Bassam R Ali

United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates

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Publications (63)222.04 Total impact

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    ABSTRACT: Purpose Fifteen missense mutations in the frizzled family receptor 4 (FZD4) reported to cause familial exudative vitreoretinopathy (FEVR), were evaluated to establish the pathological cellular mechanism of disease and to explore novel therapeutic strategies. Methods The mutations were generated by site-directed mutagenesis and expressed in HeLa and Cos-7 cell lines. Confocal fluorescence microscopy (CFM) and N-glycosylation profiling were used to observe the subcellular localization of the mutant proteins relative to wild type. Polyubiquitination studies were used to establish the involvement of the proteasome. Culturing at reduced temperatures and incubation in the presence of chemical compounds were used to enhance mutant protein processing and exit out of the ER. Results CFM of the mutants showed three distinct subcellular localizations: a plasma membrane pattern, an ER pattern and a mixed pattern to both compartments. CFM and N-glycosylation profiling established the predominant ER localization of P33S, G36N, H69Y, M105T, M105V, C181R, C204R, C204Y and G488D mutants. Co-expression of these mutants with wild-type FZD4 showed the inability of the mutants to trap wild-type FZD4. Culturing the expressing cells at reduced temperatures or in the presence of chemical agents directed at ameliorating protein misfolding resulted in partial rescue of the trafficking defects observed for M105T and C204Y mutants. Conclusion Defective trafficking resulting in haploinsufficiency is a major cellular mechanism for several missense FEVR-causing FZD4 mutants. Our findings indicate that this trafficking defect might be correctable for some mutants, which may offer opportunities for the development of novel therapeutics for this condition.
    Investigative ophthalmology & visual science 04/2014; · 3.43 Impact Factor
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    ABSTRACT: The rare autosomal genetic disorder, Spondylo-meta-epiphyseal dysplasia with short limbs and abnormal calcifications (SMED-SL), is reported to be caused by missense or splice site mutations in the human discoidin domain receptor 2 (DDR2) gene. Previously our group has established that trafficking defects and loss of ligand binding are the underlying cellular mechanisms of several SMED-SL causing mutations. Here we report the clinical characteristics of two siblings of consanguineous marriage with suspected SMED-SL and identification of a novel disease causing mutation in the DDR2 gene. Clinical evaluation and radiography were performed to evaluate the patients. All the coding exons and splice sites of the DDR2 gene were sequenced by Sanger sequencing. Subcellular localization of the mutated DDR2 protein was determined by confocal microscopy, deglycosylation assay and Western blotting. DDR2 activity was measured by collagen activation and Western analysis. In addition to the typical features of SMED-SL, one of the patients has an eye phenotype including visual impairment due to optic atrophy. DNA sequencing revealed a novel homozygous dinucleotide deletion mutation (c.2468_2469DelCT) on exon 18 of the DDR2 gene in both patients. The mutation resulted in a frameshift leading to an amino acid change at position S823 and a predicted premature termination of translation (p.S823Cfs*2). Subcellular localization of the mutant protein was analyzed in mammalian cell lines, and it was found to be largely retained in the endoplasmic reticulum (ER), which was further supported by its N-glycosylation profile. In keeping with its cellular mis-localization, the mutant protein was found to be deficient in collagen-induced receptor activation, suggesting protein trafficking defects as the major cellular mechanism underlying the loss of DDR2 function in our patients. Our results indicate that the novel mutation results in defective trafficking of the DDR2 protein leading to loss of function and disease. This confirms our previous findings that DDR2 missense mutations occurring at the kinase domain result in retention of the mutant protein in the ER.
    BMC Medical Genetics 04/2014; 15(1):42. · 2.54 Impact Factor
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    ABSTRACT: Whereas many genes associated with intellectual disability (ID) encode synaptic proteins, transcriptional defects leading to intellectual disability are less well understood. We studied a large, consanguineous pedigree of Arab origin with 7 members affected with ID and mild dysmorphic features. Homozygosity mapping and linkage analysis identified a candidate region on chromosome 17 with a maximum multipoint LOD score of 6.01. Targeted high-throughput sequencing of the exons in the candidate region identified a homozygous 4-base pair deletion (c.169_172delCACT) in the METTL23 (methyltransferase like 23) gene, which is predicted to result in a frameshift (p.His57Valfs*11). Overexpressed METTL23 protein localized to both nucleus and cytoplasm, and physically interacted with GABPA (GA binding protein transcription factor, alpha subunit). GABP, of which GABPA is a component, is known to regulate the expression of genes such as THPO (thrombopoietin) and ATP5B (ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide), and is implicated in a wide variety of important cellular functions. Overexpression of METTL23 resulted in increased transcriptional activity at the THPO promoter, while knockdown of METTL23 with siRNA resulted in decreased expression of ATP5B, thus revealing the importance of METTL23 as a regulator of GABPA function. The METTL23 mutation highlights a new transcriptional pathway underlying human intellectual function.
