Publications by authors named "Gulab Sher"

12 Publications

  • Page 1 of 1

The effect of protein mutations on drug binding suggests ensuing personalised drug selection.

Sci Rep 2021 06 29;11(1):13452. Epub 2021 Jun 29.

Department of Chemistry, Centre for Computational Science, University College London, London, WC1H 0AJ, UK.

The advent of personalised medicine promises a deeper understanding of mechanisms and therefore therapies. However, the connection between genomic sequences and clinical treatments is often unclear. We studied 50 breast cancer patients belonging to a population-cohort in the state of Qatar. From Sanger sequencing, we identified several new deleterious mutations in the estrogen receptor 1 gene (ESR1). The effect of these mutations on drug treatment in the protein target encoded by ESR1, namely the estrogen receptor, was achieved via rapid and accurate protein-ligand binding affinity interaction studies which were performed for the selected drugs and the natural ligand estrogen. Four nonsynonymous mutations in the ligand-binding domain were subjected to molecular dynamics simulation using absolute and relative binding free energy methods, leading to the ranking of the efficacy of six selected drugs for patients with the mutations. Our study shows that a personalised clinical decision system can be created by integrating an individual patient's genomic data at the molecular level within a computational pipeline which ranks the efficacy of binding of particular drugs to variant proteins.
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http://dx.doi.org/10.1038/s41598-021-92785-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241852PMC
June 2021

Molecular characteristics of Neisseria meningitidis in Qatar.

Sci Rep 2021 02 26;11(1):4812. Epub 2021 Feb 26.

Hamad Medical Corporation, Doha, Qatar.

The aim of the current study is to review the molecular characteristics of Neisseria meningitidis (N. meningitidis) in Hamad Medical Corporation, which is the provider of secondary and tertiary care in the state of Qatar. A total of 39 isolates of N. meningitidis from the period of 2013 to 2018 were revived and identified by Vitek, and susceptibility on the basis of the E test was retrieved from the patient's files. The revived isolates were subjected to multilocus sequence typing. The most common serogroup (19) of N. meningitidis was W135, of which 12 were isolated from blood and CSF. ST-11 was the most predominant ST clonal complex causing N. meningitidis cases (61.53%). Clonal complex ST-41/44 was the second most observed complex (3, 2 of which were related to serogroup B). The most frequent sequence type was 9596 (8 isolates). Determining the molecular pattern of N. meningitidis in Qatar is helpful for understanding the strains circulating in Qatar, and the study of the resistance trend of such strains may be very helpful for empirical treatment of future patients.
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http://dx.doi.org/10.1038/s41598-021-84262-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910605PMC
February 2021

Epigenetic and breast cancer therapy: Promising diagnostic and therapeutic applications.

Semin Cancer Biol 2020 Aug 25. Epub 2020 Aug 25.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar. Electronic address:

The global burden of breast cancer (BC) is increasing significantly. This trend is caused by several factors such as late diagnosis, limited treatment options for certain BC subtypes, drug resistance which all lead to poor clinical outcomes. Recent research has reported the role of epigenetic alterations in the mechanism of BC pathogenesis and its hallmarks include drug resistance and stemness features. The understanding of these modifications and their significance in the management of BC carcinogenesis is challenging and requires further attention. Nevertheless, it promises to provide novel insight needed for utilizing these alterations as potential diagnostic, prognostic markers, predict treatment efficacy, as well as therapeutic agents. This highlights the importance of continuing research development to further advance the existing knowledge on epigenetics and BC carcinogenesis to overcome the current challenges. Hence, this review aims to shed light and discuss the current state of epigenetics research in the diagnosis and management of BC.
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http://dx.doi.org/10.1016/j.semcancer.2020.08.009DOI Listing
August 2020

Outcome associated with EPCAM founder mutation c.499dup in Qatar.

Eur J Med Genet 2020 Oct 28;63(10):104023. Epub 2020 Jul 28.

