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1.
Immunity ; 50(5): 1218-1231.e5, 2019 05 21.
Artículo en Inglés | MEDLINE | ID: mdl-30952607

RESUMEN

Patients with the neurological disorder HSAN-I suffer frequent infections, attributed to a lack of pain sensation and failure to seek care for minor injuries. Whether protective CD8+ T cells are affected in HSAN-I patients remains unknown. Here, we report that HSAN-I-associated mutations in serine palmitoyltransferase subunit SPTLC2 dampened human T cell responses. Antigen stimulation and inflammation induced SPTLC2 expression, and murine T-cell-specific ablation of Sptlc2 impaired antiviral-T-cell expansion and effector function. Sptlc2 deficiency reduced sphingolipid biosynthetic flux and led to prolonged activation of the mechanistic target of rapamycin complex 1 (mTORC1), endoplasmic reticulum (ER) stress, and CD8+ T cell death. Protective CD8+ T cell responses in HSAN-I patient PBMCs and Sptlc2-deficient mice were restored by supplementing with sphingolipids and pharmacologically inhibiting ER stress-induced cell death. Therefore, SPTLC2 underpins protective immunity by translating extracellular stimuli into intracellular anabolic signals and antagonizes ER stress to promote T cell metabolic fitness.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Serina C-Palmitoiltransferasa/genética , Animales , Proliferación Celular , Células Cultivadas , Citocinas/biosíntesis , Estrés del Retículo Endoplásmico/genética , Estrés del Retículo Endoplásmico/inmunología , Femenino , Humanos , Coriomeningitis Linfocítica/virología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Transducción de Señal/inmunología , Esfingolípidos/biosíntesis
2.
Brain ; 142(6): 1561-1572, 2019 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-31135052

RESUMEN

The endoplasmic reticulum enzyme fatty acid 2-hydroxylase (FA2H) plays a major role in the formation of 2-hydroxy glycosphingolipids, main components of myelin. FA2H deficiency in mice leads to severe central demyelination and axon loss. In humans it has been associated with phenotypes from the neurodegeneration with brain iron accumulation (fatty acid hydroxylase-associated neurodegeneration, FAHN), hereditary spastic paraplegia (HSP type SPG35) and leukodystrophy (leukodystrophy with spasticity and dystonia) spectrum. We performed an in-depth clinical and retrospective neurophysiological and imaging study in a cohort of 19 cases with biallelic FA2H mutations. FAHN/SPG35 manifests with early childhood onset predominantly lower limb spastic tetraparesis and truncal instability, dysarthria, dysphagia, cerebellar ataxia, and cognitive deficits, often accompanied by exotropia and movement disorders. The disease is rapidly progressive with loss of ambulation after a median of 7 years after disease onset and demonstrates little interindividual variability. The hair of FAHN/SPG35 patients shows a bristle-like appearance; scanning electron microscopy of patient hair shafts reveals deformities (longitudinal grooves) as well as plaque-like adhesions to the hair, likely caused by an abnormal sebum composition also described in a mouse model of FA2H deficiency. Characteristic imaging features of FAHN/SPG35 can be summarized by the 'WHAT' acronym: white matter changes, hypointensity of the globus pallidus, ponto-cerebellar atrophy, and thin corpus callosum. At least three of four imaging features are present in 85% of FA2H mutation carriers. Here, we report the first systematic, large cohort study in FAHN/SPG35 and determine the phenotypic spectrum, define the disease course and identify clinical and imaging biomarkers.


Asunto(s)
Trastornos Heredodegenerativos del Sistema Nervioso/genética , Fenotipo , Paraplejía Espástica Hereditaria/genética , Niño , Estudios de Cohortes , Enfermedades Desmielinizantes/genética , Femenino , Humanos , Masculino , Oxigenasas de Función Mixta/genética , Mutación/genética , Linaje , Estudios Retrospectivos , Paraplejía Espástica Hereditaria/clasificación
3.
Neurogenetics ; 20(3): 117-127, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31011849

