Publications by authors named "Lamiae Elkhattabi"

9 Publications

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Omenn syndrome caused by a novel homozygous mutation in recombination activating gene 1.

Immunobiology 2021 May 28;226(3):152090. Epub 2021 Apr 28.

Laboratory of Genomics and Human Genetics,Institut Pasteur du Maroc, 1 Place Louis Pasteur, 20360 Casablanca, Morocco. Electronic address:

Omenn syndrome (OS) is a type of severe combined immunodeficiency (SCID) that is distinguished by, lymphadenopathy, hepatosplenomegaly, erythroderma, alopecia with normal to elevated T-cell counts, eosinophilia, and elevated serum IgE levels. Recombination activation gene (RAG) 1 or RAG2 mutations that result in partial V(D)J recombination activity are known to be the main cause of OS. Other genes (DCLRE1C, LIG4, IL7RA, common gamma chain, ADA, RMRP, and CHD7) have also been linked to OS, although with low frequency. Here, we report a two-month-old Moroccan girl from consanguineous marriage with chronic diarrhea, recurrent and opportunistic infections, failure to thrive, desquamative erythroderma, hepatosplenomegaly, and axillary lymphadenitis. The immunological assessment showed normal lymphocyte and NK cell counts but an absence of B cells, agammaglobulinemia contrasting with a high level of IgE. On the other hand, Sanger sequencing of RAG1 and RAG2 exon 2 regions revealed a new homozygous deleterious mutation in the RAG1 gene. This c.1184C > T mutation caused a change from Proline to Leucine at position 395 of the protein, leading to a partial loss of function. Early and rapid diagnosis of the disease may facilitate urgent life-saving treatment.
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http://dx.doi.org/10.1016/j.imbio.2021.152090DOI Listing
May 2021

Novel Mutation in AIFM1 Gene Associated with X-Linked Deafness in a Moroccan Family.

Hum Hered 2020 22;85(1):35-39. Epub 2021 Jan 22.

Laboratory of Genomics and Human Genetics, Institut Pasteur du Maroc, Casablanca, Morocco,

Introduction: Auditory neuropathy is a hearing disorder where outer hair cell function within the cochlea is normal, but inner hair cell and/or the auditory nerve function is disrupted. It is a heterogeneous disorder, which can have either congenital or acquired causes.

Methods: We found a disease-segregating mutation in the X-linked AIFM1 gene through whole-exome sequencing, encoding the apoptosis-inducing factor mitochondrion-associated 1.

Results: The impact of the c.1045A>G; p.(Ser349Gly) mutation on the AIFM1 protein was predicted using different bioinformatics tools. The pedigree analysis in the examined family was consistent with X-linked dominant inheritance.

Discussion/conclusion: To our knowledge, this is the first study that identifies a mutation in the AIFM1 gene in Moroccan patients suffering from X-linked auditory neuropathy.
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http://dx.doi.org/10.1159/000512712DOI Listing
January 2021

Potential inhibitors of SARS-cov-2 RNA dependent RNA polymerase protein: molecular docking, molecular dynamics simulations and MM-PBSA analyses.

J Biomol Struct Dyn 2020 Sep 2:1-14. Epub 2020 Sep 2.

Laboratory of Genomics and Human Genetics, Département de la Recherche Scientifique, Institut Pasteur du Maroc, Casablanca, Morocco.

