Muhammad Faheem

Molecular genetics of human primary microcephaly: an overview

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder that is characterised by microcephaly present at birth and non-progressive mental retardation. Microcephaly is the outcome of a smaller but architecturally normal brain; the cerebral cortex exhibits a significant decrease in size. MCPH is a neurogenic mitotic disorder, though affected patients demonstrate normal neuronal migration, neuronal apoptosis and neural function. Twelve MCPH loci (MCPH1-MCPH12) have been mapped to date from various populations around the world and contain the following genes: Microcephalin, WDR62, CDK5RAP2, CASC5, ASPM, CENPJ, STIL, CEP135, CEP152, ZNF335, PHC1 and CDK6. It is predicted that MCPH gene mutations may lead to the disease phenotype due to a disturbed mitotic spindle orientation, premature chromosomal condensation, signalling response as a result of damaged DNA, microtubule dynamics, transcriptional control or a few other hidden centrosomal mechanisms that can regulate the number of neurons produced by neuronal precursor cells. Additional findings have further elucidated the microcephaly aetiology and pathophysiology, which has informed the clinical management of families suffering from MCPH. The provision of molecular diagnosis and genetic counselling may help to decrease the frequency of this disorder.

Next Generation Sequencing of Acute Myeloid Leukemia: Influencing Prognosis

Acute myeloid leukemia (AML) is a clonal disorder of the blood forming cells characterized by accumulation of immature blast cells in the bone marrow and peripheral blood. Being a heterogeneous disease, AML has been the subject of numerous studies that focus on unraveling the clinical, cellular and molecular variations with the aim to better understand and treat the disease. Cytogenetic-risk stratification of AML is well established and commonly used by clinicians in therapeutic management of cases with chromosomal abnormalities. Successive inclusion of novel molecular abnormalities has substantially modified the classification and understanding of AML in the past decade. With the advent of next generation sequencing (NGS) technologies the discovery of novel molecular abnormalities has accelerated. NGS has been successfully used in several studies and has provided an unprecedented overview of molecular aberrations as well as the underlying clonal evolution in AML. The extended spectrum of abnormalities discovered by NGS is currently under extensive validation for their prognostic and therapeutic values. In this review we highlight the recent advances in the understanding of AML in the NGS era.

Bacteria from marine sponges: A source of new drugs.

BACKGROUNDnSponges are rich source of bioactive natural products synthesized by the symbiotic bacteria belonging to different phyla. Due to a competition for space and nutrients the marine bacteria associated with sponges could produce more antibiotic substances. To explore the proactive potential of marine microbes extensive research has been done. These bioactive metabolites have some unique properties that are pharmaceutically important.nnnMETHODSnFor this review, we have performed a non-systematic search of the available literature though various online search engines. This review provides an insight that how majority of active metabolites have been identified from marine invertebrates of which sponges predominate.nnnRESULTSnSponges harbor abundant and diverse microorganisms, which are the sources of a range of marine bioactive metabolites. From sponges and their associated microorganisms, approximately 5,300 different natural compounds are known. Current research on sponge-microbe interaction and their active metabolites has become a focal point for many researchers. Various active metabolites derived from sponges are now known to be produced by their symbiotic microflora.nnnCONCLUSIONnIn this review, we attempt to report the latest studies regarding capability of bacteria from sponges as producers of bioactive metabolite. Moreover, these sponge associated bacteria are an important source of different enzymes of industrial significance. In present review, we will address some novel approaches for discovering marine metabolites from bacteria that have the greatest potential to be used in clinical treatments.

Genome wide analysis of novel copy number variations duplications/deletions of different epileptic patients in Saudi Arabia

BackgroundEpilepsy is genetically complex neurological disorder affecting millions of people of different age groups varying in its type and severity. Copy number variants (CNVs) are key players in the genetic etiology of numerous neurodevelopmental disorders and prior findings also revealed that chromosomal aberrations are more susceptible against the pathogenesis of epilepsy. Novel technologies, such as array comparative genomic hybridization (array-CGH), may help to uncover the pathogenic CNVs in patients with epilepsy.ResultsThis study was carried out by high density whole genome array-CGH analysis with blood DNA samples from a cohort of 22 epilepsy patients to search for CNVs associated with epilepsy. Pathogenic rearrangements which include 6p12.1 microduplications in 5 patients covering a total region of 99.9kb and 7q32.3 microdeletions in 3 patients covering a total region of 63.9kb were detected. Two genes BMP5 and PODXL were located in the predicted duplicated and deleted regions respectively. Furthermore, these CNV findings were confirmed by qPCR.ConclusionWe have described, for the first time, several novel CNVs/genes implicated in epilepsy in the Saudi population. These findings enable us to better describe the genetic variations in epilepsy, and could provide a foundation for understanding the critical regions of the genome which might be involved in the development of epilepsy.