RESUMEN

Charcot-Marie-Tooth (CMT) disease is a form of inherited peripheral neuropathy that affects motor and sensory neurons. To identify the causative gene in a consanguineous family with autosomal recessive CMT (AR-CMT), we employed a combination of linkage analysis and whole exome sequencing. After excluding known AR-CMT genes, genome-wide linkage analysis mapped the disease locus to a 7.48-Mb interval on chromosome 14q32.11-q32.33, flanked by the markers rs2124843 and rs4983409. Whole exome sequencing identified two non-synonymous variants (p.T40P and p.H915Y) in the AHNAK2 gene that segregated with the disease in the family. Pathogenic predictions indicated that p.T40P is the likely causative allele. Analysis of AHNAK2 expression in the AR-CMT patient fibroblasts showed significantly reduced mRNA and protein levels. AHNAK2 binds directly to periaxin which is encoded by the PRX gene, and PRX mutations are associated with another form of AR-CMT (CMT4F). The altered expression of mutant AHNAK2 may disrupt the AHNAK2-PRX interaction in which one of its known functions is to regulate myelination.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Proteínas del Citoesqueleto/genética , Predisposición Genética a la Enfermedad , Proteínas de la Membrana/genética , Adolescente , Alelos , Biopsia , Mapeo Cromosómico , Consanguinidad , Salud de la Familia , Femenino , Fibroblastos/metabolismo , Genes Recesivos , Ligamiento Genético , Marcadores Genéticos , Haplotipos , Humanos , Escala de Lod , Pérdida de Heterocigocidad , Malasia , Masculino , Mutación Missense , Neuronas/metabolismo , Linaje , Secuenciación del Exoma
4.
Am J Hum Genet ; 98(4): 597-614, 2016 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-27040688

RESUMEN

Abnormal protein aggregation is observed in an expanding number of neurodegenerative diseases. Here, we describe a mechanism for intracellular toxic protein aggregation induced by an unusual mutation event in families affected by axonal neuropathy. These families carry distinct frameshift variants in NEFH (neurofilament heavy), leading to a loss of the terminating codon and translation of the 3' UTR into an extra 40 amino acids. In silico aggregation prediction suggested the terminal 20 residues of the altered NEFH to be amyloidogenic, which we confirmed experimentally by serial deletion analysis. The presence of this amyloidogenic motif fused to NEFH caused prominent and toxic protein aggregates in transfected cells and disrupted motor neurons in zebrafish. We identified a similar aggregation-inducing mechanism in NEFL (neurofilament light) and FUS (fused in sarcoma), in which mutations are known to cause aggregation in Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis, respectively. In summary, we present a protein-aggregation-triggering mechanism that should be taken into consideration during the evaluation of stop-loss variants.


Asunto(s)
Regiones no Traducidas 3'/genética , Axones/patología , Filamentos Intermedios/genética , Neuronas Motoras/patología , Secuencia de Aminoácidos , Esclerosis Amiotrófica Lateral/genética , Animales , Línea Celular , Enfermedad de Charcot-Marie-Tooth/genética , Mutación del Sistema de Lectura , Humanos , Filamentos Intermedios/metabolismo , Ratones , Datos de Secuencia Molecular , Neuronas Motoras/metabolismo , Mutación , Linaje , Pez Cebra/genética
5.
Am J Hum Genet ; 99(3): 607-623, 2016 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-27588448

RESUMEN

Axonal polyneuropathies are a frequent cause of progressive disability in the elderly. Common etiologies comprise diabetes mellitus, paraproteinaemia, and inflammatory disorders, but often the underlying causes remain elusive. Late-onset axonal Charcot-Marie-Tooth neuropathy (CMT2) is an autosomal-dominantly inherited condition that manifests in the second half of life and is genetically largely unexplained. We assumed age-dependent penetrance of mutations in a so far unknown gene causing late-onset CMT2. We screened 51 index case subjects with late-onset CMT2 for mutations by whole-exome (WES) and Sanger sequencing and subsequently queried WES repositories for further case subjects carrying mutations in the identified candidate gene. We studied nerve pathology and tissue levels and function of the abnormal protein in order to explore consequences of the mutations. Altogether, we observed heterozygous rare loss-of-function and missense mutations in MME encoding the metalloprotease neprilysin in 19 index case subjects diagnosed with axonal polyneuropathies or neurodegenerative conditions involving the peripheral nervous system. MME mutations segregated in an autosomal-dominant fashion with age-related incomplete penetrance and some affected individuals were isolated case subjects. We also found that MME mutations resulted in strongly decreased tissue availability of neprilysin and impaired enzymatic activity. Although neprilysin is known to degrade ß-amyloid, we observed no increased amyloid deposition or increased incidence of dementia in individuals with MME mutations. Detection of MME mutations is expected to increase the diagnostic yield in late-onset polyneuropathies, and it will be tempting to explore whether substances that can elevate neprilysin activity could be a rational option for treatment.


