural strength are evaluated by using ASTM D3039 and ASTM D790 standard method. Mode of failure is identified at microscopic level using stereo zoom microscope of fractured surfaces under different types of tests. The new material will improve the utilization of locking compression plate (LCP) as the material properties was 66% closer to the cortical bone; hence, stress shielding phenomenon can be minimized. The development of a new material of locking compression plate (LCP) for tibia fracture treatment will be successfully decreased the "stress-shielding"; thus, improved the bone healing process of tibia fracture.
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