scholarly journals Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 283
Author(s):  
Eric J. Mallack ◽  
Kerry Gao ◽  
Marc Engelen ◽  
Stephan Kemp
Keyword(s):  
Transmembrane Domain ◽  
Missense Variant ◽  
Pathogenic Variant ◽  
Atp Binding ◽  
Pathogenic Variants ◽  
Mutation Database ◽  
Variant Frequency ◽  
Additional Level ◽  
And Function ◽  
Variant Database

The progressive neurometabolic disorder X-linked adrenoleukodystrophy (ALD) is caused by pathogenic variants in the ABCD1 gene, which encodes the peroxisomal ATP-binding transporter for very-long-chain fatty acids. The clinical spectrum of ALD includes adrenal insufficiency, myelopathy, and/or leukodystrophy. A complicating factor in disease management is the absence of a genotype–phenotype correlation in ALD. Since 1999, most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database. In 2017, following the expansion of ALD newborn screening, the database was rebuilt. To add an additional level of confidence with respect to pathogenicity, for each variant, it now also reports the number of cases identified and, where available, experimental data supporting the pathogenicity of the variant. The website also provides information on a number of ALD-related topics in several languages. Here, we provide an updated analysis of the known variants in ABCD1. The order of pathogenic variant frequency, overall clustering of disease-causing variants in exons 1–2 (transmembrane domain spanning region) and 6–9 (ATP-binding domain), and the most commonly reported pathogenic variant p.Gln472Argfs*83 in exon 5 are consistent with the initial reports of the mutation database. Novel insights include nonrandom clustering of high-density missense variant hotspots within exons 1, 2, 6, 8, and 9. Perhaps more importantly, we illustrate the importance of collaboration and utility of the database as a scientific, clinical, and ALD-community-wide resource.

scholarly journals A Novel Missense Variant in the Gene PPP2R5D Causes a Rare Neurodevelopmental Disorder with Increased Phenotype

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Lulu Yan ◽  
Ru Shen ◽  
Zongfu Cao ◽  
Chunxiao Han ◽  
Yuxin Zhang ◽  
...  
Keyword(s):  
De Novo ◽  
Genetic Disorder ◽  
Neurodevelopmental Disorder ◽  
Three Dimensional ◽  
Missense Variant ◽  
Pathogenic Variant ◽  
Dimensional Structure ◽  
Chinese Family ◽  
Speech Impairment ◽  
Pathogenic Variants

PPP2R5D-related neurodevelopmental disorder, which is mainly caused by de novo missense variants in the PPP2R5D gene, is a rare autosomal dominant genetic disorder with about 100 patients and a total of thirteen pathogenic variants known to exist globally so far. Here, we present a 24-month-old Chinese boy with developmental delay and other common clinical characteristics of PPP2R5D-related neurodevelopmental disorder including hypotonia, macrocephaly, intellectual disability, speech impairment, and behavioral abnormality. Trio-whole exome sequencing (WES) and Sanger sequencing were performed to identify the causal gene variant. The pathogenicity of the variant was evaluated using bioinformatics tools. We identified a novel pathogenic variant in the PPP2R5D gene (c.620G>T, p.Trp207Leu). The variant is located in the variant hotspot region of this gene and is predicted to cause PPP2R5D protein dysfunction due to an increase in local hydrophobicity and unstable three-dimensional structure. We report a novel pathogenic variant of PPP2R5D associated with PPP2R5D-related neurodevelopmental disorder from a Chinese family. Our findings expanded the phenotypic and mutational spectrum of PPP2R5D-related neurodevelopmental disorder.

scholarly journals αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0235136
Author(s):  
Sara Morais ◽  
Jorge Oliveira ◽  
Catarina Lau ◽  
Mónica Pereira ◽  
Marta Gonçalves ◽  
...  
Keyword(s):  
Binding Sites ◽  
Autosomal Dominant ◽  
Transmembrane Domain ◽  
Laboratory Data ◽  
Atp Release ◽  
Cytoplasmic Domains ◽  
Pathogenic Variants ◽  
Distinct Disease ◽  
And Function ◽  
First Time

