scholarly journals Pathogenic Variants in ABHD16A Cause a Novel Psychomotor Developmental Disorder With Spastic Paraplegia

2021 ◽  
Vol 12 ◽  
Author(s):  
Ashraf Yahia ◽  
Liena E. O. Elsayed ◽  
Remi Valter ◽  
Ahlam A. A. Hamed ◽  
Inaam N. Mohammed ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
Loss Of Function ◽  
Spastic Paraplegia ◽  
Cellular Processes ◽  
Pathogenic Variants ◽  
Neurological Phenotype ◽  
Limb Spasticity ◽  
Lower Limb Spasticity ◽  
Generation Sequencing

Introduction: Hereditary spastic paraplegia is a clinically and genetically heterogeneous neurological entity that includes more than 80 disorders which share lower limb spasticity as a common feature. Abnormalities in multiple cellular processes are implicated in their pathogenesis, including lipid metabolism; but still 40% of the patients are undiagnosed. Our goal was to identify the disease-causing variants in Sudanese families excluded for known genetic causes and describe a novel clinico-genetic entity.Methods: We studied four patients from two unrelated consanguineous Sudanese families who manifested a neurological phenotype characterized by spasticity, psychomotor developmental delay and/or regression, and intellectual impairment. We applied next-generation sequencing, bioinformatics analysis, and Sanger sequencing to identify the genetic culprit. We then explored the consequences of the identified variants in patients-derived fibroblasts using targeted-lipidomics strategies.Results and Discussion: Two homozygous variants in ABHD16A segregated with the disease in the two studied families. ABHD16A encodes the main brain phosphatidylserine hydrolase. In vitro, we confirmed that ABHD16A loss of function reduces the levels of certain long-chain lysophosphatidylserine species while increases the levels of multiple phosphatidylserine species in patient's fibroblasts.Conclusion:ABHD16A loss of function is implicated in the pathogenesis of a novel form of complex hereditary spastic paraplegia.

scholarly journals Expression of recombinant mouse spastin in E. coli

2020 ◽  
Vol 185 ◽  
pp. 04058
Author(s):  
Yujuan Wang
Keyword(s):  
Loss Of Function ◽  
Spastic Paraplegia ◽  
Activity Assay ◽  
Expression And Purification ◽  
E Coli ◽  
Microtubule Severing ◽  
Limb Spasticity ◽  
Lower Limb Spasticity ◽  
Function Relationship ◽  
Aaa Protein

Mutations of the gene SPAST that encodes a microtubule severing enzyme, spastin, are the most frequent cause of Hereditary spastic paraplegia (HSP) disease. HSP is heterogeneous group of inherited neurodegenerative disorders characterized predominantly by progressive lower limb spasticity and weakness. Spastin belongs ATPase associated with various cellular activities (AAA) protein family and catalyzes microtubule severing. Spastin in mouse and human are highly identical in protein sequence and several spastin mutation models in mice have been generated in order to evaluate the significance of spastin loss-of-function in mammals. Expression and purification of spastin and the mutant variants determined in patients will facilitate the structure-function relationship study of spastin. Here I systemically optimized the expression condition of a truncated version of mouse spastin in E. coli. The recombinant protein and a mutant were further purified for ATPase activity assay.

scholarly journals Case report on novel mutation in SPAST gene in Polish family with spastic paraplegia

BMC Neurology ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Aleksandra Klimkowicz-Mrowiec ◽  
Anna Dziubek ◽  
Malgorzata Sado ◽  
Marek Karpiński ◽  
Agnieszka Gorzkowska
Keyword(s):  
Case Report ◽  
Genetic Testing ◽  
Family History ◽  
Lower Limb ◽  
Hereditary Spastic Paraplegia ◽  
Novel Mutation ◽  
Family Members ◽  
Spastic Paraplegia ◽  
Limb Spasticity ◽  
Lower Limb Spasticity

Abstract Background Hereditary spastic paraplegia is a large group of degenerative, neurological disorders characterized by progressive lower limb spasticity and weakness. The disease was investigated precisely but still clinicians often make incorrect or late diagnosis. Our aim was to investigate the genetic background and clinical phenotype of spastic paraplegia in large Polish family. Case presentation A 37 years old woman presented with 4-year history of walking difficulties. On neurological examination, she had signs of upper motor lesion in lower extremities. She denied sphincter dysfunction and her cognition was normal. Her family history was positive for individuals with gait problems. The initial diagnosis was familial spastic paraplegia. Genetic testing identified a novel mutation in SPAST gene. All available family members were examined and had genetic testing. The same mutation in SPAST gene was identified in other affected family members. All patients caring the mutation presented with different phenotypes. Conclusion This study presents a family with spastic paraplegia due to a novel mutation c.1390G›T(p.Glu464Term) in SPAST gene. Affected individuals showed a range of phenotypes that varied in their severity. This case report demonstrates, the signs of hereditary spastic paraplegia can be often misdiagnosed with other diseases. Therefore genetic testing should always be considered in patients with lower limb spasticity and positive family history in order to help to establish the correct diagnosis.

