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Article ; Online: Degradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome

Praseetha Kizhakkedath / Anne John / Lihadh Al-Gazali / Bassam R. Ali

Scientific Reports, Vol 8, Iss 1, Pp 1-

2018 Volume 12

Abstract: Abstract Low density lipoprotein receptor (LDLR) family members are involved in signaling in the developing brain. Previously we have reported that missense mutations in the Very Low Density Lipoprotein Receptor gene (VLDLR), causing Dysequilibrium ... ...

Abstract	Abstract Low density lipoprotein receptor (LDLR) family members are involved in signaling in the developing brain. Previously we have reported that missense mutations in the Very Low Density Lipoprotein Receptor gene (VLDLR), causing Dysequilibrium syndrome (DES), disrupt ligand-binding, due to endoplasmic reticulum (ER) retention of the mutants. We explored the degradation routes of these VLDLR mutants in cultured cells. Our results indicate that VLDLR mutants are retained in the ER for prolonged periods which could be facilitated by association with the ER-resident chaperone calnexin. The mutants were prone to aggregation and capable of eliciting ER stress. The VLDLR mutants were found to be degraded predominantly by the proteasomal pathway, since ubiquitinated VLDLR was found to accumulate in response to proteasomal inhibition. Further, the mutants were found to interact with the ER degradation adaptor protein SEL1L. The degradation of VLDLR wild type and mutant were delayed in CRISPR/Cas9 edited SEL1L knock-out cells which was reversed by exogenous expression of SEL1L. In summary, ER retention of pathogenic VLDLR mutants involves binding to calnexin, elevated ER stress, and delayed degradation which is dependent on SEL1L. Since core LDLR family members share common structural domains, common mechanisms may be involved in their ER processing.
Keywords	Medicine ; R ; Science ; Q
Subject code	571
Language	English
Publishing date	2018-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Endoplasmic reticulum quality control of LDLR variants associated with familial hypercholesterolemia

Praseetha Kizhakkedath / Anne John / Buthaina K. Al‐Sawafi / Lihadh Al‐Gazali / Bassam R. Ali

FEBS Open Bio, Vol 9, Iss 11, Pp 1994-

2019 Volume 2005

Abstract: Loss‐of‐function mutations in the low‐density lipoprotein receptor (LDLR) gene can cause familial hypercholesterolemia (FH), but detailed functional evidence for pathogenicity is limited to a few reported mutations. Here, we investigated the cellular ... ...

Abstract	Loss‐of‐function mutations in the low‐density lipoprotein receptor (LDLR) gene can cause familial hypercholesterolemia (FH), but detailed functional evidence for pathogenicity is limited to a few reported mutations. Here, we investigated the cellular pathogenic mechanisms of three mutations in LDLR causing FH, which are structurally identical to pathogenic mutations in the very low‐density lipoprotein receptor (VLDLR). Similar to the VLDLR mutants, LDLR mutants D482H and C667F were found to be localized to the ER, while D445E, which is a conserved amino acid change, did not affect the trafficking of the receptor to the plasma membrane, as confirmed by the N‐glycosylation profile. Although the ER‐retained mutant proteins were soluble, induction of ER stress was observed as indicated by spliced X‐box binding protein‐1 (XBP‐1) mRNA levels. The mutants were found to associate with ER quality control components, and their stability was enhanced by inhibitors of proteasome. Our results contribute to the growing list of transport‐deficient class II LDLR variants leading to FH and provide evidence for the involvement of endoplasmic reticulum‐associated degradation in their stability.
Keywords	ERAD ; FH ; LDLR ; missense mutation ; VLDLR ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2019-11-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Improved plasma membrane expression of the trafficking defective P344R mutant of muscle, skeletal, receptor tyrosine kinase (MuSK) causing congenital myasthenic syndrome

Milhem, Reham M / Bassam R. Ali / Lihadh Al-Gazali

international journal of biochemistry & cell biology. 2015 Mar., v. 60

2015

Abstract: Muscle, skeletal, receptor tyrosine kinase (MuSK) is a key organizer at the postsynaptic membrane and critical for proper development and maintenance of the neuromuscular junction. Mutations in MUSK result in congenital myasthenic syndrome (CMS). We ... ...