Background Rare pathogenic variants in either the ITGA2B or ITGB3 genes have been linked to autosomal dominant macrothrombocytopenia associated with abnormal platelet production and function, deserving the designation of Glanzmann Thrombasthenia-Like Syndrome (GTLS) or ITGA2B/ITGB3-related thrombocytopenia. Objectives To describe a series of patients with familial macrothrombocytopenia and decreased expression of αIIbβ3 integrin due to defects in the ITGA2B or ITGB3 genes. Methods We reviewed the clinical and laboratory records of 10 Portuguese families with GTLS (33 patients and 11 unaffected relatives), including the functional and genetic defects. Results Patients had absent to moderate bleeding, macrothrombocytopenia, low αIIbβ3 expression, impaired platelet aggregation/ATP release to physiological agonists and low expression of activation-induced binding sites on αIIbβ3 (PAC-1) and receptor-induced binding sites on its ligand (bound fibrinogen), upon stimulation with TRAP-6 and ADP. Evidence for constitutive αIIbβ3 activation, occurred in 2 out of 9 patients from 8 families studied, but also in 2 out of 12 healthy controls. We identified 7 missense variants: 3 in ITGA2B (5 families), and 4 in ITGB3 (5 families). Three variants (αIIb: p.Arg1026Trp and p.Arg1026Gln and β3: p.Asp749His) were previously reported. The remaining (αIIb: p.Gly1007Val and β3: p.Thr746Pro, p.His748Pro and p.Arg760Cys) are new, expanding the αIIbβ3 defects associated with GTLS. The integration of the clinical and laboratory data allowed the identification of two GTLS subgroups, with distinct disease severity. Conclusions Previously reported ITGA2B and ITGB3 variants related to thrombocytopenia were clustered in a confined region of the membrane-proximal cytoplasmic domains, the inner membrane clasp. For the first time, variants are reported at the outer membrane clasp, at the transmembrane domain of αIIb, and at the membrane distal cytoplasmic domains of β3. This is the largest single-center series of inherited macrothrombocytopenia associated with αIIbβ3 variants published to date.

Establishing the role of PLVAP in protein-losing enteropathy: a homozygous missense variant leads to an attenuated phenotype

2018 ◽  
Vol 55 (11) ◽  
pp. 779-784 ◽  
Author(s):  
Alina Kurolap ◽  
Orly Eshach-Adiv ◽  
Claudia Gonzaga-Jauregui ◽  
Katya Dolnikov ◽  
Adi Mory ◽  
...  
Keyword(s):  
Barrier Function ◽  
Protein Function ◽  
Transmembrane Domain ◽  
Autosomal Recessive Inheritance ◽  
Missense Variant ◽  
Protein Loss ◽  
Protein Losing Enteropathy ◽  
Family Based ◽  
And Function

BackgroundIntestinal integrity is essential for proper nutrient absorption and tissue homeostasis, with damage leading to enteric protein loss, that is, protein-losing enteropathy (PLE). Recently, homozygous nonsense variants in the plasmalemma vesicle-associated protein gene (PLVAP) were reported in two patients with severe congenital PLE. PLVAP is the building block of endothelial cell (EC) fenestral diaphragms; its importance in barrier function is supported by mouse models of Plvap deficiency.ObjectiveTo genetically diagnose two first-degree cousins once removed, who presented with PLE at ages 22 and 2.5 years.MethodsFamily-based whole exome sequencing was performed based on an autosomal recessive inheritance model. In silico analyses were used to predict variant impact on protein structure and function.ResultsWe identified a rare homozygous variant (NM_031310.2:c.101T>C;p.Leu34Pro) in PLVAP, which co-segregated with the disease. Leu34 is predicted to be located in a highly conserved, hydrophobic, α-helical region within the protein’s transmembrane domain, suggesting Leu34Pro is likely to disrupt protein function and/or structure. Electron microscopy and PLVAP immunohistochemistry demonstrated apparently normal diaphragm morphology, predicted to be functionally affected.ConclusionsBiallelic missense variants in PLVAP can cause an attenuated form of the PLE and hypertriglyceridaemia syndrome. Our findings support the role of PLVAP in the pathophysiology of PLE, expand the phenotypic and mutation spectrums and underscore PLVAP’s importance in EC barrier function in the gut.

