scholarly journals A Systematic Approach to Assess the Activity and Classification of PCSK9 Variants

2021 ◽  
Vol 22 (24) ◽  
pp. 13602
Author(s):  
Kepa B. Uribe ◽  
Kevin Chemello ◽  
Asier Larrea-Sebal ◽  
Asier Benito-Vicente ◽  
Unai Galicia-Garcia ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Solid Phase ◽  
Ldl Receptor ◽  
Underlying Mechanism ◽  
Hek293 Cells ◽  
Loss Of Function ◽  
Wild Type ◽  
Solid Phase Immunoassay ◽  
Unknown Significance

Background: Gain of function (GOF) mutations of PCSK9 cause autosomal dominant familial hypercholesterolemia as they reduce the abundance of LDL receptor (LDLR) more efficiently than wild-type PCSK9. In contrast, PCSK9 loss of function (LOF) variants are associated with a hypocholesterolemic phenotype. Dozens of PCSK9 variants have been reported, but most remain of unknown significance since their characterization has not been conducted. Objective: Our aim was to make the most comprehensive assessment of PCSK9 variants and to determine the simplest approach for the classification of these variants. Methods: The expression, maturation, secretion, and activity of nine well-established PCSK9 variants were assessed in transiently transfected HEK293 cells by Western blot and flow cytometry. Their extracellular activities were determined in HepG2 cells incubated with the purified recombinant PCSK9 variants. Their binding affinities toward the LDLR were determined by solid-phase immunoassay. Results: LDLR expression increased when cells were transfected with LOF variants and reduced when cells were transfected with GOF variants compared with wild-type PCSK9. Extracellular activities measurements yielded exactly similar results. GOF and LOF variants had increased, respectively reduced, affinities for the LDLR compared with wild-type PCSK9 with the exception of one GOF variant (R218S) that showed complete resistance to inactivation by furin. All variants were expressed at similar levels and underwent normal maturation and secretion patterns except for two LOF and two GOF mutants. Conclusions: We propose that transient transfections of HEK293 cells with a plasmid encoding a PCSK9 variant followed by LDLR expression assessment by flow cytometry is sufficient to reliably determine its GOF or LOF status. More refined experiments should only be used to determine the underlying mechanism(s) at hand.

scholarly journals SUN-564 ATG7 Overexpression Results in Reduction of Hepatocellular Lipid Content in Vitro

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Federica Tavaglione ◽  
Guido Baselli ◽  
Ester Ciociola ◽  
Umberto Vespasiani Gentilucci ◽  
Luca Valenti ◽  
...  
Keyword(s):  
Liver Disease ◽  
Lipid Content ◽  
Lipid Droplets ◽  
Low Frequency ◽  
Underlying Mechanism ◽  
Loss Of Function ◽  
Wild Type ◽  
Intracellular Lipid ◽  
Heparg Cells

Abstract Abstract: Non-alcoholic fatty liver disease (NAFLD) is currently the most common liver disease worldwide, paralleling the epidemic of obesity and type 2 diabetes. Despite the high prevalence of NAFLD, only a minority of patients progress to NASH and advanced fibrosis. The reasons for this inter-individual variability are not completely understood but can be partially accounted for by genetic risk factors (1). Although several common genetic variants associated with liver disease have been identified, there is still a proportion of NAFLD heritability that remains unknown. The rare rs143545741 C>T variant in the autophagy related 7 (ATG7) gene (P426L) has been associated with a higher risk of progressive NAFLD (2). Interestingly, ATG7 encodes a E1-like ubiquitin activating enzyme which is involved in hepatic lipophagy (3). We hypothesized that the unknown heritability of NAFLD might be partially explained by rare genetic variants, therefore not identified in the GWAS studies. Moreover, we assumed that loss-of-function variants in ATG7 might confer an increased susceptibility to NAFLD by reducing autophagic catabolism of lipid droplets in the liver. To examine the underlying mechanism of the low-frequency V471A variant and the rare T86I, L127I, Q170E, and P426L variants in ATG7, we performed in vitro experiments of HepaRG cells overexpressing the human V5-tagged ATG7. We observed a reduction in intracellular lipid content in HepaRG cells overexpressing the ATG7 wild type and the 86I mutant protein (p=0.029, n=4) but not the 127I, 170E, 426L, and 471A mutant proteins. Cells with the ATG7 127I, 170E, 426L, and 471A mutants had higher intracellular lipid content compared to cells overexpressing the wild type protein (p=0.029, n=4). Our data suggested that the low-frequency V471A variant and the rare L127I, Q170E, and P426L variants in ATG7 are loss-of-function, resulting in defective lipophagy, reduced hepatocellular lipid droplets turnover, and excessive lipid accumulation. More experiments are needed to clarify the underlying mechanism of the T86I variant. In conclusion, we highlighted a role for ATG7 in reducing hepatocellular lipid content. Furthermore, we provided evidence showing non-synonymous variants in ATG7 increase the risk of NAFLD and that these variants are loss-of-function. We speculate that ATG7 might be a new susceptibility risk genetic locus for liver disease development and progression. References: (1) Eslam et al. J Hepatol. 2018;68(2):268–279. (2) Baselli et al. The Liver Meeting 2018 - AASLD. Hepatology. October 2018. Volume 68, Issue S1. (3) Martinez-Lopez and Singh. Annu Rev Nutr. 2015;35:215–37.