The SARS-cov-2 RNA dependent RNA polymerase (nsp12) is a crucial viral enzyme that catalyzes the replication of RNA from RNA templates. The fixation of some ligands in the active site may alter the viral life cycle. The aim of the present study is to identify the conservation level of nsp12 motifs (A-G), using consurf server, and discover their interactions with rifabutin, rifampicin, rifapentin, sorangicin A, streptolydigin, myxopyronin B, VXR and VRX using AutoDockTools-1.5.6, Gromacs 2018.2 and g-mmpbsa. Thus, the most of amino acids residues located in nsp12 protein Motifs (A-G) were predicted as highly conserved. The binding energies of streptolydigin, VXR, rifabutin, rifapentine, VRX, sorangicin A, myxopyronin B and rifampicin with nsp12 protein are -8.11, -8.23, -7.14, -6.94, -6.55, -5.46, -5.33 and -5.26 kcal/mol, respectively. In the other hand, the binding energies of ligand in the same order with nsp7-nsp8-nsp12 complex are -7.23, -7.08, -7.21, -7, -6.59, -8.73, -5.52, -5.87 kcal/mol, respectively. All ligands interact with at least two nsp12 motifs. The molecular dynamics simulation of nsp12-streptolydigin and nsp12-VXR complexes shows that these two complexes are stable and the number of hydrogen bonds as a function of time, after 30 ns of simulation, varies between 0 and 6 for nsp12-streptolydigin complex and between 0 and 4 for nsp12-VXR complex. The average of free binding energies obtained using g_mmpbsa, after 30 ns of simulation, is -191.982 Kj/mol for nsp12-streptolydigin complex and -153.583 Kj/mol for nsp12-VXR complex. Our results suggest that these ligands may be used as inhibitors of SARS-cov-2 nsp12 protein.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1813628DOI Listing
September 2020

Association of c.56C > G (rs3135506) Apolipoprotein A5 Gene Polymorphism with Coronary Artery Disease in Moroccan Subjects: A Case-Control Study and an Updated Meta-Analysis.

Cardiol Res Pract 2020 4;2020:5981971. Epub 2020 Aug 4.

Laboratory of Genomics and Human Genetics, Institut Pasteur Du Maroc, Casablanca, Morocco.

Purpose: Coronary artery diseases (CAD) are clinical cardiovascular events associated with dyslipidemia in common. The interaction between environmental and genetic factors can be responsible for CAD. The present paper aimed to examine the association between c.56C > G (rs3135506) APOA5 gene polymorphism and CAD in Moroccan individuals and to perform an association update meta-analysis.

Materials And Methods: The c.56C > G variant was genotyped in 122 patients with CAD and 134 unrelated controls. Genetic association analysis and comparison of biochemical parameters were performed using statistical language. In addition, a comprehensive meta-analysis including eleven published studies in addition to our case-control study results was conducted using Review Manager 5.3. Publication bias was examined by Egger's test and funnel plot.

Results: The case-control study data showed that the c.56C > G polymorphism was associated with CAD susceptibility under codominant (-value = 0.001), recessive (-value <0.001) and log-additive (-value = 0.008) inheritance models. In addition, this polymorphism was significantly associated with increased levels of systolic and diastolic blood pressures, triglycerides, glycemia, and total cholesterol. Furthermore, meta-analysis showed a significant association between the c.56C > G gene polymorphism and increased risk of CAD under recessive (OR = 3.39[1.77-6.50], value <0.001) and homozygote codominant (OR = 3.96[2.44-6.45], value <0.001) models.

Conclusion: Our case-control study revealed a significant association between c.56C > G polymorphism and CAD in the Moroccan population. In addition, meta-analysis data supported the implication of this polymorphism in CAD susceptibility.
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http://dx.doi.org/10.1155/2020/5981971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424381PMC
August 2020

Further Evidence for the Implication of the MET Gene in Non-Syndromic Autosomal Recessive Deafness.

Hum Hered 2019 4;84(3):109-116. Epub 2019 Dec 4.