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.

scholarly journals Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project

2020 ◽  
Vol 28 (12) ◽  
pp. 1763-1768
Author(s):  
Thomas Bourinaris ◽  
◽  
Damian Smedley ◽  
Valentina Cipriani ◽  
Isabella Sheikh ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
De Novo ◽  
Age At Onset ◽  
Genetic Diagnosis ◽  
Spastic Paraplegia ◽  
Sequencing Data ◽  
Juvenile Form ◽  
Pathogenic Variants ◽  
Degenerative Disorders ◽  
Significant Gene

AbstractHereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions. Over 400 HSP families were recruited to the 100KGP. In order to obtain genetic diagnoses, gene-based burden testing was carried out for rare, predicted pathogenic variants using candidate variants from the Exomiser analysis of the genome sequencing data. A significant gene-disease association was identified for UBAP1 and HSP. Three protein truncating variants were identified in 13 patients from 7 families. All patients presented with juvenile form of pure HSP, with median age at onset 10 years, showing autosomal dominant inheritance or de novo occurrence. Additional clinical features included parkinsonism and learning difficulties, but their association with UBAP1 needs to be established.

scholarly journals MiRNA-143 mediates the proliferative signaling pathway of FSH and regulates estradiol production

2017 ◽  
Vol 234 (1) ◽  
pp. 1-14 ◽  
Author(s):  
Li Zhang ◽  
XiaoXin Zhang ◽  
Xuejing Zhang ◽  
Yu Lu ◽  
Lei Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Loss Of Function ◽  
Cellular Processes ◽  
Cell Functions ◽  
Genes Expression ◽  
Underlying Mechanisms

MicroRNAs (MiRNAs) play important regulatory roles in many cellular processes. MiR-143 is highly enriched in the mouse ovary, but its roles and underlying mechanisms are not well understood. In the current study, we show that miR-143 is located in granulosa cells of primary, secondary and antral follicles. To explore the specific functions of miR-143, we transfected miR-143 inhibitor into primary cultured granulosa cells to study the loss of function of miR-143 and the results showed that miR-143 silencing significantly increased estradiol production and steroidogenesis-related gene expression. Moreover, our in vivo and in vitro studies showed that follicular stimulating hormone (FSH) significantly decreased miR-143 expression. This function of miR-143 is accomplished by its binding to the 3’-UTR of KRAS mRNA. Furthermore, our results demonstrated that miR-143 acts as a negative regulating molecule mediating the signaling pathway of FSH and affecting estradiol production by targeting KRAS. MiR-143 also negatively acts in regulating granulosa cells proliferation and cell cycle-related genes expression. These findings indicate that miR-143 plays vital roles in FSH-induced estradiol production and granulosa cell proliferation, providing a novel mechanism that involves miRNA in regulating granulosa cell functions.

scholarly journals Phenoconversion from Spastic Paraplegia to ALS/FTD Associated with CYP7B1 Compound Heterozygous Mutations

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1876
Author(s):  
Julian Theuriet ◽  
Antoine Pegat ◽  
Pascal Leblanc ◽  
Sandra Vukusic ◽  
Cécile Cazeneuve ◽  
...  
Keyword(s):  
Lower Limb ◽  
Clinical Symptoms ◽  
Compound Heterozygous ◽  
Spastic Paraplegia ◽  
The Third ◽  
Limb Spasticity ◽  
Lower Limb Spasticity ◽  
Compound Heterozygous Mutations ◽  
Biallelic Mutations ◽  
Lateral Sclerosis

Biallelic mutations in the CYP7B1 gene lead to spastic paraplegia-5 (SPG5). We report herein the case of a patient whose clinical symptoms began with progressive lower limb spasticity during childhood, and who secondly developed amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) at the age of 67 years. Hereditary spastic paraplegia (HSP) gene analysis identified the compound heterozygous mutations c.825T>A (pTyr275*) and c.1193C>T (pPro398Leu) in CYP7B1 gene. No other pathogenic variant in frequent ALS/FTD causative genes was found. The CYP7B1 gene seems, therefore, to be the third gene associated with the phenoconversion from HSP to ALS, after the recently described UBQLN2 and ERLIN2 genes. We therefore expand the phenotype associated with CYP7B1 biallelic mutations and make an assumption about a link between cholesterol dyshomeostasis and ALS/FTD.