Abstract 831: Functional Analysis of S127 and D374 Residues of PCSK9: Distinct Hot Spots for Gain of Function

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Timothy S Fisher ◽  
Shilpa Pandit ◽  
Douglas Wisniewski ◽  
Joseph C Santoro ◽  
Rose M Cubbon ◽  
...  
Keyword(s):  
Hot Spots ◽  
Ldl Receptor ◽  
Hek293 Cells ◽  
Functional Assay ◽  
Wild Type ◽  
Time Resolved ◽  
Uptake Assay ◽  
A Cell ◽  
Ldl Uptake ◽  
Efficient Processing

Mutations within proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with dominant forms of familial hypercholesterolemia. Recent studies have shown that PCSK9 directly binds the LDL receptor (LDLR) and that addition of PCSK9 to cells promotes degradation of LDLR. Mutations associated with hypercholesterolemia (S127R and D374Y) bind the LDLR stronger and are more potent in decreasing LDL-uptake. Based on these data, we sought to better understand the mechanism by which mutations at both the S127 and D374 residues of PCSK9 affect PCSK9 function. A limited vertical scanning mutagenesis was done, resulting in the following mutants: S127(R, A, D, K, L, T) and D374(Y, A, E, F, K, L). Expression of several S127 alleles in HEK293 cells resulted in less efficient processing of PCSK9, with S127L severely defective in processing. In contrast, all D374 alleles tested had no effect on PCSK9 processing. In a cell-based functional assay of PCSK9 activity, both S127R and S127K proteins were significantly more potent (2– 4 fold) in decreasing LDL-uptake than wild-type PCSK9, while all other S127 mutants were similar to wild-type. Each D374 mutant tested was more potent than wild-type PCSK9 in reducing LDL-uptake (D374Y, F > A, L > E, K > wild-type). To determine if the potencies of S127 and D374 mutations in lowering LDL-uptake correlated with their ability to interact with the LDLR, each mutant was tested in a PCSK9-LDLR time-resolved FRET assay. Results indicate that potency in the cell-based LDL-uptake assay correlates with PCSK9’s binding affinity for the LDLR. Combination of S127R and D374Y was also found to have an additive effect in enhancing PCSK9’s ability to reduce LDL-uptake. Molecular modeling indicates that mutations at S127 and D374 which enhance PCSK9 function stabilize or destabilize the protein, respectively. In conclusion, these results suggest a model in which mutations at S127 and D374 residues modulate PCSK9’s ability to regulate LDLR function through distinct mechanisms.

scholarly journals Rapid Cl−/HCO3−exchange kinetics of AE1 in HEK293 cells and hereditary stomatocytosis red blood cells

2013 ◽  
Vol 305 (6) ◽  
pp. C654-C662 ◽  
Author(s):  
Etienne Frumence ◽  
Sandrine Genetet ◽  
Pierre Ripoche ◽  
Achille Iolascon ◽  
Immacolata Andolfo ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Blood Cell ◽  
Red Blood Cells ◽  
Anion Exchange ◽  
Red Blood Cell ◽  
Blood Cells ◽  
Hek293 Cells ◽  
Single Amino Acid ◽  
Stopped Flow ◽  
Wild Type

