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1.
Am J Hum Genet ; 104(4): 767-773, 2019 04 04.
Artículo en Inglés | MEDLINE | ID: mdl-30929741

RESUMEN

The diagnostic gap for rare neurodegenerative diseases is still considerable, despite continuous advances in gene identification. Many novel Mendelian genes have only been identified in a few families worldwide. Here we report the identification of an autosomal-dominant gene for hereditary spastic paraplegia (HSP) in 10 families that are of diverse geographic origin and whose affected members all carry unique truncating changes in a circumscript region of UBAP1 (ubiquitin-associated protein 1). HSP is a neurodegenerative disease characterized by progressive lower-limb spasticity and weakness, as well as frequent bladder dysfunction. At least 40% of affected persons are currently undiagnosed after exome sequencing. We identified pathological truncating variants in UBAP1 in affected persons from Iran, USA, Germany, Canada, Spain, and Bulgarian Roma. The genetic support ranges from linkage in the largest family (LOD = 8.3) to three confirmed de novo mutations. We show that mRNA in the fibroblasts of affected individuals escapes nonsense-mediated decay and thus leads to the expression of truncated proteins; in addition, concentrations of the full-length protein are reduced in comparison to those in controls. This suggests either a dominant-negative effect or haploinsufficiency. UBAP1 links endosomal trafficking to the ubiquitination machinery pathways that have been previously implicated in HSPs, and UBAP1 provides a bridge toward a more unified pathophysiology.


Asunto(s)
Proteínas Portadoras/genética , Mutación , Paraplejía Espástica Hereditaria/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Niño , Preescolar , Bases de Datos Factuales , Modelos Animales de Enfermedad , Endosomas/metabolismo , Salud de la Familia , Femenino , Fibroblastos/metabolismo , Genes Dominantes , Ligamiento Genético , Predisposición Genética a la Enfermedad , Genómica , Células HEK293 , Haploinsuficiencia , Humanos , Masculino , Persona de Mediana Edad , Linaje , Isoformas de Proteínas , Adulto Joven , Pez Cebra
2.
Mov Disord ; 37(6): 1175-1186, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35150594

RESUMEN

BACKGROUND: Pathogenic variants in SPTAN1 have been linked to a remarkably broad phenotypical spectrum. Clinical presentations include epileptic syndromes, intellectual disability, and hereditary motor neuropathy. OBJECTIVES: We investigated the role of SPTAN1 variants in rare neurological disorders such as ataxia and spastic paraplegia. METHODS: We screened 10,000 NGS datasets across two international consortia and one local database, indicative of the level of international collaboration currently required to identify genes causative for rare disease. We performed in silico modeling of the identified SPTAN1 variants. RESULTS: We describe 22 patients from 14 families with five novel SPTAN1 variants. Of six patients with cerebellar ataxia, four carry a de novo SPTAN1 variant and two show a sporadic inheritance. In this group, one variant (p.Lys2083del) is recurrent in four patients. Two patients have novel de novo missense mutations (p.Arg1098Cys, p.Arg1624Cys) associated with cerebellar ataxia, in one patient accompanied by intellectual disability and epilepsy. We furthermore report a recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia from seven families with a dominant inheritance pattern in four and a de novo origin in one case. One further patient carrying a de novo missense mutation (p.Gln2205Pro) has a complex spastic ataxic phenotype. Through protein modeling we show that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat. CONCLUSIONS: We show that SPTAN1 is a relevant candidate gene for ataxia and spastic paraplegia. We suggest that for the mutations identified in this study, disruption of the interlinking of spectrin helices could be a key feature of the pathomechanism. © 2022 International Parkinson and Movement Disorder Society.


Asunto(s)
Proteínas Portadoras , Ataxia Cerebelosa , Discapacidad Intelectual , Proteínas de Microfilamentos , Paraplejía Espástica Hereditaria , Proteínas Portadoras/genética , Ataxia Cerebelosa/genética , Humanos , Discapacidad Intelectual/genética , Proteínas de Microfilamentos/genética , Mutación/genética , Paraplejía/genética , Linaje , Fenotipo , Paraplejía Espástica Hereditaria/genética , Espectrina/genética
3.
J Med Genet ; 55(12): 814-823, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30415211

RESUMEN

BACKGROUND: Mutations in the metalloendopeptidase (MME) gene were initially identified as a cause of autosomal recessive Charcot-Marie-Tooth disease type 2 (CMT2). Subsequently, variants in MME were linked to other late-onset autosomal dominant polyneuropathies. Thus, our goal was to define the phenotype and mode of inheritance of patients carrying changes in MME. METHODS: We screened 197 index cases with a hereditary neuropathy of the CMT type or distal hereditary motor neuropathy (dHMN) and 10 probands with familial amyotrophic lateral sclerosis (fALS) using a custom panel of 119 genes. In addition to the index case subjects, we also studied other clinically and/or genetically affected and unaffected family members. RESULTS: We found 17 variants in MME in a total of 20 index cases, with biallelic MME mutations detected in 13 cases from nine families (three in homozygosis and six in compound heterozygosis) and heterozygous variants found in 11 families. All patients with biallelic variants had a similar phenotype, consistent with late-onset axonal neuropathy. Conversely, the phenotype of patients carrying heterozygous mutations was highly variable [CMT type 1 (CMT1), CMT2, dHMN and fALS] and mutations did not segregate with the disease. CONCLUSION: MME mutations that segregate in an autosomal recessive pattern are associated with a late-onset CMT2 phenotype, yet we could not demonstrate that MME variants in heterozygosis cause neuropathy. Our data highlight the importance of establishing an accurate genetic diagnosis in patients carrying MME mutations, especially with a view to genetic counselling.