Interaction of Different Proteins with GABA A Receptor and their Modulatory Effect on Inhibitory Neural Transmission Leads to Epilepsy

γ-Aminobutyric acid type A receptors (GABAARs) are key players in the mediation of synaptic inhibition in the mammalian brain. Several proteins have a significant role in the complex trafficking mechanisms of GABAARs to and from the neuronal surface. Proper trafficking maintain number and localization of GABAAR at the neuronal surface which is necessary for inhibitory neuronal transmission. Among many other proteins, recently identified molecular motor protein KIF5A is also involved in the GABAAR trafficking by interacting with GABARP protein. Deletion in the KIF5A can impair transportation mechanism of GABAAR, while an inappropriate inhibitory GABAAR mediated neuronal transmission leads to epilepsy. In this article, we discussed the dynamic regulation of GABAAR, role of different proteins in GABAAR trafficking, clustering and endocytosis by direct interaction with GABAAR or interaction through adaptor proteins linked with microtubules and also the dysregulation of GABAAR trafficking in epilepsy. It is concluded that various proteins are involved in the GABAAR trafficking; mutation or any other change in the interacting proteins can reduce the GABAAR trafficking and also reduces their cell surface expression which may lead to epilepsy.

Epilepsy: knowledge, attitude and awareness in Jeddah Saudi Arabia

Results Total of the 1122 respondents who completed the survey, 1023 (91%) reported their awareness of the disorder, 514 (46%) witnessed an epileptic seizure during their lifetime and 715 (64%) stated their unawareness of handling a patients with an epileptic seizure. A total of 985 (88%) reported that epilepsy is not an infectious disease, 712 (63%) believed that epilepsy is not related to evil or Jin’s possession, 794 (71%) accepted sharing of schools with epileptic patients, 877 (78%) believed that an epileptic patient is capable of living a normal life, although 548 (49%) refused to marry an epileptic patient. Additionally, 1067 (95%) showed their encouragement to build and support the existence of an organization that will support epileptic patients. Conclusions Our results showed that epilepsy is a well-known disorder in Saudi Arabia but the level of awareness was very low and it can be improved by educating the people. Residents of Jeddah seemed to accept epileptic patients for their condition but still clearly unaware of what the neurological disorder truly means. This survey showed that most of the responses were due to misunderstanding of the disorder. Hence, basic educational awareness programs and campaigns are needed for building an epileptic friendly society. Furthermore, this survey will also provide a base for international comparison of epilepsy with Saudi Arabia.

In silico inhibition of GABARAP activity using antiepileptic medicinal derived compounds.

Epilepsy is a neurological disorder affecting more than 50 million people worldwide. It can be controlled by antiepileptic drugs (AEDs) but more than 30% patients are still resistant to AEDs. To overcome this problem, researchers are trying to develop novel approaches to treat epilepsy including the use of herbal medicines. The γ-amino butyric acid type-A receptor associated protein (GABARAP) is ubiquitin-like modifier implicated in the intracellular trafficking of GABAAR. An in silico mutation was created at 116 amino acid position G116A, and an in silico study was carried out to identify the potential binding inhibitors (with antiepileptic properties) against the active sites of GABARAP. Five different plant derived compounds namely (a) Aconitine (b) Berberine (c) Montanine (d) Raubasine (e) Safranal were selected, and their quantitative structure-activity relationships (QSAR) have been conducted to search the inhibitory activity of the selected compounds. The results have shown maximum number of hydrogen bond (H-bond) interactions of Raubasine with highest interaction energy among all of the five compounds. So, Raubasine could be the best fit ligand of GABARAP but in vitro, and in vivo studies are necessary for further confirmation.

PCR-Based Molecular Diagnosis of Hepatitis Virus (HBV and HDV) in HCV Infected Patients and Their Biochemical Study

Seroprevalence of HCV indicates that HCV is found in more than 10% of HBV- or HDV-infected patients worldwide leading to liver disease. Here we show HBV and HDV coinfection association with HCV infected Pakistani patients, study of disease severity, and possible interpretation of associated risk factors in coinfected patients. A total of 730 liver diseased patients were included, out of which 501 were found positive for HCV infection via PCR. 5.1% of patients were coinfected with HBV while 1% were coinfected with HBV and HDV both. LFTs were significantly altered in dually and triply infected patients as compared to single HCV infection. Mean bilirubin, AST, and ALT levels were highest (3.25u2009mg/dL, 174u2009IU/L, and 348u2009IU/L) in patients with triple infection while dual infection LFTs (1.6u2009mg/dL, 61u2009IU/L, and 74u2009IU/L) were not high as in single infection (1.9u2009mg/dL, 76u2009IU/L, and 91u2009IU/L). The most prominent risk factor in case of single (22%) and dual infection (27%) group was “reuse of syringes” while in triple infection it was “intravenous drug users” (60%). It is concluded that HBV and HDV coinfections are strongly associated with HCV infected Pakistani patients and in case of severe liver disease the possibility of double and triple coinfection should be kept in consideration.

Microarray based comparative genome hybridization detects genomic imbalances deletions and duplications in different epileptic patients of Saudi Arabia

Materials and methods We performed genome wide study of CNVs in epileptic patients by using high density array comparative genome hybridization (CGH) technology for the identification of novel chromosomal aberrations. For this purpose, a cohort of 60 patients suffering with epileptic disorders was recruited. Investigation by array CGH was done for the detection of their chromosomal aberrations. The attained results were analyzed by microarray data analysis software PARTEK and the novelty of CNVs was checked by using Database of Genomic Variants (DGV). Furthermore, array CGH results amplification and deletions were confirmed by quantitative real time PCR.