Abstract	Muscle, skeletal, receptor tyrosine kinase (MuSK) is a key organizer at the postsynaptic membrane and critical for proper development and maintenance of the neuromuscular junction. Mutations in MUSK result in congenital myasthenic syndrome (CMS). We hypothesized that the CMS-causing missense mutation (P344R), found within the cysteine-rich domain of the protein, will affect its conformational tertiary structure. Consequently, the protein will misfold, get retained in the endoplasmic reticulum (ER) and lose its biological function through degradation by the highly conserved ER associated degradation (ERAD) machinery. We report that P344R-MuSK mutant is trafficking-deficient when expressed at 37°C in HeLa, COS-7 and HEK293 cell lines. It colocalized with the ER marker calnexin in contrast to wild-type MuSK which localized to the plasma membrane. The N-glycosylation status of P344R-MuSK is that of an immature and not properly post-translationally modified protein. Inhibition of protein synthesis showed that the P344R mutant's half-life is shorter than wild-type MuSK protein. Proteasomal inhibition resulted in the stabilization of the mutant protein. The mutant protein is highly ubiquitinated compared to wild-type confirming targeting for proteasomal degradation. The mutant showed around 50% of its in vivo autophosphorylation activity. P344R-MuSK mutant's trafficking defect is correctable by culturing the expressing cells at 27°C. Moreover, chemical compounds namely 2.5% glycerol, 1% dimethyl sulfoxide, 10μM thapsigargin and 1μM curcumin improved the maturation and exit of the mutant protein from the ER. These findings open perspectives for potential therapeutic intervention for patients with CMS harboring the P344R-MuSK mutation.
Keywords	calnexin ; cell lines ; curcumin ; dimethyl sulfoxide ; endoplasmic reticulum ; glycerol ; glycosylation ; half life ; missense mutation ; muscles ; mutants ; patients ; plasma membrane ; protein phosphorylation ; receptor protein-tyrosine kinase ; synapse ; therapeutics
Language	English
Dates of publication	2015-03
Size	p. 119-129.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1228429-4
ISSN	1878-5875 ; 1357-2725
ISSN (online)	1878-5875
ISSN	1357-2725
DOI	10.1016/j.biocel.2014.12.015
Database	NAL-Catalogue (AGRICOLA)

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Article: Defective cellular trafficking of the bone morphogenetic protein receptor type II by mutations underlying familial pulmonary arterial hypertension

John, Anne / Bassam R. Ali / Lihadh Al-Gazali / Praseetha Kizhakkedath

Gene. 2015 Apr. 25, v. 561

2015

Abstract: Familial pulmonary arterial hypertension (FPAH) is a relatively rare but fatal disorder characterized by elevated arterial pressure caused by abnormal proliferation of endothelial cells of the arteries, which eventually leads to heart failure and death. ... ...

Abstract	Familial pulmonary arterial hypertension (FPAH) is a relatively rare but fatal disorder characterized by elevated arterial pressure caused by abnormal proliferation of endothelial cells of the arteries, which eventually leads to heart failure and death. FPAH is inherited as an autosomal dominant trait and is caused by heterozygous mutations in the BMPR2 gene encoding the bone morphogenetic protein type II receptor (BMPR2). BMPR2 belongs to the TGF Î²/BMP super-family of receptors involved in a signal transduction cascade via the SMAD signaling pathway. The BMPR2 polypeptide is composed of 1038 amino acids and consists of a ligand binding domain, a kinase domain and a cytoplasmic tail. To investigate the cellular and functional consequence of BMPR2 mutations, C-terminally FLAG-tagged constructs of eighteen pathogenic BMPR2 missense mutants were generated by site directed mutagenesis and expressed in HeLa and HEK-293T cell lines. The subcellular localizations of the mutant proteins were investigated using immunostaining and confocal microscopy. Post-translational modifications of the proteins were analyzed by Endoglycosidase H deglycosylation assay. Our results indicated that mutations in the ligand binding domain affecting highly conserved cysteine residues resulted in retention of the mutant proteins in the endoplasmic reticulum (ER), as evident from their co-localization with the ER resident protein calnexin. The kinase domain mutants showed both ER and plasma membrane (PM) distributions, while the cytoplasmic tail domain variants were localized exclusively to the PM. The subcellular localizations of the mutants were further confirmed by their characteristic glycosylation profiles. In conclusion, our results indicate that ER quality control (ERQC) is involved in the pathological mechanism of several BMPR2 receptor missense mutations causing FPAH, which can be explored as a potential therapeutic target in the future.
Keywords	arteries ; bone morphogenetic proteins ; calnexin ; confocal microscopy ; cysteine ; death ; endoplasmic reticulum ; endothelial cells ; genes ; glycosylation ; heart failure ; heterozygosity ; hypertension ; inheritance (genetics) ; ligands ; missense mutation ; mutants ; plasma membrane ; polypeptides ; post-translational modification ; quality control ; receptors ; signal transduction ; site-directed mutagenesis ; transforming growth factor beta
Language	English
Dates of publication	2015-0425
Size	p. 148-156.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	391792-7
ISSN	1879-0038 ; 0378-1119
ISSN (online)	1879-0038
ISSN	0378-1119
DOI	10.1016/j.gene.2015.02.038
Database	NAL-Catalogue (AGRICOLA)