Asunto(s)
Axones/patología , Genes Dominantes/genética , Mutación/genética , Neprilisina/genética , Polineuropatías/genética , Polineuropatías/patología , Tejido Adiposo/metabolismo , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Alelos , Péptidos beta-Amiloides/metabolismo , Animales , Enfermedad de Charcot-Marie-Tooth/complicaciones , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/patología , Análisis Mutacional de ADN , Bases de Datos Genéticas , Demencia/complicaciones , Demencia/genética , Exoma/genética , Heterocigoto , Humanos , Ratones , Persona de Mediana Edad , Mutación Missense/genética , Neprilisina/análisis , Neprilisina/sangre , Neprilisina/deficiencia , Penetrancia , Polineuropatías/complicaciones , Piel/metabolismo , Nervio Sural
6.
Mol Cell Probes ; 41: 61-63, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30142390

RESUMEN

TTR amyloidosis (ATTR) is a fatal condition caused by extracellular deposits of misfolded transthyretin. Patients often present with cardiac disease, but manifestations may also involve other organs including the peripheral nervous system. ATTR is considered familial when heterozygous mutations in the TTR gene are present (ATTRmutant or ATTRm), or acquired when no TTR aberrations are detected (ATTRwildtype or ATTRwt). We hypothesized that TTR copy number variants (CNVs), which would escape the standard diagnostic approaches, contribute to ATTR-related phenotypes, and developed a multiplex ligation-dependent probe amplification-based (MLPA-based), TTR-specific copy number screening tool. High inter-sample and intra-sample homogeneity of MLPA signals and the expected drop in signal intensity for restriction digest-based positive controls validated this tool. Subsequent application to 13 patients diagnosed with ATTRwt, and to 93 patients presenting with late onset and presumably inherited polyneuropathy did not identify TTR CNVs. We discuss insufficient sensitivity of the assay as well as non-existence and non-pathogenicity of TTR CNVs as potentially underlying our negative finding, but suggest size and composition of our cohorts as more likely explanations. Our CNV-screening tool will be made available to initiatives interested in screening additional and potentially more appropriate patient samples.


Asunto(s)
Dosificación de Gen , Prealbúmina/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad
8.
Ann Neurol ; 79(3): 419-27, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26659848

RESUMEN

OBJECTIVE: To use linkage analysis and whole exome sequencing to identify the genetic mutation in a multigenerational Australian family with Charcot-Marie-Tooth disease type 2 (CMT2) and pyramidal signs. METHODS: Genome-wide linkage analysis was performed to map the locus. Whole exome sequencing was undertaken on selected individuals (3 affected, 1 normal), and segregation analysis and mutation screening were carried out using high-resolution melt analysis. The GEM.app database was queried to identify additional families with mutations. RESULTS: Significant linkage (2-point LOD score ≥ +3) and haplotype analysis mapped a new locus for CMT2 and pyramidal signs to a 6.6Mb interval on chromosome 22q12.1-q12.3. Whole exome sequencing identified a novel mutation (p.R252W) in the microrchidia CW-type zinc finger 2 (MORC2) gene mapping within the linkage region. The mutation fully segregated with the disease phenotype in the family. Screening additional families and querying unsolved CMT2 exomes, we identified the p.R252W mutation in 2 unrelated early onset CMT2 families and a second mutation p.E236G in 2 unrelated CMT2 families. Both the mutations occurred at highly conserved amino acid residues and were absent in the normal population. INTERPRETATION: We have identified a new locus in which MORC2 mutations are the likely pathogenic cause of CMT2 and pyramidal signs in these families. MORC2 encodes the human CW-type zinc finger 2 protein, which is a chromatin modifier involved in the regulation of DNA repair as well as gene transcription.


Asunto(s)
Axones/patología , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/patología , Predisposición Genética a la Enfermedad/genética , Tractos Piramidales/patología , Factores de Transcripción/genética , Adulto , Femenino , Humanos , Masculino , Mutación/genética
9.
Am J Hum Genet ; 92(6): 965-73, 2013 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-23664120

