A Novel SPG7 Gene Pathogenic Variant in a Cypriot Family With Autosomal Recessive Spastic Ataxia

The SPG7 gene encodes the paraplegin protein, an inner mitochondrial membrane—localized protease. It was initially linked to pure and complicated hereditary spastic paraplegia with cerebellar atrophy, and now represents a frequent cause of undiagnosed cerebellar ataxia and spastic ataxia. We hereby report the molecular characterization and the clinical features of a large Cypriot family with five affected individuals presenting with spastic ataxia in an autosomal recessive transmission mode, due to a novel SPG7 homozygous missense variant. Detailed clinical histories of the patients were obtained, followed by neurological and neurophysiological examinations. Whole exome sequencing (WES) of the proband, in silico gene panel analysis, variant filtering and family segregation analysis of the candidate variants with Sanger sequencing were performed. RNA and protein expression as well as in vitro protein localization studies and mitochondria morphology evaluation were carried out towards functional characterization of the identified variant. The patients presented with typical spastic ataxia features while some intrafamilial phenotypic variation was noted. WES analysis revealed a novel homozygous missense variant in the SPG7 gene (c.1763C > T, p. Thr588Met), characterized as pathogenic by more than 20 in silico prediction tools. Functional studies showed that the variant does not affect neither the RNA or protein expression, nor the protein localization. However, aberrant mitochondrial morphology has been observed thus indicating mitochondrial dysfunction and further demonstrating the pathogenicity of the identified variant. Our study is the first report of an SPG7 pathogenic variant in the Cypriot population and broadens the spectrum of SPG7 pathogenic variants.

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Homozygous missense variant in the TTN gene causing autosomal recessive limb-girdle muscular dystrophy type 10

BMC Medical Genetics ◽

10.1186/s12881-019-0895-7 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 5

Author(s):

Amjad Khan ◽

Rongrong Wang ◽

Shirui Han ◽

Muhammad Umair ◽

Safdar Abbas ◽

...

Keyword(s):

Muscular Dystrophy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Autosomal Recessive ◽

Missense Variant ◽

Pathogenic Variant ◽

Limb Girdle Muscular Dystrophy ◽

Molecular Diagnostic ◽

Sequencing Analysis ◽

Whole Exome

Abstract Background Limb-girdle muscular dystrophies (LGMDs) are large group of heterogeneous genetic diseases, having a hallmark feature of muscle weakness. Pathogenic mutations in the gene encoding the giant skeletal muscle protein titin (TTN) are associated with several muscle disorders, including cardiomyopathy, recessive congenital myopathies and limb-girdle muscular dystrophy (LGMD) type10. The phenotypic spectrum of titinopathies is expanding, as next generation sequencing (NGS) technology makes screening of this large gene possible. Aim This study aimed to identify the pathogenic variant in a consanguineous Pakistani family with autosomal recessive LGMD type 10. Methods DNA from peripheral blood samples were obtained, whole exome sequencing (WES) was performed and several molecular and bioinformatics analysis were conducted to identify the pathogenic variant. TTN coding and near coding regions were further amplified using PCR and sequenced via Sanger sequencing. Results Whole exome sequencing analysis revealed a novel homozygous missense variant (c.98807G > A; p.Arg32936His) in the TTN gene in the index patients. No heterozygous individuals in the family presented LGMD features. The variant p.Arg32936His leads to a substitution of the arginine amino acid at position 32,936 into histidine possibly causing LGMD type 10. Conclusion We identified a homozygous missense variant in TTN, which likely explains LGMD type 10 in this family in line with similar previously reported data. Our study concludes that WES is a successful molecular diagnostic tool to identify pathogenic variants in large genes such as TTN in highly inbred population.

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Bi-allelic variants in TSPOAP1, encoding the active zone protein RIMBP1, cause autosomal recessive dystonia

10.1101/2020.05.24.086215 ◽

2020 ◽

Cited By ~ 1

Author(s):

Niccolò E. Mencacci ◽

Marisa M. Brockmann ◽

Jinye Dai ◽

Sander Pajusalu ◽

Burcu Atasu ◽

...