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Z 79/715: Show issues

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Article ; Online: A homozygous splicing mutation in ELAC2 suggests phenotypic variability including intellectual disability with minimal cardiac involvement

Nadia A. Akawi / Salma Ben-Salem / Jozef Hertecant / Anne John / Thachillath Pramathan / Praseetha Kizhakkedath / Bassam R. Ali / Lihadh Al-Gazali

Orphanet Journal of Rare Diseases, Vol 11, Iss 1, Pp 1-

2016 Volume 9

Abstract: Abstract Background The group of ELAC2-related encephalomyopathies is a recent addition to the rapidly growing heterogeneous mitochondrial disorders. Results We describe a highly inbred consanguineous Pakistani family with multiple affected children in 2 ...

Abstract	Abstract Background The group of ELAC2-related encephalomyopathies is a recent addition to the rapidly growing heterogeneous mitochondrial disorders. Results We describe a highly inbred consanguineous Pakistani family with multiple affected children in 2 branches exhibiting moderately severe global developmental delay. Using homozygosity mapping, we mapped the phenotype in this family to a single locus on chromosome 17. In addition, whole-exome sequencing identified a homozygous splicing mutation (c.1423 + 2 T > A) in ELAC2 gene that disrupted the canonical donor splice site of intron 15 of all known isoforms. A noticeable reduction in ELAC2 expression was observed in patients compared to controls. In addition, patients exhibited significantly increased levels of 5′ end unprocessed mt-RNAs compared to the control fibroblast cells. Conclusions The only three previously reported families with defects in ELAC2 gene exhibited infantile hypertrophic cardiomyopathy and complex I deficiency. In contrast, our patients exhibited intellectual disability as the main feature with minimal cardiac involvement. Therefore our findings expand the phenotypic spectrum of ELAC2- associated disorders illustrating clinical heterogeneity of mutations in this gene. In addition, ELAC2 mutations should be considered when evaluating patient with mainly intellectual disability phenotypes.
Keywords	ELAC2 ; Mitochondrial disorder ; 5′ end unprocessed mt-RNAs ; Splice site mutation ; Intellectual disability ; Respiratory chain complex I (RCCI) deficiency ; Medicine ; R
Subject code	610
Language	English
Publishing date	2016-10-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Clathrin heavy chain 22 contributes to the control of neuropeptide degradation and secretion during neuronal development

Michael S. Nahorski / Georg H. H. Borner / Samiha S. Shaikh / Alexandra K. Davies / Lihadh Al-Gazali / Robin Antrobus / C. Geoffrey Woods

Scientific Reports, Vol 8, Iss 1, Pp 1-

2018 Volume 11

Abstract: Abstract The repertoire of cell types in the human nervous system arises through a highly orchestrated process, the complexity of which is still being discovered. Here, we present evidence that CHC22 has a non-redundant role in an early stage of neural ... ...