Anion exchanger 1 (AE1) or band 3 is a membrane protein responsible for the rapid exchange of chloride for bicarbonate across the red blood cell membrane. Nine mutations leading to single amino-acid substitutions in the transmembrane domain of AE1 are associated with dominant hereditary stomatocytosis, monovalent cation leaks, and reduced anion exchange activity. We set up a stopped-flow spectrofluorometry assay coupled with flow cytometry to investigate the anion transport and membrane expression characteristics of wild-type recombinant AE1 in HEK293 cells, using an inducible expression system. Likewise, study of three stomatocytosis-associated mutations (R730C, E758K, and G796R), allowed the validation of our method. Measurement of the rapid and specific chloride/bicarbonate exchange by surface expressed AE1 showed that E758K mutant was fully active compared with wild-type (WT) AE1, whereas R730C and G796R mutants were inactive, reinforcing previously reported data on other experimental models. Stopped-flow analysis of AE1 transport activity in red blood cell ghost preparations revealed a 50% reduction of G796R compared with WT AE1 corresponding to a loss of function of the G796R mutated protein, in accordance with the heterozygous status of the AE1 variant patients. In conclusion, stopped-flow led to measurement of rapid transport kinetics using the natural substrate for AE1 and, conjugated with flow cytometry, allowed a reliable correlation of chloride/bicarbonate exchange to surface expression of AE1, both in recombinant cells and ghosts and therefore a fine comparison of function between different stomatocytosis samples. This technical approach thus provides significant improvements in anion exchange analysis in red blood cells.

scholarly journals Mutations in FIGLA Associated With Premature Ovarian Insufficiency in a Chinese Population

2021 ◽  
Vol 8 ◽  
Author(s):  
Libin Mei ◽  
Yanru Huang ◽  
Xiaoling Wu ◽  
Huang He ◽  
Ronghui Ye ◽  
...  
Keyword(s):  
Chromatin Immunoprecipitation ◽  
Target Genes ◽  
Gene Mutations ◽  
Underlying Mechanism ◽  
Premature Ovarian Insufficiency ◽  
Hek293 Cells ◽  
Chinese Patients ◽  
Luciferase Reporter ◽  
Wild Type ◽  
Ovarian Insufficiency

Objective: Premature ovarian insufficiency (POI) is one of the most common reproductive endocrinological causes of infertility in women of child-bearing age. The purpose of this study was to identify FIGLA gene mutations in Chinese patients with POI and to investigate the underlying mechanism.Methods: A total of 113 patients with idiopathic POI and 100 healthy controls were recruited for the analysis of FIGLA variants. Based on the identification of common mutations in the FIGLA, wild-type and mutant plasmids were constructed and transfected into HEK293 cells. Luciferase reporter genes were used to determine the effect of wild-type and mutant FIGLA genotypes on the transcriptional activity of its downstream targets, the zona pellucida glycoprotein genes ZP1, ZP2, and ZP3. Chromatin immunoprecipitation was used to determine the level of binding between wild-type and mutant FIGLA with the ZP1, ZP2, and ZP3 promoters.Results: Three different FIGLA mutations were identified in four patients with POI. Two patients carried the mutation c.11C>A (p.A4E), and the other two patients, respectively, carried the mutations c.625G>A (p.V209I) and c.84C>A (p.D28E). The luciferase reporter assay indicated that ZP1, ZP2, and ZP3 transcriptional activities were significantly reduced in individuals with FIGLA mutations. Chromatin immunoprecipitation indicated that the FIGLA mutation significantly decreased binding with the ZP1, ZP2, and ZP3 promoters.Conclusion:FIGLA mutation affects gene transcriptional regulation of its downstream target genes ZP1, ZP2, and ZP3, highlighting a new candidate genetic factor that causes POI. Our study demonstrates that FIGLA has a regulatory effect on reproduction-specific genes, thereby providing a basis for elucidating the specific regulatory mechanism of FIGLA in germ cell growth and development.

scholarly journals CD16b: Primary Structure of Human Neutrophil Antigen Epitopes and Their Functional Consequences