Laboratoire de Génomique et Génétique Humaine, Institut Pasteur du Maroc, Casablanca, Morocco,

Mutations in the mesenchymal epithelial transition factor (MET) gene are frequently associated with multiple human cancers but can also lead to human non-syndromic autosomal recessive deafness (DFNB97). In the present study, we identified a novel homozygous missense mutation in the METgene causing a non-syndromic hearing impairment DFNB97 form. Whole-exome sequencing was performed to determine the genetic causes of hearing loss in a Moroccan consanguineous family with an affected daughter. The structural analysis of native and mutant in the SEMA domain of the MET receptor was investigated using a molecular dynamics simulation (MDS) approach. We identified a novel pathogenic homozygous c.948A>G (p.Ile316Met) mutation in the MET gene in one deaf Moroccan young girl carrying a total bilateral non-syndromic hearing impairment. The results of the MDS approach show that an Ile316Met mutation in the SEMA domain leads to protein flexibility loss. This may produce a major impact on the structural conformation of the MET receptor, which also affects the function and binding site of the receptor. This is the first time that a mutation in the MET gene is described in a Moroccan family. Moreover, this study reports the second family in the world associating deafness and mutation in the MET gene.
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http://dx.doi.org/10.1159/000503450DOI Listing
May 2020

Computational Analysis of nsSNPs of Gene in Severe Combined Immunodeficiency Using Molecular Modeling and Dynamics Simulation.

J Immunol Res 2019 3;2019:5902391. Epub 2019 Nov 3.

Laboratory of Genomics and Human Genetics, Institut Pasteur Du Maroc, 20360 Casablanca, Morocco.

Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency (PID), characterized by fatal opportunistic infections. The gene encodes adenosine deaminase, an enzyme that catalyzes the irreversible deamination of adenosine and deoxyadenosine in the catabolic pathway of purine. Mutations of the gene have been identified in patients with severe combined immunodeficiency. In this study, we performed a bioinformatics analysis of the human gene to identify potentially harmful nonsynonymous SNPs and their effect on protein structure and stability. Using eleven prediction tools, we identified 15 nsSNPs (H15D, H15P, H17Q, H17Y, D19N, T26I, G140E, C153F, A183D, G216R, H258Y, C262Y, S291L, S291W, and K34OE) as harmful. The results of ConSurf's analysis revealed that all these nsSNPs are localised in the highly conserved positions and affect the structure of the native proteins. In addition, our computational analysis showed that the H15D, G140E, G216R, and S291L mutations identified as being associated with severe combined immunodeficiency affect protein structure. Similarly, the results of the analyses of Rmsd, Rmsf, and Rg showed that all these factors influence protein stability, flexibility, and compaction with different levels of impact. This study is the first comprehensive computational analysis of nsSNPs of the gene. However, functional analyses are needed to elucidate the biological mechanisms of these polymorphisms in severe combined immunodeficiency.
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http://dx.doi.org/10.1155/2019/5902391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875294PMC
April 2020

In Silico Analysis of Coding/Noncoding SNPs of Human Gene and Characterization of Their Impact on Resistin Stability and Structure.

J Diabetes Res 2019 20;2019:4951627. Epub 2019 May 20.

Laboratoire de Génomique et Génétique Humaine, Institut Pasteur du Maroc, Casablanca, Morocco.

Resistin () is a gene coding for proinflammatory adipokine called resistin secreted by macrophages in humans. Single nucleotide polymorphisms (SNPs) in are linked to obesity and insulin resistance in various populations. Using dbSNP, 78 nonsynonymous SNPs (nsSNPs) were retrieved and tested on a PredictSNP 1.0 megaserver. Among these, 15 nsSNPs were predicted as highly deleterious and thus subjected to further analyses, such as conservation, posttranscriptional modifications, and stability. The 3D structure of human resistin was generated by homology modeling using Swiss model. Root-mean-square deviation (RMSD), hydrogen bonds (h-bonds), and interactions were estimated. Furthermore, UTRscan served to identify UTR functional SNPs. Among the 15 most deleterious nsSNPs, 13 were predicted to be highly conserved including variants in posttranslational modification sites. Stability analysis predicted 9 nsSNPs (I32S, C51Y, G58E, G58R, C78S, G79C, W98C, C103G, and C104Y) which can decrease protein stability with at least three out of the four algorithms used in this study. These nsSNPs were chosen for structural analysis. Both variants C51Y and C104Y showed the highest RMS deviations (1.137 Å and 1.308 Å, respectively) which were confirmed by the important decrease in total h-bonds. The analysis of hydrophobic and hydrophilic interactions showed important differences between the native protein and the 9 mutants, particularly I32S, G79C, and C104Y. Six SNPs in the 3'UTR (rs920569876, rs74176247, rs1447199134, rs943234785, rs76346269, and rs78048640) were predicted to be implicated in polyadenylation signal. This study revealed 9 highly deleterious SNPs located in the human gene coding region and 6 SNPs within the 3'UTR that may alter the protein structure. Interestingly, these SNPs are worth to be analyzed in functional studies to further elucidate their effect on metabolic phenotype occurrence.
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http://dx.doi.org/10.1155/2019/4951627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545779PMC
February 2020