Abstract	Abstract The repertoire of cell types in the human nervous system arises through a highly orchestrated process, the complexity of which is still being discovered. Here, we present evidence that CHC22 has a non-redundant role in an early stage of neural precursor differentiation, providing a potential explanation of why CHC22 deficient patients are unable to feel touch or pain. We show the CHC22 effect on neural differentiation is independent of the more common clathrin heavy chain CHC17, and that CHC22-dependent differentiation is mediated through an autocrine/paracrine mechanism. Using quantitative proteomics, we define the composition of clathrin-coated vesicles in SH-SY5Y cells, and determine proteome changes induced by CHC22 depletion. In the absence of CHC22 a subset of dense core granule (DCG) neuropeptides accumulated, were processed into biologically active ‘mature’ forms, and secreted in sufficient quantity to trigger neural differentiation. When CHC22 is present, however, these DCG neuropeptides are directed to the lysosome and degraded, thus preventing differentiation. This suggests that the brief reduction seen in CHC22 expression in sensory neural precursors may license a step in neuron precursor neurodevelopment; and that this step is mediated through control of a novel neuropeptide processing pathway.
Keywords	Medicine ; R ; Science ; Q
Subject code	612
Language	English
Publishing date	2018-02-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Compound heterozygous variants in the multiple PDZ domain protein (MPDZ) cause a case of mild non-progressive communicating hydrocephalus

Nesreen K. Al-Jezawi / Aisha M. Al-Shamsi / Jehan Suleiman / Salma Ben-Salem / Anne John / Ranjit Vijayan / Bassam R. Ali / Lihadh Al-Gazali

BMC Medical Genetics, Vol 19, Iss 1, Pp 1-

2018 Volume 11

Abstract: Abstract Background Congenital hydrocephalus (CH) results from the accumulation of excessive amounts of cerebrospinal fluid (CSF) in the brain, often leading to severe neurological impairments. However, the adverse effects of CH can be reduced if the ... ...

Abstract	Abstract Background Congenital hydrocephalus (CH) results from the accumulation of excessive amounts of cerebrospinal fluid (CSF) in the brain, often leading to severe neurological impairments. However, the adverse effects of CH can be reduced if the condition is detected and treated early. Earlier reports demonstrated that some CH cases are caused by mutations in L1CAM gene encoding the neural cell adhesion molecule L1. On the other hand, recent studies have implicated the multiple PDZ domain (MPDZ) gene in some severe forms of CH, inherited in an autosomal recessive pattern. Methods In this study, whole-exome and Sanger sequencing were performed on a 9 months old Emirati child clinically diagnosed by CH. In addition, in silico, cellular, and molecular assays have been conducted to confirm pathogenicity of the identified variants and to establish disease mechanism. Results Whole exome sequencing revealed two compound heterozygous novel variants (c.394G > A and c.1744C > G) in the affected child within the MPDZ gene. Segregation analysis revealed that each of the parents is heterozygous for one of the two variants and therefore passed that variant to their child. The outcome of the in silico and bioinformatics analyses came in line with the experimental data, suggesting that the two variants are most likely disease causing. Conclusions The compound heterozygous variants identified in this study are the most likely cause of CH in the affected child. The study further confirms MPDZ as a gene underlying some CH cases.
Keywords	Congenital hydrocephalus ; Multiple PDZ ; L1CAM ; Compound heterozygous variants ; Autosomal recessive ; Internal medicine ; RC31-1245 ; Genetics ; QH426-470
Subject code	572
Language	English
Publishing date	2018-03-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Allele and genotype frequencies of the two single nucleotide polymorphisms in the VKORC1 gene that are most important for warfarin treatment among Emiratis

Hayat S Al-Jaibeji / Anne John / Lihadh Al-Gazali / Karem Soliman / Abderrahim Oulhaj / Theodora Katsila / Angela Brand / George P Patrinos / Bassam R Ali

Hamdan Medical Journal, Vol 9, Iss 1, Pp 75-

2016 Volume 84

Abstract: Warfarin is the most widely prescribed anticoagulant worldwide. However, warfarin doses vary up to 20-fold and side-effects (at high doses) or therapy failure (at lower doses) are major risks of treatment. The target enzyme of warfarin, vitamin K epoxide ...