RESUMEN

Dominant congenital spinal muscular atrophy (DCSMA) is a disorder of developing anterior horn cells and shows lower-limb predominance and clinical overlap with hereditary spastic paraplegia (HSP), a lower-limb-predominant disorder of corticospinal motor neurons. We have identified four mutations in bicaudal D homolog 2 (Drosophila) (BICD2) in six kindreds affected by DCSMA, DCSMA with upper motor neuron features, or HSP. BICD2 encodes BICD2, a key adaptor protein that interacts with the dynein-dynactin motor complex, which facilitates trafficking of cellular cargos that are critical to motor neuron development and maintenance. We demonstrate that mutations resulting in amino acid substitutions in two binding regions of BICD2 increase its binding affinity for the cytoplasmic dynein-dynactin complex, which might result in the perturbation of BICD2-dynein-dynactin-mediated trafficking, and impair neurite outgrowth. These findings provide insight into the mechanism underlying both the static and the slowly progressive clinical features and the motor neuron pathology that characterize BICD2-associated diseases, and underscore the importance of the dynein-dynactin transport pathway in the development and survival of both lower and upper motor neurons.


Asunto(s)
Proteínas Portadoras/genética , Atrofia Muscular Espinal/genética , Mutación Missense , Paraplejía/genética , Adulto , Anciano , Proteínas Portadoras/metabolismo , Niño , Preescolar , Dineínas Citoplasmáticas/metabolismo , Femenino , Genes Dominantes , Ligamiento Genético , Estudio de Asociación del Genoma Completo , Células HEK293 , Haplotipos , Humanos , Masculino , Proteínas Asociadas a Microtúbulos , Persona de Mediana Edad , Atrofia Muscular Espinal/congénito , Atrofia Muscular Espinal/metabolismo , Paraplejía/metabolismo , Linaje , Polimorfismo de Nucleótido Simple , Unión Proteica , Adulto Joven
10.
Brain ; 138(Pt 2): 293-310, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25497877

RESUMEN

Spinal muscular atrophy is a disorder of lower motor neurons, most commonly caused by recessive mutations in SMN1 on chromosome 5q. Cases without SMN1 mutations are subclassified according to phenotype. Spinal muscular atrophy, lower extremity-predominant, is characterized by lower limb muscle weakness and wasting, associated with reduced numbers of lumbar motor neurons and is caused by mutations in DYNC1H1, which encodes a microtubule motor protein in the dynein-dynactin complex and one of its cargo adaptors, BICD2. We have now identified 32 patients with BICD2 mutations from nine different families, providing detailed insights into the clinical phenotype and natural history of BICD2 disease. BICD2 spinal muscular atrophy, lower extremity predominant most commonly presents with delayed motor milestones and ankle contractures. Additional features at presentation include arthrogryposis and congenital dislocation of the hips. In all affected individuals, weakness and wasting is lower-limb predominant, and typically involves both proximal and distal muscle groups. There is no evidence of sensory nerve involvement. Upper motor neuron signs are a prominent feature in a subset of individuals, including one family with exclusively adult-onset upper motor neuron features, consistent with a diagnosis of hereditary spastic paraplegia. In all cohort members, lower motor neuron features were static or only slowly progressive, and the majority remained ambulant throughout life. Muscle MRI in six individuals showed a common pattern of muscle involvement with fat deposition in most thigh muscles, but sparing of the adductors and semitendinosus. Muscle pathology findings were highly variable and included pseudomyopathic features, neuropathic features, and minimal change. The six causative mutations, including one not previously reported, result in amino acid changes within all three coiled-coil domains of the BICD2 protein, and include a possible 'hot spot' mutation, p.Ser107Leu present in four families. We used the recently solved crystal structure of a highly conserved region of the Drosophila orthologue of BICD2 to further-explore how the p.Glu774Gly substitution inhibits the binding of BICD2 to Rab6. Overall, the features of BICD2 spinal muscular atrophy, lower extremity predominant are consistent with a pathological process that preferentially affects lumbar lower motor neurons, with or without additional upper motor neuron involvement. Defining the phenotypic features in this, the largest BICD2 disease cohort reported to date, will facilitate focused genetic testing and filtering of next generation sequencing-derived variants in cases with similar features.