Keyword(s):

Active Zone ◽

Autosomal Recessive ◽

Critical Role ◽

Cerebellar Atrophy ◽

Missense Variant ◽

Loss Of Function ◽

Generalized Dystonia ◽

Motor Abnormalities ◽

Vitro Analysis

ABSTRACTDystonia is a debilitating hyperkinetic movement disorder, frequently transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense and missense variants in TSPOAP1, encoding the active zone RIM-binding protein 1 (RIMBP1), as a novel genetic cause of autosomal recessive dystonia in seven subjects from three unrelated families. Subjects carrying loss-of-function variants presented with juvenile- onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy. Conversely, subjects carrying a pathogenic missense variant (p.Gly1808Ser) presented with isolated adult-onset focal dystonia. In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses. In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks. Our findings establish a direct link between presynaptic RIMBP1 dysfunction and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis.

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Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies

Genetics in Medicine ◽

10.1038/s41436-021-01260-4 ◽

2021 ◽

Author(s):

Maria Iqbal ◽

Reza Maroofian ◽

Büşranur Çavdarlı ◽

Florence Riccardi ◽

Michael Field ◽

...

Keyword(s):

In Silico ◽

Autosomal Recessive ◽

Neurodevelopmental Disorder ◽

Three Dimensional ◽

In Silico Analysis ◽

Missense Variant ◽

The Third ◽

Dimerization Interface ◽

Silico Analysis

Abstract Purpose We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition. Methods We performed a detailed clinical characterization of 19 individuals from nine unrelated, consanguineous families with a neurodevelopmental disorder. We used genome/exome sequencing approaches, linkage and cosegregation analyses to identify disease-causing variants, and we performed three-dimensional molecular in silico analysis to predict causality of variants where applicable. Results In all affected individuals who presented with a neurodevelopmental syndrome with progressive microcephaly, seizures, and intellectual disability we identified biallelic disease-causing variants in Protocadherin-gamma-C4 (PCDHGC4). Five variants were predicted to induce premature protein truncation leading to a loss of PCDHGC4 function. The three detected missense variants were located in extracellular cadherin (EC) domains EC5 and EC6 of PCDHGC4, and in silico analysis of the affected residues showed that two of these substitutions were predicted to influence the Ca2+-binding affinity, which is essential for multimerization of the protein, whereas the third missense variant directly influenced the cis-dimerization interface of PCDHGC4. Conclusion We show that biallelic variants in PCDHGC4 are causing a novel autosomal recessive neurodevelopmental disorder and link PCDHGC4 as a member of the clustered PCDH family to a Mendelian disorder in humans.

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Nanoscopic quantification of sub-mitochondrial morphology, mitophagy and mitochondrial dynamics in living cells derived from patients with mitochondrial diseases

Journal of Nanobiotechnology ◽

10.1186/s12951-021-00882-9 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Weiwei Zou ◽

Qixin Chen ◽

Jesse Slone ◽

Li Yang ◽

Xiaoting Lou ◽

...

Keyword(s):

Oxidative Phosphorylation ◽

Optic Atrophy ◽

Respiratory Function ◽

Clinical Symptoms ◽

Mitochondrial Dynamics ◽

Cerebellar Atrophy ◽

Mitochondrial Diseases ◽

Living Cells ◽

Mitochondrial Morphology ◽

Mitochondrial Oxidative Phosphorylation

AbstractSLC25A46 mutations have been found to lead to mitochondrial hyper-fusion and reduced mitochondrial respiratory function, which results in optic atrophy, cerebellar atrophy, and other clinical symptoms of mitochondrial disease. However, it is generally believed that mitochondrial fusion is attributable to increased mitochondrial oxidative phosphorylation (OXPHOS), which is inconsistent with the decreased OXPHOS of highly-fused mitochondria observed in previous studies. In this paper, we have used the live-cell nanoscope to observe and quantify the structure of mitochondrial cristae, and the behavior of mitochondria and lysosomes in patient-derived SLC25A46 mutant fibroblasts. The results show that the cristae have been markedly damaged in the mutant fibroblasts, but there is no corresponding increase in mitophagy. This study suggests that severely damaged mitochondrial cristae might be the predominant cause of reduced OXPHOS in SLC25A46 mutant fibroblasts. This study demonstrates the utility of nanoscope-based imaging for realizing the sub-mitochondrial morphology, mitophagy and mitochondrial dynamics in living cells, which may be particularly valuable for the quick evaluation of pathogenesis of mitochondrial morphological abnormalities.