Abstract	Warfarin is the most widely prescribed anticoagulant worldwide. However, warfarin doses vary up to 20-fold and side-effects (at high doses) or therapy failure (at lower doses) are major risks of treatment. The target enzyme of warfarin, vitamin K epoxide reductase complex 1 (VKORC1), is encoded by the highly polymorphic VKORC1 gene and gene polymorphisms contributes to approximately 30% of the variability in dose. In this study, we used polymerase chain reaction (PCR) and direct DNA sequencing to genotype the two most clinically important variants (rs9923231 and rs7294) of the VKORC1 gene among Emiratis. We genotyped 117 healthy Emirati nationals and found that the frequencies of the rs9923231 genotypes GG, GA and AA are 0.256, 0.496 and 0.248, respectively. The frequency of the G allele for this single nucleotide polymorphism (SNP) is 0.504 while the frequency of the A allele is 0.496. However, the frequencies of the rs7294 GG, GA and AA genotypes are 0.462, 0.393 and 0.145, respectively. The alleles frequencies for this SNP were 0.660 for the G allele and 0.340 for the A allele. Genotypes and allele frequencies of the two studied SNPs were found to be different between the Emirati population studied and Indian and Chinese populations; however, they were similar to the frequencies found in Caucasians and other regional populations, such as the Saudis, Turkish and Iranians. These findings are potentially important for determining the starting warfarin dose for Emirati patients requiring anticoagulant treatment.
Keywords	Medicine ; R
Subject code	572
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Wolters Kluwer Medknow Publications
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Centriolar satellites assemble centrosomal microcephaly proteins to recruit CDK2 and promote centriole duplication

Andrew Kodani / Timothy W Yu / Jeffrey R Johnson / Divya Jayaraman / Tasha L Johnson / Lihadh Al-Gazali / Lāszló Sztriha / Jennifer N Partlow / Hanjun Kim / Alexis L Krup / Alexander Dammermann / Nevan J Krogan / Christopher A Walsh / Jeremy F Reiter

eLife, Vol

2015 Volume 4

Abstract: Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the ... ...

Abstract	Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. Thus, centriolar satellites build a MCPH complex critical for human neurodevelopment that promotes CDK2 centrosomal localization and centriole duplication.
Keywords	centriole ; microcephaly ; centrosome ; centriolar satellite ; cell cycle ; brain development ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2015-08-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Endoplasmic reticulum quality control is involved in the mechanism of endoglin-mediated hereditary haemorrhagic telangiectasia.

Bassam R Ali / Imen Ben-Rebeh / Anne John / Nadia A Akawi / Reham M Milhem / Nouf A Al-Shehhi / Mouza M Al-Ameri / Shamma A Al-Shamisi / Lihadh Al-Gazali

PLoS ONE, Vol 6, Iss 10, p e

2011 Volume 26206

Abstract: Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant genetic condition affecting the vascular system and is characterised by epistaxis, arteriovenous malformations and mucocutaneous and gastrointestinal telangiectases. This disorder ... ...

Abstract	Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant genetic condition affecting the vascular system and is characterised by epistaxis, arteriovenous malformations and mucocutaneous and gastrointestinal telangiectases. This disorder affects approximately 1 in 8,000 people worldwide. Significant morbidity is associated with this condition in affected individuals, and anaemia can be a consequence of repeated haemorrhages from telangiectasia in the gut and nose. In the majority of the cases reported, the condition is caused by mutations in either ACVRL1 or endoglin genes, which encode components of the TGF-beta signalling pathway. Numerous missense mutations in endoglin have been reported as causative defects for HHT but the exact underlying cellular mechanisms caused by these mutations have not been fully established despite data supporting a role for the endoplasmic reticulum (ER) quality control machinery. For this reason, we examined the subcellular trafficking of twenty-five endoglin disease-causing missense mutations. The mutant proteins were expressed in HeLa and HEK293 cell lines, and their subcellular localizations were established by confocal fluorescence microscopy alongside the analysis of their N-glycosylation profiles. ER quality control was found to be responsible in eight (L32R, V49F, C53R, V125D, A160D, P165L, I271N and A308D) out of eleven mutants located on the orphan extracellular domain in addition to two (C363Y and C382W) out of thirteen mutants in the Zona Pellucida (ZP) domain. In addition, a single intracellular domain missense mutant was examined and found to traffic predominantly to the plasma membrane. These findings support the notion of the involvement of the ER's quality control in the mechanism of a significant number, but not all, missense endoglin mutants found in HHT type 1 patients. Other mechanisms including loss of interactions with signalling partners as well as adverse effects on functional residues are likely to be the cause of the mutant proteins' loss of function.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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