Chromosomal Abnormalities in Patients with Intellectual Disability: A 21-Year Retrospective Study.

Hum Hered 2018 7;83(5):274-282. Epub 2019 May 7.

Laboratory of Genomics and Human Genetics, Institut Pasteur du Maroc, Casablanca, Morocco,

Background: Intellectual disability (ID) has been defined as a considerably reduced ability to understand new or complex information and to learn new skills. It is associated with life-long intellectual and adaptive functioning impairments that have a profound impact on individuals, families, and society. It affects about 3% of the general population. ID often comes out with other mental conditions like attention deficit, hyperactivity, and autism spectrum disorders (ASD), and it can be part of a malformation syndrome that affects other organs. It may be syndromic (S-ID) or non-syndromic (NS-ID).

Objective: The aims of this study were to identify the profile of intellectually disable patients being referred for cytogenetic analysis in Morocco, to determine the prevalence of chromosomal abnormalities in a Moroccan group, and to compare the results with those of analogous studies from other countries.

Participants: We included data from Moroccan patients with NS-ID and others with S-ID (mostly Down syndrome cases) who have been referred between 1996 and 2016. 1,626 patients were involved in this study, 1,200 were referred with a clinical diagnosis of Down syndrome, 37 were clinically diagnosed for ASD with ID, and 389 were suspected of NS-ID.

Results: We identified 1,200 cases of Down syndrome. In 1,096 analyses (91.3%), a cytogenetic variant of trisomy 21 was identified: standard trisomy 21 in 1,037 cases (94.6%), a translocation in 34 cases (3.10%), and mosaicism in 25 cases (2.3%). The cytogenetic analysis among ASD with ID cases did not reveal any specific chromosomal abnormalities. The present study also shows that chromosomal abnormalities were present in 6.43% of the patients with NS-ID (25 abnormal karyotypes out of 389 NS-ID cases). Autosomal structural abnormalities were the largest proportion of chromosomal aberrations.

Conclusion: The high rate of chromosomal abnormalities found in the Moroccan patients studied demonstrates the capital importance of cytogenetic evaluation in patients who show ID or any clinical development abnormality.
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http://dx.doi.org/10.1159/000499710DOI Listing
October 2019

A novel mutation in SLITRK6 causes deafness and myopia in a Moroccan family.

Gene 2018 Jun 15;659:89-92. Epub 2018 Mar 15.

Human Molecular Genetics Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco. Electronic address:

Deafness and myopia syndrome is characterized by moderate-profound, bilateral, congenital or prelingual deafness and high myopia. Autosomal recessive non-syndromic hearing loss is one of the most prevalent human genetic sensorineural defects. Myopia is by far the most common human eye disorder that is known to have a clear heritable component. The analysis of the two exons of SLITRK6 gene in a Moroccan family allowed us to identify a novel single deleterious mutation c.696delG, p.Trp232Cysfs*10 at homozygous state in the exon 2 of the SLITRK6, a gene reported to cause deafness and myopia in various populations.
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http://dx.doi.org/10.1016/j.gene.2018.03.042DOI Listing
June 2018