Asunto(s)
Proteínas Asociadas a Microtúbulos/genética , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patología , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Mutación/genética , Linaje , Fenotipo , Unión Proteica , Columna Vertebral/patología , Adulto Joven
11.
Am J Med Genet B Neuropsychiatr Genet ; 171(6): 875-8, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27184211

RESUMEN

Congenital insensitivity to pain and anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by recurrent episodes of unexplained high fever, loss of pain perception and temperature sensation, absent sweating, repeated traumatic and thermal injuries, and mild mental retardation. After exclusion of obviously pathogenic mutations in NTRK1, the most common cause of CIPA, whole exome sequencing (WES) was carried out in a CIPA patient with unrelated parents. No mutations in known HSAN genes were identified. However, filtering for genes carrying two rare sequence variations detected 13 homozygous single nucleotide variants (SNV), all being located on chromosome 1. Further analysis strongly suggested that this finding might be best explained by uniparental disomy of chromosome 1. Because NTRK1 is also located on chromosome 1, we re-evaluated WES data and detected a novel intronic sequence variation at position c.2188-12 C>A, homozygously because of uniparental disomy. Subsequent analysis of NTRK1 transcripts in peripheral blood cells of the patient revealed an influence of the variant on mRNA splicing. The C>A transversion generated a novel splice-site, which led to the incorporation of 10 intronic bases into the NTRK1 mRNA and consequently to a non-functional gene product. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Insensibilidad Congénita al Dolor/genética , Receptor trkA/genética , Niño , Exoma/genética , Femenino , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Homocigoto , Humanos , Intrones/genética , Dolor/genética , Linaje , Receptor trkA/metabolismo , Disomía Uniparental/genética , Disomía Uniparental/patología
12.
Am J Hum Genet ; 91(1): 139-45, 2012 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-22703882

RESUMEN

The distal hereditary motor neuropathies (dHMNs) are a heterogeneous group of neurodegenerative disorders affecting the lower motoneuron. In a family with both autosomal-dominant dHMN and dHMN type V (dHMN/dHMN-V) present in three generations, we excluded mutations in all genes known to be associated with a dHMN phenotype through Sanger sequencing and defined three potential loci through linkage analysis. Whole-exome sequencing of two affected individuals revealed a single candidate variant within the linking regions, i.e., a splice-site alteration in REEP1 (c.304-2A>G). A minigene assay confirmed complete loss of splice-acceptor functionality and skipping of the in-frame exon 5. The resulting mRNA is predicted to be expressed at normal levels and to encode an internally shortened protein (p.102_139del). Loss-of-function REEP1 mutations have previously been identified in dominant hereditary spastic paraplegia (HSP), a disease associated with upper-motoneuron pathology. Consistent with our clinical-genetic data, we show that REEP1 is strongly expressed in the lower motoneurons as well. Upon exogeneous overexpression in cell lines we observe a subcellular localization defect for p.102_139del that differs from that observed for the known HSP-associated missense mutation c.59C>A (p.Ala20Glu). Moreover, we show that p.102_139del, but not p.Ala20Glu, recruits atlastin-1, i.e., one of the REEP1 binding partners, to the altered sites of localization. These data corroborate the loss-of-function nature of REEP1 mutations in HSP and suggest that a different mechanism applies in REEP1-associated dHMN.


Asunto(s)
Proteínas de Transporte de Membrana/genética , Mutación , Enfermedades del Sistema Nervioso Periférico/genética , Línea Celular , Exoma , Femenino , Humanos , Masculino , Linaje , Análisis de Secuencia de ADN
13.
J Peripher Nerv Syst ; 20(1): 52-9, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25676889

RESUMEN

Mutations in the gene encoding inverted formin FH2 and WH2 domain-containing protein (INF2), a Cdc42 effector involved in the regulation of actin dynamics, cause focal segmental glomerulosclerosis (FSGS) and intermediate Charcot-Marie-Tooth neuropathy combined with FSGS (FSGS-CMT). Here, we report on six patients from four families with sensorimotor polyneuropathy and FSGS. Nerve conduction velocities were moderately slowed, and amplitudes of sensory and motor potentials were decreased. One patient had internal hydrocephalus and was intellectually disabled. Molecular genetic testing revealed two known and two novel missense mutations in the second and fourth exons of the INF2 gene. Investigations of one nerve biopsy confirmed the diagnosis of intermediate-type CMT and revealed occasional abnormal in- and outfoldings of myelin sheaths and expansions of the endoplasmic reticulum in axons and Schwann cells. While earlier reports suggested that mutations causing FSGS-CMT are restricted to exons 2 and 3 of the INF2 gene, we found one CMT-FSGS causing mutation (p.Glu184Lys) in exon 4 extending the critical region of INF2 for rapid CMT-FSGS molecular genetic diagnosis. Study of a nerve biopsy showed abnormalities that might be related to the known role of the INF2-binding partner CDC42 in myelination.


