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Background: a-mannosidosis (MAN) is a rare genetic condition that segregates in an autosomal recessive manner. Lack of lysosomal alpha-mannosidase is the underlying cause of the disease. Symptoms of the disease gradually worsen with the age. Newborns are usually asymptomatic, however, some cases are reported with either congenital ankle equinus or hydrocephalus during the first year. Primary symptoms are characterized by immune deficiency, hearing loss, skeletal abnormalities, progressive mental, motor and speech functions' impairment followed by facial asymmetry. Methods: We studied two Saudi families (A and B) with bilateral moderate hearing loss (family A) and clubfoot with glaucoma (family B). Clinical diagnosis was not reached based on phenotype of patients. Therefore, hypothesis-free whole exome sequencing (WES) was performed on DNA samples from affected individuals of both the families, followed by Sanger sequencing and segregation analysis to validate the segregation of the identified variant. Furthermore, 3D protein modelling was performed to determine the in silico effects of the identified variant on the protein structure and function. Results: Re-examination of clinical features revealed that the patients in family A have speech delay and hearing impairment along with craniostenosis, whereas the patients from family B have only clubfoot and glaucoma. WES identified a well known pathogenic homozygous frameshift variant (NM_000528.4: c.2402dupG; p.S802fs*129) in MAN2B1 in both the families. Sanger sequencing confirmed the segregation of the variant with the disease phenotype in both the families. 3D structural modeling of the MAN2B1 protein revealed significant changes in the tertiary structure of the mutant protein, which would affect enzyme function. This report presents a new case where partial and novel a-mannosidosis phenotypes are associated with a MAN2B1 gene pathogenic variant. Conclusion: Patients in both the families have manifested peculiar set of clinical symptoms associated with a-mannosidosis. Family A manifested partial clinical symptoms missing several characteristic features like intellectual disability, dysmorphic features, neurological and abdominal manifestations, whereas family B has no reported clinical symptoms related to a-mannosidosis except the novel symptoms including club foot and glaucoma which has never been reported earlier The current findings support the evidence that biallelic variants of MAN2B1 are associated with new clinical variants of a-mannosidosis. [ABSTRACT FROM AUTHOR]

Nephrotic syndrome (NS) represents a heterogeneous group of kidney disorders characterized by excessive proteinuria, hypoalbuminemia and edema. Defects in the filtration barrier of the glomeruli results in the development of NS. The genetic cause of NS remains to be fully elucidated. However, previous studies based on positional cloning of genes mutated in NS have provided limited insight into the pathogenesis of this disease. Mutations in phospholipase C ε-1 (PLCE1) have been reported as a cause of early onset NS characterized by histology of diffuse mesangial sclerosis. In the present study, the underlying cause of NS in a consanguineous family was identified. Clinical and molecular aspects of a consanguineous Saudi family comprised of five individuals with steroid resistant NS were examined. Seven healthy individuals from the same family were also studied. Whole exome sequencing (WES) was performed to detect the genetic defect underlying NS. WES identified a homozygous novel insertion mutation (c.6272_6273insT) in the PLCE1 gene. Pedigree and segregation analysis confirmed an autosomal recessive inheritance pattern. This mutation may result in a bi-allelic loss of the C-terminal Ras-associating domain in PLCE1 that results in NS. The present study expanded the mutational spectrum of PLCE1 in NS. In addition, the present study provided further evidence that supports the important involvement of PLCE1 in the physiological function of the glomerular filtration barrier. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa (RP) is a group of inherited progressive retinal dystrophies (RD) and is characterized by photoreceptor degeneration. RP is clinically and genetically heterogeneous disorder. More than 70 genes are known and, thus, identification of causative genes and mutations in known genes is challenging. This study was designed to identify the underlying genetic defect in a large extended Saudi family with multiple RP affected members. Fundus photography, Optical Coherence Tomography (OCT) and visual field perimetry were performed for affected individuals. Whole exome sequencing was used to detect the underlying genetic defect in a large family with 12 affected individuals showing autosomal recessive isolated RP. WES data analysis identified a novel insertion mutation in the EYS (eyes shut homolog) gene (c.910_911insT; p.Trp304LeufsTer8). Sanger sequencing validates the variant discovered through exome in all 12 affected individuals and showed that this mutation is segregating with RP phenotype in an autosomal recessive manner in 51 individuals of the family tested here. Our study expands the mutation spectrum of EYS gene in RP patients and extends the body of evidence that supports the importance of EYS gene in eye development. [ABSTRACT FROM AUTHOR]

TGF β is a potent regulator of several biological functions in many cell types, but its role in the differentiation of human bone marrow-derived skeletal stem cells (hMSCs) is currently poorly understood. In the present study, we demonstrate that a single dose of TGF β 1 prior to induction of osteogenic or adipogenic differentiation results in increased mineralized matrix or increased numbers of lipid-filled mature adipocytes, respectively. To identify the mechanisms underlying this TGF β -mediated enhancement of lineage commitment, we compared the gene expression profiles of TGF β 1-treated hMSC cultures using DNA microarrays. In total, 1932 genes were upregulated, and 1298 genes were downregulated. Bioinformatics analysis revealed that TGF β l treatment was associated with an enrichment of genes in the skeletal and extracellular matrix categories and the regulation of the actin cytoskeleton. To investigate further, we examined the actin cytoskeleton following treatment with TGF β 1 and/or cytochalasin D. Interestingly, cytochalasin D treatment of hMSCs enhanced adipogenic differentiation but inhibited osteogenic differentiation. Global gene expression profiling revealed a significant enrichment of pathways related to osteogenesis and adipogenesis and of genes regulated by both TGF β 1 and cytochalasin D. Our study demonstrates that TGF β 1 enhances hMSC commitment to either the osteogenic or adipogenic lineages by reorganizing the actin cytoskeleton.