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Background: HMGXB4 (additionally known as HMG2L1) is a non-histone DNA-binding protein that contains a single HMG-box domain. HMGXB4 was originally described in Xenopus where it was seen to negatively regulate the Wnt/ß-catenin signaling pathway. Materials and methods: In this study, we conducted a genetic and clinical evaluation of a single family with three affected individuals suffering from intellectual disability (ID), global developmental delay (GDD) and dysmorphic facial features.Whole genome sequencing (WGS) and Sanger sequencing were performed on the affected individuals' DNA to identify genetic variations. Additionally, a reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to assess gene expression in both the affected and unaffected individuals in the family. Result: WGS identified a homozygous frameshift variant c.1193_1196del p. (Lys398Argfs × 25) in exon 5 of the HMGXB4 gene (OMIM 604702), which completely segregated the disease phenotype in the family. Furthermore, RT-qPCR revealed a substantial decrease in the HMGXB4 gene expression in the affected individuals as compared to the unaffected individuals of the family. Conclusions: The current study is the first evidence linking a genetic variant in the HMGXB4 gene to ID, GDD, and dysmorphic facial features. Therefore, it is possible that HMGXB4 contributes significantly to developmental milestones and may be responsible for neurodevelopmental disorders in humans.
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BACKGROUND: Neuron navigator 3 (NAV3) is characterized as one of the neuron navigator family (NAV1, NAV2, NAV3) proteins predominantly expressed in the nervous system. The NAV3-encoded protein comprises a conserved AAA and coiled-coil domains characteristic of ATPases, which are associated with different cellular activities. METHODS: We describe a Saudi proband presenting a complex recessive neurodevelopmental disorder (NDD). Whole exome sequencing (WES) followed by Sanger sequencing, 3D protein modeling and RT-qPCR was performed. RESULTS: WES revealed a bi-allelic frameshift variant (c.2604_2605delAG; p.Val870SerfsTer12) in exon 12 of the NAV3 gene. Furthermore, RT-qPCR revealed a significant decrease in the NAV3 mRNA expression in the patient sample, and 3D protein modeling revealed disruption of the overall secondary structure. CONCLUSION: For the time, we associate a bi-allelic variant in the NAV3 gene causing NDD in humans.
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Mutación del Sistema de Lectura , Trastornos del Neurodesarrollo , Femenino , Humanos , Masculino , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , LinajeRESUMEN
Polydactyly is a very common digit anomaly, having extra digits in hands and/or toes. Non-syndromic polydactyly in both autosomal dominant and autosomal recessive forms are caused by disease-causing variants in several genes, including GLI1, GLI3, ZNF141, FAM92A, IQCE, KIAA0825, MIPOL1, STKLD1, PITX1, and DACH1. Whole exome sequencing (WES) followed by bi-directional Sanger sequencing was performed for the single affected individual (II-1) of the family to reveal the disease causative variant/gene. 3D protein modeling and structural molecular docking was performed to determine the effect of the identified mutation on the overall protein structure. WES revealed a novel biallelic missense variant (c.472G>C; p.Ala158Pro) in exon 6 of the FAM92A gene. The identified variant segregated perfectly with the disease phenotype using Sanger sequencing. Furthermore, Insilco analysis revealed that the variant significantly changes the protein secondary structure, and substantially impact the stability of FAM92A. We report the second FAM92A disease-causing mutation associated with recessive non-syndromic postaxial polydactyly. The data further confirms the contribution of FAM92A in limb development and patterning.
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Secuenciación del Exoma , Homocigoto , Linaje , Polidactilia , Dedos del Pie , Femenino , Humanos , Masculino , Dedos/anomalías , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Mutación/genética , Mutación Missense/genética , Fenotipo , Polidactilia/genética , Dedos del Pie/anomalíasRESUMEN
BACKGROUND: Congenital disorders of glycosylation (CDG) are a group of heterogeneous disorders caused by abnormal lipid or protein glycosylation. Variants in the FCSK gene have been reported to cause CDG. Defective FCSK-induced CDG (FCSK-CDG) has only been reported previously in three unrelated children. METHODS: In this study, we genetically and clinically examined a 3-year-old proband with resolved infantile spasms and normal development. Standard whole-exome sequencing (WES) and Sanger sequencing were performed to identify the functional impact of the variant. RESULTS: WES revealed a rare biallelic missense variant (c.3013G>C; p.Val1005Leu) in FCSK. RT-qPCR showed a significant depletion in FCSK gene expression in the affected individual. Western blotting revealed reduced FCSK expression at the protein level compared to that in the control. Furthermore, 3D protein modeling suggested changes in the secondary structure, which might affect the overall FCSK protein function. CONCLUSION: This study broadens the mutation and phenotypic spectrum of FCSK-associated developmental disorders.