Asunto(s)
Axones/patología , Glomeruloesclerosis Focal y Segmentaria/genética , Proteínas de Microfilamentos/genética , Mutación/genética , Células de Schwann/patología , Adolescente , Adulto , Enfermedad de Charcot-Marie-Tooth/complicaciones , Enfermedad de Charcot-Marie-Tooth/genética , Niño , Femenino , Forminas , Pruebas Genéticas , Glomeruloesclerosis Focal y Segmentaria/complicaciones , Humanos , Músculo Esquelético/patología , Nervios Periféricos/diagnóstico por imagen , Nervios Periféricos/metabolismo , Nervios Periféricos/patología , Ultrasonografía , Adulto Joven
14.
Neurobiol Dis ; 65: 211-9, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24521780

RESUMEN

Charcot-Marie-Tooth disease type 2B (CMT2B) is an inherited axonal peripheral neuropathy. It is characterised by prominent sensory loss, often complicated by severe ulcero-mutilations of toes or feet, and variable motor involvement. Missense mutations in RAB7A, the gene encoding the small GTPase Rab7, cause CMT2B and increase Rab7 activity. Rab7 is ubiquitously expressed and is involved in degradation through the lysosomal pathway. In the neurons, Rab7 plays a role in the long-range retrograde transport of signalling endosomes in the axons. Here we developed the first animal model of CMT2B, modelling one of the mutations (L129F) in Drosophila melanogaster. Behavioural assays show that this model recapitulates several hallmarks of the human disease. Upon expression of mutant Rab7 in the sensory neurons, larvae present with a reduction of temperature and pain perception. Furthermore, the larvae exhibit a crawling defect when the mutant protein is expressed in the motor neurons. Analysis of axonal transport of Rab7 positive vesicles in sensory neurons of Drosophila larvae and in neurites of mammalian neuroblastoma cells demonstrates that mutant vesicles pause less than their wild-type counterparts. This latter finding indicates that alterations in vesicle transport might contribute to the pathomechanism of CMT2B.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Mutación/genética , Proteínas de Unión al GTP rab/genética , Animales , Animales Modificados Genéticamente , Conducta Animal/fisiología , Diferenciación Celular , Línea Celular Transformada , Dendritas/patología , Modelos Animales de Enfermedad , Drosophila , Proteínas de Drosophila/genética , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Laminopatías , Larva , Masculino , Actividad Motora/genética , Neuroblastoma/patología , Células Receptoras Sensoriales/patología , Transducción Genética , Proteínas de Unión a GTP rab7
15.
Am J Hum Genet ; 88(1): 99-105, 2011 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-21194679

RESUMEN

Hereditary sensory neuropathy type I (HSN I) is an axonal form of autosomal-dominant hereditary motor and sensory neuropathy distinguished by prominent sensory loss that leads to painless injuries. Unrecognized, these can result in delayed wound healing and osteomyelitis, necessitating distal amputations. To elucidate the genetic basis of an HSN I subtype in a family in which mutations in the few known HSN I genes had been excluded, we employed massive parallel exon sequencing of the 14.3 Mb disease interval on chromosome 14q. We detected a missense mutation (c.1065C>A, p.Asn355Lys) in atlastin-1 (ATL1), a gene that is known to be mutated in early-onset hereditary spastic paraplegia SPG3A and that encodes the large dynamin-related GTPase atlastin-1. The mutant protein exhibited reduced GTPase activity and prominently disrupted ER network morphology when expressed in COS7 cells, strongly supporting pathogenicity. An expanded screen in 115 additional HSN I patients identified two further dominant ATL1 mutations (c.196G>C [p.Glu66Gln] and c.976 delG [p.Val326TrpfsX8]). This study highlights an unexpected major role for atlastin-1 in the function of sensory neurons and identifies HSN I and SPG3A as allelic disorders.


Asunto(s)
GTP Fosfohidrolasas/genética , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Animales , Secuencia de Bases , Células COS , Chlorocebus aethiops , Cromosomas Humanos Par 14/genética , Retículo Endoplásmico/enzimología , Exones , Femenino , Proteínas de Unión al GTP , Genes Dominantes , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Proteínas de la Membrana , Datos de Secuencia Molecular , Mutación , Mutación Missense , Análisis de Secuencia de ADN , Paraplejía Espástica Hereditaria/genética
16.
Amyloid ; 31(1): 42-51, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37599395