Diagnostic Genomic Division, Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, Doha, 3050, Qatar.

Tufting enteropathy (TE) is a rare autosomal recessive congenital enteropathy that usually requires long-term parenteral nutrition (PN). In the Arabic Peninsula, four distinct EPCAM mutations have been identified to cause TE. As consanguineous marriages are socially favored, pre-marital and pre-conception testing has become a critical disease prevention strategy. This study aimed to identify the pathogenic EPCAM mutations causing TE in Qatari families and determine possible genotype-phenotype correlations. Twenty-two TE patients from seven multiplex families with TE were identified. Blood samples were collected from patients and first-degree relatives. Exons of the gene were amplified and sequenced. Retrospective chart review and/or family interviews were conducted to determine phenotypic characteristics of the disease. Sequence analysis revealed a single, previously described c.499dup mutation in exon 5 of all families tested, suggesting a founder effect. Of the 18 patients whose full clinical information was available, three patients (17%) were off PN with a good quality of life, without intestinal transplantation, and one (6%) was receiving partial PN. Our patients with TE were severely stunted compared to a similar group of patients receiving long-term PN for short bowel syndrome, suggesting that this could possibly be due to TE rather than secondary to inadequate nutrition. Our study identified the EPCAM mutation c.499dup as the genetic defect causing TE in all the participant Qatari families. This finding should facilitate early diagnosis of TE and genetic counseling. Furthermore, it should aid in the prevention of TE through pre-marital screening, antenatal diagnosis, and pre-implantation genetic diagnosis.
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http://dx.doi.org/10.1016/j.ejmg.2020.104023DOI Listing
October 2020

Role of non-coding RNAs in the progression and resistance of cutaneous malignancies and autoimmune diseases.

Semin Cancer Biol 2020 Jul 25. Epub 2020 Jul 25.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar; Department of Medicine, Weill Cornell Medicine Qatar, Qatar Foundation-Education City, Doha 24144, Qatar; Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; College of Medicine, Qatar University, Doha 2713, Qatar.

Skin, the largest organ of human body, is vital for the existence and survival of human beings. Further, developmental and physiological mechanisms associated with cutaneous biology are vital for homeostasis as their deregulations converge towards pathogenesis of a number of skin diseases, including cancer. It has now been well accepted that most of the transcribed human genome lacks protein translational potential and has been termed as non-coding RNAs (nc-RNAs), which includes circular RNA (circRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), micro RNA (miRNA), long noncoding RNA (lncRNA), and piwi-interacting RNA (piRNAs). These nc-RNAs have gained great attention in both preclinical and clinical research as they are critical in most of the regulatory mechanisms of biological homeostasis and disease development by controlling the gene expression at transcriptional, post-transcriptional and epigenetic level. In this review we have illustrated how nc-RNAs are critical in the development and maintenance of cutaneous homeostasis and functioning and also, most importantly, how the dysregulated expression and functioning of nc-RNAs play critical role in the pathogenesis of cutaneous diseases including cancer and the autoimmune skin diseases. Considering the vital role of nc-RNAs in cancer resistance, metastasis and autoimmune diseases, we have also highlighted their role as promising prognostic and therapeutic targets for the cutaneous diseases.
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http://dx.doi.org/10.1016/j.semcancer.2020.07.003DOI Listing
July 2020

Prevalence and Type Distribution of High-Risk Human Papillomavirus (HPV) in Breast Cancer: A Qatar Based Study.

Cancers (Basel) 2020 Jun 10;12(6). Epub 2020 Jun 10.

Breast Cancer Unit, Hamad General Hospital, Hamad Medical Corporation, Doha P.O. Box 3050, Qatar.