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3680-3680
Author(s):  
Ulrich J Sachs ◽  
Angelika Reil ◽  
Piyapong Simtong ◽  
Sentot Santoso
Keyword(s):  
Cell Lines ◽  
Human Neutrophil ◽  
Conflicts Of Interest ◽  
Solid Phase ◽  
Hek293 Cells ◽  
Adhesion Assay ◽  
Wild Type ◽  
Capture Assay ◽  
Diagnostic Work ◽  
And Function

Abstract Neutrophil specific Fcg receptor IIIb (CD16b) is a glycosylphosphatidylinositol-anchored low-affinity glycoprotein that plays a significant role in phagocytosis and the clearance of immune complexes. CD16b has numerous polymorphic variants; the most relevant variants are associated with human neutrophil antigens (HNA) -1a, -1b, and -1c. HNA-1a and HNA-1b differ in four amino acids (aa) (positions 36, 65, 82 and 106). One additional aa mutation on HNA-1b at position 78 results in HNA-1c. Immunization against CD16b variants can lead to the production of alloantibodies (aabs) responsible for neonatal alloimmune neutropenia (NIN), autoimmune neutropenia of infancy (AIN) and transfusion-related acute lung injury (TRALI). The exact contribution of five aa mutations for the formation of HNA-1a, -1b and -1c and function of CD16b is currently unknown. In this study, permutation of each polymorphic aa from wild-type CD16b cDNA constructs was performed and stably expressed on HEK293 cells. In total, 3 cell lines expressing wild-type (HNA-1a, -1b and -1c) and 18 cell lines expressing mutant variants were produced; 14 derived from HNA-1a or HNA-1b (panel 1) and 4 derived from HNA-1c (panel 2). When panel 1 was tested with well-defined aabs by antigen capture assay, 4 cell lines reacted with anti-HNA-1a only, 4 with anti-HNA-1b only, 4 with both aabs, and 4 did not react with both aabs. These results indicate that aa36 and aa65 are responsible for the formation of the HNA-1a and HPA-1b epitope(s), respectively. Analysis of panel 2 showed that 2/4 mutant variants reacted with anti-HNA-1c exclusively, suggesting that the HNA-1c epitope is formed by Ala78Asp irrespective of the other polymorphic aa. To analyze the binding affinity of CD16b variants, adhesion assay onto immobilized IgG was performed. In comparison to HNA-1a, HNA-1b cells bound slightly weaker to IgG (p<0.002). In contrast, HNA-1c cells interacted significantly stronger with IgG in comparison to both, HNA-1a and -1b cells (p<0.0001). Similar results were obtained with HNA-1a, -1b and -1c recombinant proteins by direct protein-binding analysis (solid phase ELISA and Surface Plasmon Resonance). Interestingly, all mutant variants carrying HNA-1c bound also stronger to IgG than HNA-1a and -1b transfected cells. Similar results were observed with HNA-1c phenotyped neutrophils. In conclusion, although HNA-1a and HNA-1b differ in four aa positions, only two (aa36, aa65) are necessary for the complete formation of the respective epitopes. In contrast, the HNA-1c epitope is created by only one aa mutation (Ala78Asp). Furthermore, our results show that HNA-1c exhibits higher affinity to IgG compared to HNA-1a and HNA-1b forms. Accordingly, the Ala78Asp mutation is not only responsible for epitope formation, but is also involved in the regulation of CD16 affinity. Characterization of HNA-1 epitopes by tailored recombinant tools will help us to improve our diagnostic work-up in patients with suspected NIN, AIN and TRALI and our understanding on the role of CD16 polymorphism in other diseases such as, immune complex-mediated disorders. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Effect of Single Nucleotide Variations in the Transmembrane Domain of OATP1B1 on in vitro Functionality

2021 ◽  
Author(s):  
Wilma Kiander ◽  
Kati-Sisko Vellonen ◽  
Melina M. Malinen ◽  
Mikko Gynther ◽  
Marja Hagström ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Cellular Localization ◽  
Transmembrane Domain ◽  
Organic Anion ◽  
Hek293 Cells ◽  
Protein Abundance ◽  
Loss Of Function ◽  
Wild Type ◽  
The Impact