RESUMEN

Aims: Novel ribonucleic acid interference (RNAi) therapeutics such as patisiran and inotersen have been shown to benefit neurologic disease course and quality of life in patients with hereditary transthyretin amyloidosis (ATTRv). We aimed to determine the impact of RNAi therapeutics on myocardial amyloid load using quantitative single photon emission computed tomography/computed tomography (SPECT/CT) imaging in patients with ATTRv-related cardiomyopathy (ATTRv-CM). We furthermore compared them with wild-type ATTR-CM (ATTRwt-CM) patients treated with tafamidis.Methods and results: ATTRv-CM patients underwent [99mTc]-radiolabeled diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy and quantitative SPECT/CT imaging before and after 12 months (IQR: 11.0-12.0) of treatment with RNAi therapeutics (patisiran: n = 5, inotersen: n = 4). RNAi treatment significantly reduced quantitative myocardial uptake as measured by standardised uptake value (SUV) retention index (baseline: 5.09 g/mL vs. follow-up: 3.19 g/mL, p = .028) in ATTRv-CM patients without significant improvement in cardiac function. Tafamidis treatment resulted in a significant reduction in SUV retention index (4.96 g/mL vs. 3.27 g/mL, p < .001) in ATTRwt-CM patients (historical control cohort: n = 40) at follow-up [9.0 months (IQR: 7.0-10.0)] without beneficial impact on cardiac function.Conclusions: RNAi therapeutics significantly reduce quantitative myocardial uptake in ATTRv-CM patients, comparable to tafamidis treatment in ATTRwt-CM patients, without impact on cardiac function. Serial 99mTc-DPD SPECT/CT imaging may be a valuable tool to quantify and monitor response to disease-specific therapies in both ATTRv-CM and ATTRwt-CM.


Asunto(s)
Neuropatías Amiloides Familiares , Cardiomiopatías , Humanos , Calidad de Vida , Compuestos de Organotecnecio , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/genética , Neuropatías Amiloides Familiares/diagnóstico por imagen , Neuropatías Amiloides Familiares/tratamiento farmacológico , Neuropatías Amiloides Familiares/genética , Miocardio
17.
Traffic ; 12(7): 902-11, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21438969

RESUMEN

Cytotoxic T lymphocytes (CTL) are potent killers of virally infected and tumorigenic cells. Upon recognition of target cells, CTL undergo polarized secretion of secretory lysosomes at the immunological synapse (IS) that forms between CTL and target. However, the molecular machinery involved in the polarization of secretory lysosomes is still largely uncharacterized. In this paper, we investigated the role of Rab7 in the polarization of secretory lysosomes. We show that silencing of Rab7 by RNA interference reduces the ability of CTL to kill targets. GTP-bound Rab7 and Rab interacting lysosomal protein, RILP, interact and both localize to secretory lysosomes in CTL. Over-expression of RILP recruits dynein to the membranes of secretory lysosomes and triggers their movement toward the centrosome. Together, these results suggest that Rab7 may play a role in secretory lysosome movement toward the centrosome by interacting with RILP to recruit the minus-end motor, dynein.


Asunto(s)
Vesículas Secretoras/metabolismo , Linfocitos T Citotóxicos/metabolismo , Proteínas de Unión al GTP rab/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proteínas Portadoras/metabolismo , Proteínas del Citoesqueleto/metabolismo , Dineínas/metabolismo , Guanosina Trifosfato/metabolismo , Células HeLa , Humanos , Lisosomas/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas Asociadas a Microtúbulos , Mutación , Interferencia de ARN , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Proteínas de Unión al GTP rab/genética , Proteínas de Unión a GTP rab7
18.
Am J Hum Genet ; 87(4): 513-22, 2010 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-20920666

RESUMEN

Hereditary sensory and autonomic neuropathy type I (HSAN-I) is an axonal peripheral neuropathy associated with progressive distal sensory loss and severe ulcerations. Mutations in the first subunit of the enzyme serine palmitoyltransferase (SPT) have been associated with HSAN-I. The SPT enzyme catalyzes the first and rate-limiting step in the de novo sphingolipid synthesis pathway. However, different studies suggest the implication of other genes in the pathology of HSAN-I. Therefore, we screened the two other known subunits of SPT, SPTLC2 and SPTLC3, in a cohort of 78 HSAN patients. No mutations were found in SPTLC3, but we identified three heterozygous missense mutations in the SPTLC2 subunit of SPT in four families presenting with a typical HSAN-I phenotype. We demonstrate that these mutations result in a partial to complete loss of SPT activity in vitro and in vivo. Moreover, they cause the accumulation of the atypical and neurotoxic sphingoid metabolite 1-deoxy-sphinganine. Our findings extend the genetic heterogeneity in HSAN-I and enlarge the group of HSAN neuropathies associated with SPT defects. We further show that HSAN-I is consistently associated with an increased formation of the neurotoxic 1-deoxysphinganine, suggesting a common pathomechanism for HSAN-I.