scholarly journals Role of the N-terminal transmembrane domain in the endo-lysosomal targeting and function of the human ABCB6 protein

2015 ◽  
Vol 467 (1) ◽  
pp. 127-139 ◽  
Author(s):  
Katalin Kiss ◽  
Nora Kucsma ◽  
Anna Brozik ◽  
Gabor E. Tusnady ◽  
Ptissam Bergam ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Transmembrane Domain ◽  
Intracellular Localization ◽  
Atp Binding ◽  
Multivesicular Bodies ◽  
Molecular Dissection ◽  
Terminal Domain ◽  
Lysosomal Targeting ◽  
And Function

The intracellular localization of ATP-binding cassette, sub family B (ABCB) 6 is a matter of debate. We show that ABCB6 is internalized from the plasma membrane to multivesicular bodies and lysosomes. Molecular dissection of the ABCB6 protein reveals a role of its N-terminal domain in targeting.

scholarly journals A Founder Pathogenic Variant of PPIB Unique to Chinese Population Causes Osteogenesis Imperfecta IX

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenting Zhu ◽  
Kai Yan ◽  
Xijing Chen ◽  
Wei Zhao ◽  
Yiqing Wu ◽  
...  
Keyword(s):  
Osteogenesis Imperfecta ◽  
Founder Effect ◽  
Chinese Population ◽  
Disease Incidence ◽  
Genetic Disorder ◽  
Missense Variant ◽  
Bone Fragility ◽  
Pathogenic Variant ◽  
Pathogenic Variants ◽  
Specific Allele

Background: Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility. PPIB pathogenic variants cause a perinatal lethal form of OI type IX. A limited number of pathogenic variants have been reported so far worldwide.Methods: We identified a rare pedigree whose phenotype was highly consistent with OI-IX. Exome sequencing was performed to uncover the causal variants. The variant pathogenicity was classified following the ACMG/AMP guidelines. The founder effect and the age of the variant were assessed.Results: We identified a homozygous missense variant c.509G > A/p.G170D in PPIB in an affected fetus. This variant is a Chinese-specific allele and can now be classified as pathogenic. We estimated the allele frequency (AF) of this variant to be 0.0000427 in a Chinese cohort involving 128,781 individuals. All patients and carriers shared a common haplotype, indicative of a founder effect. The estimated age of variant was 65,160 years. We further identified pathogenic variants of PPIB in gnomAD and ClinVar databases, the conserved estimation of OI type IX incidence to be 1/1,000,000 in Chinese population.Conclusion: We reported a founder pathogenic variant in PPIB specific to the Chinese population. We further provided our initial estimation of OI-IX disease incidence in China.

scholarly journals Structural analysis of pathogenic missense mutations in GABRA2 and identification of a novel de novo variant in the desensitization gate

2019 ◽  
Author(s):  
Alba Sanchis-Juan ◽  
Marcia A Hasenahuer ◽  
James A Baker ◽  
Amy McTague ◽  
Katy Barwick ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Neuronal Excitability ◽  
Transmembrane Domain ◽  
De Novo ◽  
Structural Information ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Missense Mutations ◽  
Pathogenic Variants ◽  
Activation Gate

AbstractCys-loop receptors are vital for controlling neuronal excitability in the brain and their dysfunction results in numerous neurological disorders. Recently, six de novo missense variants in GABRA2 gene, a member of this family, have been associated with early infantile epileptic encephalopathy (EIEE) and intellectual disability with seizures. Here, using whole-genome sequencing we identified a de novo missense variant in GABRA2 gene in a patient with EIEE and developmental delay. We perform protein structural analysis of the seven variants and show that all the mutations are in the transmembrane domain, either close to the desensitization gate, the activation gate or in inter-subunit interfaces. Further investigations demonstrated that the majority of pathogenic variants reported are at equivalent positions in other Cys-loop receptors, emphasizing the importance of these residues for the adequate function of the receptor. Also, a comparison of the distribution of the mutations in all the Cys-loop receptors showed that pathogenic variants are more common in the transmembrane helices, more specifically in the M2 helix, highlighting the importance of this segment. Our study expands the clinical spectrum of individuals with pathogenic missense mutations in GABRA2, defines the regions where pathogenic mutations are in the protein structure, and highlights the value of considering sequence, evolutionary, and structural information from other Cys-loop receptors as a strategy for variant interpretation of novel missense mutations in GABRA2.