    Human Molecular Genetics 02/2014; · 7.69 Impact Factor
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    ABSTRACT: Germline heterozygous mutations in the tumor suppresser NF1 gene cause a cancer predisposition syndrome known as neurofibromatosis type 1 (NF1). This disease is one of the most common multisystem disorders with an estimated incidence of 1 in 3,000 to 1 in 4,000 births. Clinically, NF1 patients are prone to develop "café au lait" spots, neurofibromas, Lisch nodules, freckling of the axillary, or inguinal region and optic nerve gliomas. In the present study, we report clinical and molecular findings of five unrelated patients and seven cases from four families with NF1 from UAE. To reveal the genetic defects underlying NF1 in our cohort of patients, we screened the whole coding and splice site regions of the NF1 gene. In addition, MLPA or CGH array has been used to screen for structural variations including deletions, indels, and complex rearrangements. This resulted in the identification of five distinct novel mutations and two previously reported ones. These variations included three missense and one nonsense mutations, one single base, one dinucleotide, and one large deletion. Four mutations were inherited, and the remaining were absent from both parents and therefore are "de novo" mutations. This analysis represents the spectrum of NF1 mutations in UAE and supports the premise of absence of hotspot mutations in the NF1 gene. Moreover, no obvious genotype-phenotype correlations were observed in our patients.
    Child s Nervous System 01/2014; · 1.24 Impact Factor
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    ABSTRACT: Background Congenital myasthenic syndromes with endplate acetylcholinesterase deficiency are very rare autosomal recessive disorders characterized by onset of the disease in early childhood, general weakness exacerbated by exertion, ophthalmoplegia and refractoriness to anticholinesterase drugs. To date, all reported cases have been attributed to mutations in 18 genes including the COLQ gene which encodes for a specific collagen that anchors acetylcholinesterase at the basal lamina of the neuromuscular junction. We identified an inbred Syrian family with two children of consanguineous parents from two branches affected with congenital myasthenic syndrome with endplate acetylcholinesterase deficiency. Method The absence of acetylcholinesterase antibodies was demonstrated biochemically in the patients. Consequently, all the coding regions, exon-intron boundaries and the 5’ and 3’ untranslated regions of the COLQ gene were amplified and sequenced using the Sanger sequencing method. Results We observed that the severity of the phenotype in the two affected children was variable. One patient had mild symptoms that included difficulties in gait and feeding with mild respiratory insufficiency. Her sibling died in the first months of life due to severe respiratory failure. The second patient had severe symptoms from birth and has been mechanically ventilated. DNA sequencing revealed a novel homozygous single nucleotide substitution mutation (c.1010T>C) in the COLQ gene in both patients. This substitution leads to a missense amino acid substitution at position 337 of the protein (p.Ile337Thr). This mutation is likely to impair the COLQ’s trimeric organization and therefore it’s anchoring within the synaptic basal lamina. Conclusion We identified the molecular cause underlying CMS in two patients. The marked phenotypic variation suggests that other factors including modifier genes may affect the severity of this disease.