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First report of X-linked hypohidrotic ectodermal dysplasia with a hemizygous c.1142G > C in the EDA gene: variant of uncertain significance or new pathogenic variant?

Italian Journal of Pediatrics ◽

10.1186/s13052-021-01078-5 ◽

2021 ◽

Vol 47 (1) ◽

Author(s):

Mario Tumminello ◽

Antonella Gangemi ◽

Federico Matina ◽

Melania Guardino ◽

Bianca Lea Giuffrè ◽

...

Keyword(s):

Ectodermal Dysplasia ◽

Genetic Disorder ◽

Missense Variant ◽

Pathogenic Variant ◽

Hypohidrotic Ectodermal Dysplasia ◽

Variant Of Uncertain Significance ◽

Uncertain Significance ◽

Clinical Potential ◽

Genomic Variant ◽

Eda Gene

Abstract Background Hypohidrotic Ectodermal Dysplasia (HED) is a genetic disorder which affects structures of ectodermal origin. X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common form of disease. XLHED is characterized by hypotrichosis, hypohydrosis and hypodontia. The cardinal features of classic HED become obvious during childhood. Identification of a hemizygous EDA pathogenic variant in an affected male confirms the diagnosis. Case presentation We report on a male newborn with the main clinical characteristics of the X-linked HED including hypotrichosis, hypodontia and hypohidrosis. Gene panel sequencing identified a new hemizygous missense variant of uncertain significance (VUS) c.1142G > C (p.Gly381Ala) in the EDA gene, located on the X chromosome and inherited from the healthy mother. Conclusion Despite the potential functional impact of VUS remains uncharacterized, our goal is to evaluate the clinical potential consequences of missense VUS on EDA gene. Even if the proband’s phenotype is characteristic for classic HED, further reports of patients with same clinical phenotype and the same genomic variant are needed to consider this novel VUS as responsible for the development of HED.

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Ataxia with oculomotor apraxia type 2: an evolving axonal neuropathy

Practical Neurology ◽

10.1136/practneurol-2017-001711 ◽

2017 ◽

Vol 18 (1) ◽

pp. 52-56

Author(s):

Tahira N Choudry ◽

David Hilton-Jones ◽

Graham Lennox ◽

Henry Houlden

Keyword(s):

Autosomal Recessive ◽

Age Of Onset ◽

Axonal Neuropathy ◽

Elevated Serum ◽

Cerebellar Atrophy ◽

Recessive Ataxia ◽

Autosomal Recessive Ataxia ◽

Oculomotor Apraxia ◽

Ataxia With Oculomotor Apraxia

A 23-year-old woman had presented initially to a podiatrist complaining of poorly fitting shoes during her adolescence. After extensive neurological review, she was diagnosed with ataxia with oculomotor apraxia type 2. This is a progressive autosomal recessive ataxia associated with cerebellar atrophy, peripheral neuropathy and an elevated serum α-fetoprotein. Within Europe, it is the most frequent autosomal recessive ataxia after Friedreich’s ataxia and is due to mutations in the senataxin (SETX) gene. The age of onset is approximately 15 years.The diagnosis of oculomotor apraxia type 2 is often challenging. We provide a framework for assessing a young ataxic patient with or without oculomotor apraxia and review clues that will aid diagnosis. The prognosis, level of disability, cancer and immunosuppression risk all markedly differ between the conditions. Patients and their families need the correct diagnosis for genetic counselling, management and long-term surveillance with appropriate subspecialty services.

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Novel compound heterozygous mutation in SACS gene leads to a milder autosomal recessive spastic ataxia of Charlevoix‐Saguenay, ARSACS , in a Finnish family

Clinical Case Reports ◽

10.1002/ccr3.722 ◽

2016 ◽

Vol 4 (12) ◽

pp. 1151-1156 ◽

Cited By ~ 7

Author(s):

Johanna Palmio ◽

Mikko Kärppä ◽

Peter Baumann ◽

Sini Penttilä ◽

Jukka Moilanen ◽

...