scholarly journals Molecular Genetic Study of Congenital Ichthyosiform Erythroderma (CIE) Reveals a Novel Likely Pathogenic Variant in an Iranian Pedigree

2021 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Aazam Ahmadi Shadmehri ◽  
Javad Tavakkoly Bazzaz ◽  
Mojtaba Darbouye ◽  
Mohmmad Amin Tabatabaeifar
Keyword(s):  
Novel Mutation ◽  
Molecular Genetic ◽  
Missense Variant ◽  
Missense Mutations ◽  
Molecular Genetic Study ◽  
Iranian Patient ◽  
Congenital Ichthyosis ◽  
Pathogenic Variants ◽  
And Function ◽  
Congenital Ichthyosiform Erythroderma

Introduction: Congenital ichthyosiform erythroderma (CIE) is a subtype of autosomal recessive congenital ichthyosis (ARCI), a group of ineffective keratinization disorders, which mainly results from missense mutations in the transglutaminase 1 (TGM1) gene. Case Presentation: Herein, a 9-year-old male case of CIE is presented, for whom we conducted genetic testing to uncover the underlying molecular cause of his condition. We performed whole-exome sequencing (WES) on the DNA extracted from blood, and the data was analyzed for checking pathogenic variants. Analysis of the WES data identified a novel missense variant, c.1165C >T (p. Arg389Cys), in the TGM1 gene. Evaluation of this variant via in silico tools showed its detrimental consequences on the stability and function of the encoded protein. The variant was characterized as likely pathogenic based on the American College of Medical Genetics and Genomics guidelines for variant interpretation. Analysis of all available family members confirmed the co-segregation of this novel variant with the CIE disease within the family. Conclusions: This study reported the successful application of WES and bioinformatics analysis to identify a novel mutation in a well-established ARCI-causing residue in an Iranian patient.

scholarly journals Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome

2021 ◽  
Author(s):  
Pauline Arnaud ◽  
Hélène Morel ◽  
Olivier Milleron ◽  
Laurent Gouya ◽  
Christine Francannet ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Somatic Mosaicism ◽  
Variant Calling ◽  
Copy Number Variations ◽  
Pathogenic Variant ◽  
Single Nucleotide Variants ◽  
Bioinformatics Analyses ◽  
Single Nucleotide ◽  
Fbn1 Gene ◽  
Pathogenic Variants

Abstract Purpose Individuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands. Methods Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene. Results These five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations. Conclusion This underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.

scholarly journals Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

2021 ◽  
Vol 22 (6) ◽  
pp. 2824
Author(s):  
Jan H. Döring ◽  
Julian Schröter ◽  
Jerome Jüngling ◽  
Saskia Biskup ◽  
Kerstin A. Klotz ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Transmembrane Domain ◽  
Potassium Conductance ◽  
Epileptic Encephalopathy ◽  
Clinical Spectrum ◽  
The Novel ◽  
Developmental Abnormalities ◽  
Pathogenic Variants ◽  
Infantile Seizures ◽  
Early Developmental

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants.

scholarly journals Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype

2021 ◽  
Author(s):  
Paolo Zanoni ◽  
Katharina Steindl ◽  
Deepanwita Sengupta ◽  
Pascal Joset ◽  
Angela Bahr ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Mild Phenotype ◽  
Psychological Issues ◽  
Missense Variants ◽  
Mild Developmental Delay ◽  
Pathogenic Variants ◽  
In Silico Modeling ◽  
And Function ◽  
Methylation Activity

Abstract Purpose Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf–Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood. Methods We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro. Results The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2’s folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants. Conclusion NSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch–Steindl syndrome after the delineators of this phenotype.

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