    Pediatric Neurology. 01/2014;
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    ABSTRACT: Variants in the head and tail domains of the MYO7A gene, encoding myosin VIIA, cause Usher syndrome type 1B (USH1B) and nonsyndromic deafness (DFNB2, DFNA11). In order to identify the genetic defect(s) underling profound deafness in two consanguineous Arab families living in UAE, we have sequenced a panel of 19 genes involved in Usher syndrome and nonsyndromic deafness in the index cases of the two families. This analysis revealed a novel homozygous insertion of AG (c.1952_1953insAG/p.C652fsX11) in exon 17 of the MYO7A gene in an Iraqi family, and a homozygous point mutation (c.5660C>T/p.P1887L) in exon 41 affecting the same gene in a large Palestinian family. Moreover, some individuals from the Palestinian family also harbored a novel heterozygous truncating variant (c.1267C>T/p.R423X) in the DFNB31 gene, which is involved in autosomal recessive nonsyndromic deafness type DFNB31 and Usher syndrome type II. Assuming an autosomal recessive mode of inheritance in the two inbred families, we conclude that the homozygous variants in the MYO7A gene are the disease-causing mutations in these families. Furthermore, given the absence of retinal disease in all affected patients examined, particularly a 28 year old patient, suggests that at least one family may segregate a DFNB2 presentation rather than USH1B. This finding further supports the premise that the MYO7A gene is responsible for two distinct diseases and gives evidence that the p.P1887L mutation in a homozygous state may be responsible for nonsyndromic hearing loss.
    Molecular Biology Reports 11/2013; · 2.51 Impact Factor
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    ABSTRACT: Geleophysic dysplasia (GD) is an autosomal recessive disorder characterized by short stature, brachydactyly, stiff joints, thick skin, and cardiac valvular abnormalities that are often responsible for early death. Mutations in ADAMTSL2 and FBN1 genes have been shown to cause GD due to the dysregulation of transforming growth factor-β signaling pathways. Small numbers of mutations in ADAMTSL2 have been reported so far in patients with GD type 1 (GD1). In this study, we clinically evaluated two children from two consanguineous Arab families living in the United Arab Emirates with GD1. In addition we have sequenced all the coding exons of ADAMTSL2 gene using Sanger sequencing. The two patients exhibited most of the typical features of this rare bone dysplasia. Molecular analysis of the ADAMTSL2 gene revealed two novel homozygous missense mutations (c.938T>C, p.M313T and c.499G>A, p.D167N). The mutations segregated well in the studied families with the parents being heterozygous. In addition, bioinformatics analyses showed that these mutations are affecting conserved amino acids residues and thus strongly support their pathogenicity. We describe the clinical phenotypes of two patients with GD1 that are caused by two novel homozygous missense mutations in the ADAMTSL2 gene. Birth Defects Research (Part A), 2013. © 2013 Wiley Periodicals, Inc.
    Birth Defects Research Part A Clinical and Molecular Teratology 09/2013; · 2.27 Impact Factor
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    ABSTRACT: The chemokine receptors components play crucial roles in the immune system and some of them serve as co-receptors for the HIV virus. Several studies have documented that variants in chemokine receptors are correlated with susceptibility and resistance to infection with HIV virus. For example, mutations in the chemokine receptor 5 gene (CCR5) resulting in loss-of-function (such as the homozygous CCR5∆32) confer high degree of resistance to HIV infection, Heterozygotes for these variants exhibit slow progression to AIDS. The prevalence of CCR5 polymorphisms varies among ethnic and geographical groups. For example, the CCR5∆32 variant is present in 10-15% of north Europeans but is rarely encountered among Africans. This study aims to identify the prevalence of some CCR5 variants in two geographically distant Arab populations (namely Emiratis and Tunisians). The prevalence of CCR5 gene variants including CCR5∆32, FS299, C101X, A29S and C178R has been determined using PCR and direct DNA sequencing. A total of 403 unrelated healthy individuals (253 Emiratis and 150 Tunisians) were genotyped for the CCR5∆32 variant using PCR amplification and gel electrophoresis. In addition, 200 Emiratis have been screened for other SNPs using Sanger DNA sequencing. Among Emiratis, the allele frequency of the CCR5∆32 variant has been found to be 0.002. In addition, two variants L55Q and A159 were found at a frequency of 0.002. Moreover, the prevalence of the CCR5∆32 variant in Tunisians was estimated to be 0.013 which is relatively higher than its frequency in Emiratis but lower than Europeans. We conclude that the allele frequency of the most critical CCR5 ploymorphism (∆32) is extremely low among Emiratis compared to other Arabs and North Europeans. In addition, very low allele frequencies of other CCR5 polymorphisms have been detected among Emiratis.