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Trastornos Congénitos de Glicosilación , Exoma , Humanos , Glicosilación , Fenotipo , Mutación , Mutación Missense , Trastornos Congénitos de Glicosilación/genéticaRESUMEN
CDC42 (cell division cycle protein 42) belongs to the Rho GTPase family that is known to control the signaling axis that regulates several cellular functions, including cell cycle progression, migration, and proliferation. However, the functional characterization of the CDC42 gene in mammalian physiology remains largely unclear. Here, we report the genetic and functional characterization of a non-consanguineous Saudi family with a single affected individual. Clinical examinations revealed poor wound healing, heterotopia of the brain, pancytopenia, and recurrent infections. Whole exome sequencing revealed a de novo missense variant (c.101C > A, p.Pro34Gln) in the CDC42 gene. The functional assays revealed a substantial reduction in the growth and motility of the patient cells as compared to the normal cells control. Homology three-dimensional (3-D) modeling of CDC42 revealed that the Pro34 is important for the proper protein secondary structure. In conclusion, we report a candidate disease-causing variant, which requires further confirmation for the etiology of CDC42 pathogenesis. This represents the first case from the Saudi population. The current study adds to the spectrum of mutations in the CDC42 gene that might help in genetic counseling and contributes to the CDC42-related genetic and functional characterization. However, further studies into the molecular mechanisms that are involved are needed in order to determine the role of the CDC42 gene associated with aberrant cell migration and immune response.
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Encéfalo/anomalías , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Pancitopenia/genética , Reinfección/etiología , Cicatrización de Heridas/genética , Proteína de Unión al GTP cdc42/deficiencia , Biopsia , Encéfalo/diagnóstico por imagen , Biología Computacional/métodos , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética/métodos , Humanos , Imagen por Resonancia Magnética , Modelos Moleculares , Mutación , Pancitopenia/diagnóstico , Linaje , Conformación Proteica , Reinfección/diagnóstico , Relación Estructura-Actividad , Secuenciación del Exoma , Adulto Joven , Proteína de Unión al GTP cdc42/químicaRESUMEN
Diabetic patients have increased likelihood of developing breast cancer. Advanced glycation endproducts (AGEs) underlie the pathogenesis of diabetic complications but their impact on breast cancer cells is not understood. This study aims to determine the effects of methylglyoxal-derived bovine serum albumin AGEs (MG-BSA-AGEs) on the invasive MDA-MB-231 breast cancer cell line. By performing cell counting, using wound-healing assay, invasion assay and zymography analysis, we found that MG-BSA-AGEs increased MDA-MB-231 cell proliferation, migration and invasion through Matrigel™ associated with an enhancement of matrix metalloproteinase (MMP)-9 activities, in a dose-dependent manner. Using Western blot and flow cytometry analyses, we demonstrated that MG-BSA-AGEs increased expression of the receptor for AGEs (RAGE) and phosphorylation of key signaling protein extracellular signal-regulated kinase (ERK)-1/2. Furthermore, in MG-BSA-AGE-treated cells, phospho-protein micro-array analysis revealed enhancement of phosphorylation of the ribosomal protein 70 serine S6 kinase beta 1 (p70S6K1), which is known to be involved in protein synthesis, the signal transducer and activator of transcription (STAT)-3 and the mitogen-activated protein kinase (MAPK) p38, which are involved in cell survival. Blockade of MG-BSA-AGE/RAGE interactions using a neutralizing anti-RAGE antibody inhibited MG-BSA-AGE-induced MDA-MB-231 cell processes, including the activation of signaling pathways. Throughout the study, non-modified BSA had a negligible effect. In conclusion, AGEs might contribute to breast cancer development and progression partially through the regulation of MMP-9 activity and RAGE signal activation. The up-regulation of RAGE and the concomitant increased phosphorylation of p70S6K1 induced by AGEs may represent promising targets for drug therapy to treat diabetic patients with breast cancer.