Human papillomavirus (HPV) has been implicated in the etiology of a variety of human cancers. Studies investigating the presence of high-risk (HR) HPV in breast tissue have generated considerable controversy over its role as a potential risk factor for breast cancer (BC). This is the first investigation reporting the prevalence and type distribution of high-risk HPV infection in breast tissue in the population of Qatar. A prospective comparison blind research study herein reconnoitered the presence of twelve HR-HPV types' DNA using multiplex PCR by screening a total of 150 fresh breast tissue specimens. Data obtained shows that HR-HPV types were found in 10% of subjects with breast cancer; of which the presence of HPV was confirmed in 4/33 (12.12%) of invasive carcinomas. These findings, the first reported from the population of Qatar, suggest that the selective presence of HPV in breast tissue is likely to be a related factor in the progression of certain cases of breast cancer.
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http://dx.doi.org/10.3390/cancers12061528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352582PMC
June 2020

Molecular Diagnosis of Rare Autosomal Recessive Escobar Syndrome in a Consanguineous Pakistani Family.

Genet Test Mol Biomarkers 2018 Dec 21;22(12):714-718. Epub 2018 Nov 21.

Medical Genetics Research Laboratory, Department of Biotechnology, Quaid-i-Azam University, Islamabad, Pakistan.

Escobar syndrome, a nonlethal variant of multiple pterygium syndromes (MPS), is a rare autosomal recessive disorder characterized by pterygia and multiple joint contractures along with other anomalies. Variants in cholinergic receptor nicotinic gamma subunit () have been previously reported in patients with Escobar syndrome. We studied a consanguineous Pakistani family affected with Escobar syndrome to identify the underlying genetic defect through short tandem repeat (STR) genotyping and direct DNA sequencing. Genotyping with microsatellite markers (D2S427, D2S2344, and D2S206) revealed linkage of the disease phenotype in the family to the locus. Using Sanger sequencing, we identified a homozygous nonsense variant c.136C>T (p.R46*), predicted to produce a truncated protein that leads to acetylcholine receptor deficiency, causing MPS. The unaffected parents and siblings in the family were heterozygous carriers of this disease-causing variant. We report the identification of a nonsense variant in a consanguineous Pakistani family affected with Escobar syndrome.
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http://dx.doi.org/10.1089/gtmb.2018.0122DOI Listing
December 2018

Genetic Testing of a Large Consanguineous Pakistani Family Affected with Mucolipidosis III Gamma Through Next-Generation Sequencing.

Genet Test Mol Biomarkers 2018 Sep;22(9):541-545

1 Medical Genetics Research Laboratory, Department of Biotechnology, Quaid-i-Azam University , Islamabad, Pakistan .

Background: Mucolipidosis III gamma (MLIIIγ) is a rare autosomal recessive disorder characterized by radiographic evidence of mild-to-moderate dysostosis multiplex, progressive joint stiffness and pain, scoliosis, and normal to mildly impaired cognitive development. Cardiac valve involvement and respiratory complications can be significant. MLIIIγ is caused by mutations in the GNPTG, which encodes the γ subunit of the enzyme N-acetylglucosamine-1-phosphotransferase.

Objective: Clinical and genetic study of seven individuals of a consanguineous Pakistani family affected with mucolipidosis phenotype who never pursued medical care.

Methods: Genome-wide homozygosity mapping was performed using Affymetrix Human SNP Array 6.0 followed by whole exome and Sanger sequencing.

Results: The affected individuals showed characteristic clinical features of MLIIIγ. Whole-genome single nucleotide polymorphism genotyping identified a region of homozygosity shared by affected individuals of the family on chromosome 16p13.3. Whole exome sequencing identified a novel 4-bp deletion in the GNPTG segregating in the family in agreement with autosomal recessive pattern.

Conclusions: We identified a novel mutation in the GNPTG gene as the underlying cause of MLIIIγ in a Pakistani family. This study supports the role of next-generation sequencing technologies for the molecular diagnosis of rare inherited disorders.
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http://dx.doi.org/10.1089/gtmb.2018.0123DOI Listing
September 2018

A novel CHSY1 gene mutation underlies Temtamy preaxial brachydactyly syndrome in a Pakistani family.