    Gene 08/2013; · 2.20 Impact Factor
  • Gene 07/2013; · 2.20 Impact Factor
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    ABSTRACT: BACKGROUND: Inherited intellectual disability (ID) conditions are a group of genetically heterogeneous disorders that lead to variable degrees of cognition deficits. It has been shown that inherited ID can be caused by mutations in over 100 different genes and there is evidence for the presence of as yet unidentified genes in a significant proportion of patients. We aimed at identifying the defective gene underlying an autosomal recessive ID in two sibs of an Emirati family. METHODS: A combined approach involving homozygosity mapping and whole-exome sequencing was used to identify the causative mutation. RNA analysis was performed to gain further insight into the pathogenic effect of the detected mutation. RESULTS: We have identified a homozygous splicing mutation (c.1219_1222+1delAAAGG) in the LINS gene in the affected children. LINS is the human homologue of the Drosophila segment polarity gene lin that encodes an essential regulator of the wingless/Wnt signaling. The identified mutation alters the first consensus nucleotide of the 5' donor splice junction of intron 5 and the 3' end of exon 5. Transcript analysis revealed that this change leads to an exon skipping event resulting in direct splicing of exon 4 to exon 6. Another mutation in LINS has been described very briefly in an Iranian family with autosomal recessive ID and microcephaly. CONCLUSION: Our study confirms that LINS, a modulator of the WNT pathway, is an indispensable gene to human cognition and this finding sheds further light on the importance of WNT signaling in human brain development and/or function.
    Orphanet Journal of Rare Diseases 06/2013; 8(1):87. · 4.32 Impact Factor
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    ABSTRACT: Mutations in voltage-gated potassium channel Kv7.2 are responsible for benign familial neonatal seizures type 1, a rare monogenic autosomal dominant inherited epilepsy syndrome. We describe a novel mutation (c.1126_1127delA) in exon 9 of KCNQ2, the gene encoding for the Kv7.2 channel, in a large Emirati family with benign familial neonatal seizures type 1. The mutation leads to a frameshift at amino acid position 376, triggering loss of function and haploinsufficiency. Patients with this mutation manifest repeated clonic seizures with normal interictal electroencephalograms and favorable prognoses. Signs occur within the first days of age, lingering well into puberty. KCNQ2 mutation screening, alongside genetic counseling, should be included in diagnostic evaluations of neonatal epileptic patients, potentially sparing the need for unnecessary investigations and treatment. To our knowledge, this report is the first of a KCNQ2 mutation in an Emirati family with benign familial neonatal seizures type 1.
    Pediatric Neurology 01/2013; 48(1):63-6. · 1.42 Impact Factor
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    ABSTRACT: Lysosomal storage disorders (LSD) are rare entities of recessive inheritance. The presence of a "founder" mutation in isolated communities with a high degree of consanguinity (e.g., tribes in the Middle East North Africa, MENA, region) is expected to lead to unusually high disease prevalence. The primary aim of this study was to estimate the prevalence of LSD and report their mutation spectrum in UAE. Between 1995 and 2010, 119 patients were diagnosed with LSD (65 Emiratis and 54 non-Emiratis). Genotyping was performed in 59 (50 %) patients (39 Emirati from 17 families and 20 non-Emiratis from 17 families). The prevalence of LSD in Emiratis was 26.9/100,000 live births. Sphingolipidoses were relatively common (9.8/100,000), with GM1-gangliosidosis being the most prevalent (4.7/100,000). Of the Mucopolysaccharidoses VI, IVA and IIIB were the predominant subtypes (5.5/100,000). Compared to Western countries, the prevalence of fucosidosis, Batten disease, and α-mannosidosis was 40-, sevenfold, and fourfold higher in UAE, respectively. The prevalence of Pompe disease (2.7/100,000) was similar to The Netherlands, but only the infantile subtype was found in UAE. Sixteen distinct LSD mutations were identified in 39 Emirati patients. Eight (50 %) mutations were reported only in Emirati, of which three were novel [c.1694G>T in the NAGLU gene, c.1336 C>T in the GLB1 gene, and homozygous deletions in the CLN3 gene]. Twenty-seven (42 %) patients were clustered in five of the 70 Emirati tribes. These findings highlight the need for tribal-based premarital testing and genetic counseling.