Abstract Purpose Organic Anion Transporting Polypeptide 1B1 (OATP1B1) mediates hepatic influx and clearance of many drugs, including statins. The SLCO1B1 gene is highly polymorphic and its function-impairing variants can predispose patients to adverse effects. The effects of rare genetic variants of SLCO1B1 are mainly unexplored. We examined the impact of eight naturally occurring rare variants and the well-known SLCO1B1 c.521C > T (V174A) variant on in vitro transport activity, cellular localization and abundance. Methods Transport of rosuvastatin and 2,7-dichlorofluorescein (DCF) in OATP1B1 expressing HEK293 cells was measured to assess changes in activity of the variants. Immunofluorescence and confocal microscopy determined the cellular localization of OATP1B1 and LC–MS/MS based quantitative targeted absolute proteomics analysis quantified the amount of OATP1B1 in crude membrane fractions. Results All studied variants, with the exception of P336R, reduced protein abundance to varying degree. V174A reduced protein abundance the most, over 90% compared to wild type. Transport function was lost in G76E, V174A, L193R and R580Q variants. R181C decreased activity significantly, while T345M and L543W retained most of wild type OATP1B1 activity. P336R showed increased activity and H575L decreased the transport of DCF significantly, but not of rosuvastatin. Decreased activity was interrelated with lower absolute protein abundance in the studied variants. Conclusions Transmembrane helices 2, 4 and 11 appear to be crucial for proper membrane localization and function of OATP1B1. Four of the studied variants were identified as loss-of-function variants and as such could make the individual harboring these variants susceptible to altered pharmacokinetics and adverse effects of substrate drugs.

Evaluation of flow-cytometry for the monitoring of infectious human rotavirus in water

1997 ◽  
Vol 35 (11-12) ◽  
pp. 451-453
Author(s):  
F. X. Abad ◽  
A. Bosch ◽  
J. Comas ◽  
D. Villalba ◽  
R. M. Pintó
Keyword(s):  
Flow Cytometry ◽  
Water Samples ◽  
Wild Type ◽  
Cell Monolayers ◽  
Naturally Occurring ◽  
Human Rotavirus ◽  
Faecal Samples

A method has been developed for the detection of infectious human rotavirus (HRV), based on infection of MA104 and CaCo-2 cell monolayers and ulterior flow cytometry. The sensitivity of the flow cytometry procedure for the cell-adapted HRV enabled the detection of 200 and 2 MPNCU in MA104 and CaCo-2 cells, respectively. Flow cytometry performed five days after infection of CaCo-2 enabled the detection of naturally occurring wild-type HRV in faecal samples and concentrated water samples.

scholarly journals Mutations in fbiD (Rv2983) as a Novel Determinant of Resistance to Pretomanid and Delamanid in Mycobacterium tuberculosis

2020 ◽  
Vol 65 (1) ◽  
pp. e01948-20
Author(s):  
Dalin Rifat ◽  
Si-Yang Li ◽  
Thomas Ioerger ◽  
Keshav Shah ◽  
Jean-Philippe Lanoix ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Clinical Evidence ◽  
Clinical Samples ◽  
Loss Of Function ◽  
Wild Type ◽  
Content Type ◽  
Solid Media ◽  
High Level ◽  
Level Resistance

ABSTRACTThe nitroimidazole prodrugs delamanid and pretomanid comprise one of only two new antimicrobial classes approved to treat tuberculosis (TB) in 50 years. Prior in vitro studies suggest a relatively low barrier to nitroimidazole resistance in Mycobacterium tuberculosis, but clinical evidence is limited to date. We selected pretomanid-resistant M. tuberculosis mutants in two mouse models of TB using a range of pretomanid doses. The frequency of spontaneous resistance was approximately 10−5 CFU. Whole-genome sequencing of 161 resistant isolates from 47 mice revealed 99 unique mutations, of which 91% occurred in 1 of 5 genes previously associated with nitroimidazole activation and resistance, namely, fbiC (56%), fbiA (15%), ddn (12%), fgd (4%), and fbiB (4%). Nearly all mutations were unique to a single mouse and not previously identified. The remaining 9% of resistant mutants harbored mutations in Rv2983 (fbiD), a gene not previously associated with nitroimidazole resistance but recently shown to be a guanylyltransferase necessary for cofactor F420 synthesis. Most mutants exhibited high-level resistance to pretomanid and delamanid, although Rv2983 and fbiB mutants exhibited high-level pretomanid resistance but relatively small changes in delamanid susceptibility. Complementing an Rv2983 mutant with wild-type Rv2983 restored susceptibility to pretomanid and delamanid. By quantifying intracellular F420 and its precursor Fo in overexpressing and loss-of-function mutants, we provide further evidence that Rv2983 is necessary for F420 biosynthesis. Finally, Rv2983 mutants and other F420H2-deficient mutants displayed hypersusceptibility to some antibiotics and to concentrations of malachite green found in solid media used to isolate and propagate mycobacteria from clinical samples.