Eur J Med Genet 2014 Jan 20;57(1):21-4. Epub 2013 Nov 20.

Department of Biotechnology, Quaid-i-Azam University, Islamabad 45320, Pakistan. Electronic address:

Temtamy preaxial brachydactyly syndrome (TPBS) is an autosomal recessive rare disorder characterized by hyperphalangism of digits, facial dysmorphism, dental anomalies, sensorineural hearing loss, delayed motor and mental development, and growth retardation. Loss of function mutations have been recently reported in the CHSY1 gene to cause the TPBS. Here, we report a novel missense mutation (c.1897 G > A) in the CHSY1 gene in two TPBS patients from a consanguineous Pakistani family. The mutation predicted substitution of a highly conserved aspartate amino acid residue to asparagine at position 633 in the protein (D633N). Polyphen analysis supported the pathogenicity of D36N mutation. Our finding extends the body of recent evidence that supports the role of CHSY1 as a potential mediator of BMP signaling.
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http://dx.doi.org/10.1016/j.ejmg.2013.11.001DOI Listing
January 2014

UGT1A1 gene mutations in Pakistani children suffering from inherited nonhemolytic unconjugated hyperbilirubinemias.

Ann Hum Genet 2013 Nov 29;77(6):482-7. Epub 2013 Aug 29.

Department of Biotechnology, Quaid-i-Azam University, Islamabad, Pakistan.

Two inherited unconjugated hyperbilirubinemias, Crigler-Najjar syndrome and Gilbert syndrome, arise due to deficiency of UGT1A1 enzyme activity. Crigler-Najjar syndrome type 1 (CN1) lies at the extreme severe end of the spectrum of UGT1A1 activity characterized by complete absence, followed by the less severe Crigler-Najjar syndrome type 2 (CN2). Gilbert syndrome is the mild form having only partial loss of UGT1A1 activity. The present study aimed to identify molecular genetic defects underlying unconjugated hyperbilirubinemias in children from six consanguineous Pakistani families. The patients were clinically diagnosed by exclusion of other unconjugated hyperbilirubinemias. Differential diagnosis of CN1 and CN2 was made on the basis of patient's response to phenobarbitone. The promoter region, coding exons, and adjacent splice sites of the UGT1A1 gene were PCR amplified from genomic DNA of all patients and their families, and were sequenced. DNA sequence analysis identified five different homozygous mutations: two novel missense mutations p.Y230C (proband A) and p.D36N (proband B), a 4-bp insertion c.622-625dupCAGC/p.Q208QfsX50 (probands C and E), a nonsense mutation p.R341X (proband D), and a TA insertion A(TA)7TAA in the promoter region (proband F). The present study extends the spectrum of UGT1A1 gene mutations and may be helpful in the diagnosis of Crigler-Najjar syndrome and Gilbert syndrome.
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http://dx.doi.org/10.1111/ahg.12039DOI Listing
November 2013

Nitazoxanide and probiotics for the treatment of recurrent Clostridium difficile infection in a peritoneal dialysis patient.

South Med J 2009 Jul;102(7):746-7

Infectious Disease Research Institute, Advanced Care Hospitalists, Tampa, FL, USA.

Nitazoxanide has been proven to be efficacious for the treatment of Clostridium difficile infection (CDI), but data is limited in peritoneal dialysis (PD) patients. This report details the successful utilization of nitazoxanide and probiotics to treat multirecurrent CDI in a PD patient. A 58-year-old woman was admitted with hypotension, nausea and vomiting attributed to metronidazole therapy for CDI, her third CDI treatment regimen in 3 months. During her admission, the patient developed CDI and was started on a 6-week regimen of nitazoxanide and probiotics to assist in re-establishing the colonic flora. The regimen was well tolerated and the patient remained disease free at follow up, four months later.
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http://dx.doi.org/10.1097/SMJ.0b013e3181a82bbbDOI Listing
July 2009
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