Keyword(s):

Autosomal Recessive ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Spastic Ataxia

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Biochemical Characterization of the GBA2 c.1780G>C Missense Mutation in Lymphoblastoid Cells from Patients with Spastic Ataxia

International Journal of Molecular Sciences ◽

10.3390/ijms19103099 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3099 ◽

Cited By ~ 6

Author(s):

Anna Malekkou ◽

Maura Samarani ◽

Anthi Drousiotou ◽

Christina Votsi ◽

Sandro Sonnino ◽

...

Keyword(s):

Missense Mutation ◽

Autosomal Recessive ◽

Biochemical Characterization ◽

Fold Increase ◽

Loss Of Function ◽

Spastic Paraplegia ◽

Spastic Ataxia ◽

Autosomal Recessive Cerebellar Ataxia ◽

Compensatory Effect

The GBA2 gene encodes the non-lysosomal glucosylceramidase (NLGase), an enzyme that catalyzes the conversion of glucosylceramide (GlcCer) to ceramide and glucose. Mutations in GBA2 have been associated with the development of neurological disorders such as autosomal recessive cerebellar ataxia, hereditary spastic paraplegia, and Marinesco-Sjogren-Like Syndrome. Our group has previously identified the GBA2 c.1780G>C [p.Asp594His] missense mutation, in a Cypriot consanguineous family with spastic ataxia. In this study, we carried out a biochemical characterization of lymphoblastoid cell lines (LCLs) derived from three patients of this family. We found that the mutation strongly reduce NLGase activity both intracellularly and at the plasma membrane level. Additionally, we observed a two-fold increase of GlcCer content in LCLs derived from patients compared to controls, with the C16 lipid being the most abundant GlcCer species. Moreover, we showed that there is an apparent compensatory effect between NLGase and the lysosomal glucosylceramidase (GCase), since we found that the activity of GCase was three-fold higher in LCLs derived from patients compared to controls. We conclude that the c.1780G>C mutation results in NLGase loss of function with abolishment of the enzymatic activity and accumulation of GlcCer accompanied by a compensatory increase in GCase.

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Autosomal recessive chondrodysplasia with severe short stature caused by a biallelic COL10A1 variant

Journal of Medical Genetics ◽

10.1136/jmedgenet-2017-104885 ◽

2017 ◽

Vol 55 (6) ◽

pp. 403-407 ◽

Cited By ~ 4

Author(s):

Noor ul Ain ◽

Outi Makitie ◽

Sadaf Naz

Keyword(s):

Short Stature ◽

Skeletal Dysplasia ◽

In Silico ◽

Autosomal Recessive ◽

Limb Deformity ◽

Mild Phenotype ◽

Whole Exome ◽

New Type ◽

Severe Short Stature ◽

Amino Acid Conservation

BackgroundHeterozygous mutations in COL10A1 underlie metaphyseal chondrodysplasia, Schmid type (MCDS), an autosomal dominant skeletal dysplasia.ObjectiveTo identify the causative variant in a large consanguineous Pakistani family with severe skeletal dysplasia and marked lower limb deformity.MethodsWhole exome sequencing was completed followed by Sanger sequencing to verify segregation of the identified variants. In silico variant pathogenicity predictions and amino acid conservation analyses were performed.ResultsA homozygous c.133 C>T (p.Pro45Ser) variant was identified in COL10A1 in all six severely affected individuals (adult heights 119–130 cm, mean ~−6.33 SD). The individuals heterozygous for the variant had mild phenotype of short stature (adult heights 140–162 cm, mean ~−2.15 SD) but no apparent skeletal deformities. The variant was predicted to be pathogenic by in silico prediction tools and was absent from public databases and hundred control chromosomes. Pro45 is conserved in orthologues and is located in the non-collagenous 2 domain of COL10A1, variants of which have never been associated with skeletal dysplasia.ConclusionsThis first report of individuals with a homozygous variant in COL10A1 defines a new type of autosomal recessive skeletal dysplasia. The observations in COL10A1 variant carriers suggest a phenotypic overlap between the mildest forms of MCDS and idiopathic short stature.

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