scholarly journals The NALCN Channel Regulator UNC-80 Functions in a Subset of Interneurons To Regulate Caenorhabditis elegans Reversal Behavior

2019 ◽  
Vol 10 (1) ◽  
pp. 199-210 ◽  
Author(s):  
Chuanman Zhou ◽  
Jintao Luo ◽  
Xiaohui He ◽  
Qian Zhou ◽  
Yunxia He ◽  
...  
Keyword(s):  
Plant Hormone ◽  
Neuronal Excitability ◽  
Resting Membrane Potential ◽  
Loss Of Function ◽  
Wild Type ◽  
C Elegans ◽  
Link Type ◽  
Complex Functions ◽  
And Function ◽  
Multiple Loss

NALCN (Na+leak channel, non-selective) is a conserved, voltage-insensitive cation channel that regulates resting membrane potential and neuronal excitability. UNC79 and UNC80 are key regulators of the channel function. However, the behavioral effects of the channel complex are not entirely clear and the neurons in which the channel functions remain to be identified. In a forward genetic screen for C. elegans mutants with defective avoidance response to the plant hormone methyl salicylate (MeSa), we isolated multiple loss-of-function mutations in unc-80 and unc-79. C. elegans NALCN mutants exhibited similarly defective MeSa avoidance. Interestingly, NALCN, unc-80 and unc-79 mutants all showed wild type-like responses to other attractive or repelling odorants, suggesting that NALCN does not broadly affect odor detection or related forward and reversal behaviors. To understand in which neurons the channel functions, we determined the identities of a subset of unc-80-expressing neurons. We found that unc-79 and unc-80 are expressed and function in overlapping neurons, which verified previous assumptions. Neuron-specific transgene rescue and knockdown experiments suggest that the command interneurons AVA and AVE and the anterior guidepost neuron AVG can play a sufficient role in mediating unc-80 regulation of the MeSa avoidance. Though primarily based on genetic analyses, our results further imply that MeSa might activate NALCN by direct or indirect actions. Altogether, we provide an initial look into the key neurons in which the NALCN channel complex functions and identify a novel function of the channel in regulating C. elegans reversal behavior through command interneurons.

scholarly journals Identification of a novel homozygous loss-of-function mutation in FUCA1 gene causing severe fucosidosis: A case report

2021 ◽  
Vol 49 (4) ◽  
pp. 030006052110059
Author(s):  
Xinwen Zhang ◽  
Shaozhi Zhao ◽  
Hongwei Liu ◽  
Xiaoyan Wang ◽  
Xiaolei Wang ◽  
...  
Keyword(s):  
Amino Acids ◽  
Lysosomal Storage Disorder ◽  
Autosomal Recessive ◽  
Signs And Symptoms ◽  
Lysosomal Storage ◽  
Loss Of Function ◽  
Wild Type ◽  
Single Nucleotide ◽  
Whole Exome ◽  
Exon 1

Fucosidosis is a rare lysosomal storage disorder characterized by deficiency of α-L-fucosidase with an autosomal recessive mode of inheritance. Here, we describe a 4-year-old Chinese boy with signs and symptoms of fucosidosis but his parents were phenotypically normal. Whole exome sequencing (WES) identified a novel homozygous single nucleotide deletion (c.82delG) in the exon 1 of the FUCA1 gene. This mutation will lead to a frameshift which will result in the formation of a truncated FUCA1 protein (p.Val28Cysfs*105) of 132 amino acids approximately one-third the size of the wild type FUCA1 protein (466 amino acids). Both parents were carrying the mutation in a heterozygous state. This study expands the mutational spectrum of the FUCA1 gene associated with fucosidosis and emphasises the benefits of WES for accurate and timely clinical diagnosis of this rare disease.

Sign in / Sign up

Export Citation Format

Share Document