Upper Motor Neuron Disorders Hereditary Spastic Paraplegia and Primary Lateral Sclerosis

2017 ◽  
Author(s):  
Sabrina Paganoni ◽  
Nazem Atassi
Keyword(s):  
Motor Neuron ◽  
Hereditary Spastic Paraplegia ◽  
Disease Modeling ◽  
Primary Lateral Sclerosis ◽  
Spastic Paraplegia ◽  
Underlying Pathophysiology ◽  
Primary Lateral ◽  
Lateral Sclerosis

Upper motor neuron (UMN) syndromes are a group of rare, degenerative neurological disorders that are classified as either hereditary spastic paraplegia (HSP) or primary lateral sclerosis (PLS). Our understanding of their underlying pathophysiology is unfortunately very limited and has been a significant barrier to the development of disease-modifying treatments. Recent advances in genetics and in vitro and in vivo disease modeling have provided new insights into disease mechanisms and hold the promise to lead to the future development of mechanism-based therapies.

scholarly journals Genetic analyses of the NF1 gene in Turkish neurofibromatosis type I patients and definition of three novel variants

2017 ◽  
Vol 20 (1) ◽  
pp. 13-20 ◽  
Author(s):  
SD Ulusal ◽  
H Gürkan ◽  
E Atlı ◽  
SA Özal ◽  
M Çiftdemir ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Genetic Diagnosis ◽  
Neurofibromatosis Type ◽  
Type I ◽  
Neurofibromatosis Type I ◽  
Next Generation ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
Nf1 Gene ◽  
Generation Sequencing

Abstract Neurofibromatosis Type I (NF1) is a multi systemic autosomal dominant neurocutaneous disorder predisposing patients to have benign and/or malignant lesions predominantly of the skin, nervous system and bone. Loss of function mutations or deletions of the NF1 gene is responsible for NF1 disease. Involvement of various pathogenic variants, the size of the gene and presence of pseudogenes makes it difficult to analyze. We aimed to report the results of 2 years of multiplex ligation-dependent probe amplification (MLPA) and next generation sequencing (NGS) for genetic diagnosis of NF1 applied at our genetic diagnosis center. The MLPA, semiconductor sequencing and Sanger sequencing were performed in genomic DNA samples from 24 unrelated patients and their affected family members referred to our center suspected of having NF1. In total, three novel and 12 known pathogenic variants and a whole gene deletion were determined. We suggest that next generation sequencing is a practical tool for genetic analysis of NF1. Deletion/duplication analysis with MLPA may also be helpful for patients clinically diagnosed to carry NF1 but do not have a detectable mutation in NGS.

scholarly journals Biallelic ERBB3 loss-of-function variants are associated with a novel multisystem syndrome without congenital contracture

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Niu Li ◽  
Yufei Xu ◽  
Yi Zhang ◽  
Guoqiang Li ◽  
Tingting Yu ◽  
...  
Keyword(s):  
Postnatal Growth ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Atrioventricular Canal ◽  
Multiple Systems ◽  
Feeding Difficulties ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Compound Heterozygous Variants

Abstract Background Gain-of-function pathogenic variants of the Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene contribute to the occurrence and development of a variety of human carcinomas through activation of phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) signaling. ERBB3 gene homozygous germline variants, whose loss of function may cause autosomal recessive congenital contractural syndrome, were recently identified. This study aims to identify the disease-causing gene in a Chinese pedigree with variable phenotypes involving multiple systems, including developmental delay, postnatal growth retardation, transient lower limb asymmetry, facial malformations, atrioventricular canal malformation, bilateral nystagmus and amblyopia, feeding difficulties, immunodeficiency, anemia, and liver damage, but without congenital contracture. Methods Trio-whole exome sequencing (WES) was performed to identify the disease-causing gene in a 24-month-old Chinese female patient. The pathogenicity of the identified variants was evaluated using in silico tools and in vitro functional studies. Results Trio-WES revealed compound heterozygous variants of c.1253 T > C (p.I418T) and c.3182dupA (p.N1061Kfs*16) in the ERBB3 gene. Functional studies showed that p.I418T resulted in normal expression of ERBB3, which was capable of interacting with ERBB2. However, the variant impaired ERBB3 phosphorylation, consequently blocking ERBB2 phosphorylation and AKT and ERK activation. The truncated protein resulting from the c.3182dupA variant also lacked the capacity to activate downstream signaling pathways. Conclusions We report the first patient with a novel multisystem syndrome disorder without congenital contracture resulting from biallelic loss-of-function variants of ERBB3.

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