    JIMD reports. 01/2013;
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    ABSTRACT: Carpenter syndrome is caused by mutations in the RAB23 gene that encodes a small GTPase of the Rab subfamily of proteins. Rab proteins are known to be involved in the regulation of cellular trafficking and signal transduction. Currently, only few mutations in RAB23 have been reported in patients with Carpenter syndrome. In this paper, we report the clinical features, molecular and functional analysis of 2 children from an Emirati consanguineous family with this syndrome. The affected children exhibit the typical features including craniosynostosis, typical facial appearance, polysyndactyly, and obesity. Molecular analysis of the RAB23 gene revealed a homozygous mutation affecting the first nucleotide of the acceptor splice site of exon 5 (c.482-1G>A). This mutation affects the authentic mRNA splicing and activates a cryptic acceptor site within exon 5. Thus, the erroneous splicing results in an eight nucleotide deletion, followed by a frameshift and premature termination codon at position 161 (p.V161fsX3). Due to the loss of the C-terminally prenylatable cysteine residue, the truncated protein will probably fail to associate with the target cellular membranes due to the absence of the necessary lipid modification. The p.V161fsX3 extends the spectrum of RAB23 mutations and points to the crucial role of prenylation in the pathogenesis of Carpenter syndrome within this family.
    Molecular syndromology 01/2013; 3(6):255-261.
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    ABSTRACT: We have recently shown that the hemorrhagic destruction of the brain, subependymal calcification and congenital cataracts is caused by biallelic mutations in the gene encoding junctional adhesion molecule 3 (JAM3) protein. Affected members from three new families underwent detailed clinical examination including imaging of the brain. Affected individuals presented with a distinctive phenotype comprising hemorrhagic destruction of the brain, subependymal calcification and congenital cataracts. All patients had a catastrophic clinical course resulting in death in 7 out of 10 affected individuals. Sequencing the coding exons of JAM3 revealed three novel homozygous mutations: c.2T>G (p.M1R), c.346G>A (p.E116K) and c.656G>A (p.C219Y). The p.M1R mutation affects the start codon and therefore is predicted to impair protein synthesis. Cellular studies showed that the p.C219Y mutation resulted in a significant retention of the mutated protein in the endoplasmic reticulum, suggesting a trafficking defect. The p.E116K mutant traffics normally to the plasma membrane as the wild type and may have lost its function due to the lack of interaction with an interacting partner. Our data further support the importance of JAM3 in the development and function of the vascular system and the brain.
    Human Mutation 12/2012; · 5.21 Impact Factor
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    ABSTRACT: We report on four families affected by a clinical presentation of complex hereditary spastic paraplegia (HSP) due to recessive mutations in DDHD2, encoding one of the three mammalian intracellular phospholipases A(1) (iPLA(1)). The core phenotype of this HSP syndrome consists of very early-onset (<2 years) spastic paraplegia, intellectual disability, and a specific pattern of brain abnormalities on cerebral imaging. An essential role for DDHD2 in the human CNS, and perhaps more specifically in synaptic functioning, is supported by a reduced number of active zones at synaptic terminals in Ddhd-knockdown Drosophila models. All identified mutations affect the protein's DDHD domain, which is vital for its phospholipase activity. In line with the function of DDHD2 in lipid metabolism and its role in the CNS, an abnormal lipid peak indicating accumulation of lipids was detected with cerebral magnetic resonance spectroscopy, which provides an applicable diagnostic biomarker that can distinguish the DDHD2 phenotype from other complex HSP phenotypes. We show that mutations in DDHD2 cause a specific complex HSP subtype (SPG54), thereby linking a member of the PLA(1) family to human neurologic disease.
    The American Journal of Human Genetics 11/2012; · 11.20 Impact Factor

Publication Stats

653 Citations
222.04 Total Impact Points

Institutions

  • 2007–2014
    • United Arab Emirates University
      • • College of Medicine and Health Sciences
      • • Department of Pathology
      Al Ain, Abu Dhabi, United Arab Emirates
  • 2009–2013
    • Tawam Hospital
      Al Ain, Abu Dhabi, United Arab Emirates
  • 2012
    • IBMS
      Londinium, England, United Kingdom
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
  • 1999–2007
    • Imperial College London
      • • Section of Computational and Systems Medicine (CSM)
      • • Faculty of Medicine
      • • Division of Cell and Molecular Biology
      • • Centre for Molecular Microbiology and Infection
      London, ENG, United Kingdom