Asunto(s)
Neuropatías Hereditarias Sensoriales y Autónomas/genética , Serina C-Palmitoiltransferasa/genética , Secuencia de Bases , Línea Celular , Clonación Molecular , Estudios de Cohortes , Análisis Mutacional de ADN , Cartilla de ADN/genética , Prueba de Complementación Genética , Humanos , Repeticiones de Microsatélite/genética , Datos de Secuencia Molecular , Mutación Missense/genética , Serina C-Palmitoiltransferasa/metabolismo
19.
Pediatr Nephrol ; 28(2): 339-43, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22961558

RESUMEN

BACKGROUND: Mutations in inverted formin, FH2, and WH2 domain containing (INF2) are common causes of dominant focal segmental glomerulosclerosis. INF2 encodes a member of the diaphanous-related formin family, which regulates actin and microtubule cytoskeletons. Charcot-Marie-Tooth neuropathy (CMT) is a group of inherited disorders affecting peripheral neurons. Many reports have shown that glomerulopathy can associate with CMT. However, it has been unclear whether these two processes in the same individual represent one disorder or if they are two separate diseases. CASE DIAGNOSIS/TREATMENT: Recently, INF2 mutations were identified in 12 of 16 patients with CMT-associated glomerulopathy, suggesting that these mutations are a common cause of the dual phenotype. In this study, we report two cases of CMT-associated glomerulopathy that both showed INF2 mutations. A novel INF2 mutation, p. L77P, was identified in a family in which the dual phenotype was inherited in a dominant fashion. The pathogenic effect of p. L77P was proposed using a structural homology model. In addition, we identified a patient with a sporadic CMT-associated glomerulopathy carrying a known INF2 mutation: p. L128P. CONCLUSIONS: Our study confirms the link between INF2 mutations and CMT-associated glomerulopathy and widens the spectrum of pathogenic mutations.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Glomeruloesclerosis Focal y Segmentaria/genética , Proteínas de Microfilamentos/genética , Adolescente , Adulto , Enfermedad de Charcot-Marie-Tooth/complicaciones , Femenino , Forminas , Glomeruloesclerosis Focal y Segmentaria/complicaciones , Glomeruloesclerosis Focal y Segmentaria/patología , Humanos , Masculino , Mutación , Adulto Joven
20.
Nat Genet ; 36(3): 271-6, 2004 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-14981520

RESUMEN

Distal hereditary motor neuropathy (dHMN) or distal spinal muscular atrophy (OMIM #182960) is a heterogeneous group of disorders characterized by an almost exclusive degeneration of motor nerve fibers, predominantly in the distal part of the limbs. Silver syndrome (OMIM #270685) is a rare form of hereditary spastic paraparesis mapped to chromosome 11q12-q14 (SPG17) in which spasticity of the legs is accompanied by amyotrophy of the hands and occasionally also the lower limbs. Silver syndrome and most forms of dHMN are autosomal dominantly inherited with incomplete penetrance and a broad variability in clinical expression. A genome-wide scan in an Austrian family with dHMN-V (ref. 4) showed linkage to the locus SPG17, which was confirmed in 16 additional families with a phenotype characteristic of dHMN or Silver syndrome. After refining the critical region to 1 Mb, we sequenced the gene Berardinelli-Seip congenital lipodystrophy (BSCL2) and identified two heterozygous missense mutations resulting in the amino acid substitutions N88S and S90L. Null mutations in BSCL2, which encodes the protein seipin, were previously shown to be associated with autosomal recessive Berardinelli-Seip congenital lipodystrophy (OMIM #269700). We show that seipin is an integral membrane protein of the endoplasmic reticulum (ER). The amino acid substitutions N88S and S90L affect glycosylation of seipin and result in aggregate formation leading to neurodegeneration.


Asunto(s)
Subunidades gamma de la Proteína de Unión al GTP/genética , Neuropatía Hereditaria Motora y Sensorial/genética , Huesos/anomalías , Heterogeneidad Genética , Humanos , Neuronas Motoras/patología , Mutación Missense , Paraparesia/genética , Síndrome
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