Asunto(s)
Estudios de Asociación Genética , Patrón de Herencia , Metaloendopeptidasas/genética , Mutación , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/genética , Fenotipo , Adulto , Anciano , Alelos , Sustitución de Aminoácidos , Electromiografía , Fenómenos Electrofisiológicos , Femenino , Frecuencia de los Genes , Genes Recesivos , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Metaloendopeptidasas/metabolismo , Persona de Mediana Edad , Linaje
4.
Am J Hum Genet ; 95(2): 143-61, 2014 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-25065914

RESUMEN

Intragenic copy-number variants (CNVs) contribute to the allelic spectrum of both Mendelian and complex disorders. Although pathogenic deletions and duplications in SPAST (mutations in which cause autosomal-dominant spastic paraplegia 4 [SPG4]) have been described, their origins and molecular consequences remain obscure. We mapped breakpoint junctions of 54 SPAST CNVs at nucleotide resolution. Diverse combinations of exons are deleted or duplicated, highlighting the importance of particular exons for spastin function. Of the 54 CNVs, 38 (70%) appear to be mediated by an Alu-based mechanism, suggesting that the Alu-rich genomic architecture of SPAST renders this locus susceptible to various genome rearrangements. Analysis of breakpoint Alus further informs a model of Alu-mediated CNV formation characterized by small CNV size and potential involvement of mechanisms other than homologous recombination. Twelve deletions (22%) overlap part of SPAST and a portion of a nearby, directly oriented gene, predicting novel chimeric genes in these subjects' genomes. cDNA from a subject with a SPAST final exon deletion contained multiple SPAST:SLC30A6 fusion transcripts, indicating that SPAST CNVs can have transcriptional effects beyond the gene itself. SLC30A6 has been implicated in Alzheimer disease, so these fusion gene data could explain a report of spastic paraplegia and dementia cosegregating in a family with deletion of the final exon of SPAST. Our findings provide evidence that the Alu genomic architecture of SPAST predisposes to diverse CNV alleles with distinct transcriptional--and possibly phenotypic--consequences. Moreover, we provide further mechanistic insights into Alu-mediated copy-number change that are extendable to other loci.


Asunto(s)
Adenosina Trifosfatasas/genética , Elementos Alu/genética , Proteínas de Transporte de Catión/genética , Variaciones en el Número de Copia de ADN/genética , Paraplejía Espástica Hereditaria/genética , Secuencia de Bases , Línea Celular Transformada , Genotipo , Humanos , Isoformas de Proteínas/genética , Proteínas Recombinantes de Fusión/genética , Análisis de Secuencia de ADN , Eliminación de Secuencia , Espastina
6.
Mov Disord ; 32(2): 264-273, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27862279

RESUMEN

BACKGROUND: The spinocerebellar ataxias (SCAs) form a clinically, genetically, and pathological heterogeneous group of autosomal-dominant degenerative diseases. In particular, SCA36 is characterized by a late-onset, slowly progressive cerebellar syndrome typically associated with sensorineural hearing loss. This study was aimed at analyzing the neurodegenerative process underlying SCA36 through fluorodeoxyglucose positron emission tomography (FDG-PET) and MRI scans. METHODS: Twenty SCA36 patients underwent a study consisting of FDG-PET and MRI scans. Clinical motor evaluation was performed through the Scale for the Assessment and Rating of Ataxia (SARA). FDG-PET was carried out using a voxel-by-voxel and region-of-interest analysis. MRI evaluation was based on visual inspection and volumetric analysis. RESULTS: SARA ranged from 0 to 24.5 (4 patients asymptomatic, 3 with unspecific symptoms, and 13 with cerebellar signs). FDG-PET revealed hypometabolism in the asymptomatic stage in the vermis and right cerebellar hemisphere. In the ataxic stage, hypometabolism spread to both cerebellar hemispheres and the brain stem. MRI was normal in asymptomatic and preataxic individuals and showed superior cerebellar vermis atrophy early in the ataxic stage, diffuse cerebellar atrophy some years into the disease course, and a pattern of olivopontocerebellar atrophy in the oldest patients. There was no significant cerebellar atrophy in patients younger than 50 years. CONCLUSIONS: We present the first FDG-PET study of SCA36 and one of the largest neuroimaging study of SCAs. Our results revealed neuronal dysfunctions in the vermis and right cerebellar hemisphere as soon as a decade before the onset of motor symptoms. In the ataxic stage, dysfunctions spread to both hemispheres and the brain stem. © 2016 International Parkinson and Movement Disorder Society.


Asunto(s)
Tronco Encefálico/diagnóstico por imagen , Cerebelo/diagnóstico por imagen , Progresión de la Enfermedad , Imagen por Resonancia Magnética/métodos , Tomografía de Emisión de Positrones/métodos , Índice de Severidad de la Enfermedad , Ataxias Espinocerebelosas/diagnóstico , Adulto , Anciano , Tronco Encefálico/metabolismo , Tronco Encefálico/patología , Vermis Cerebeloso/diagnóstico por imagen , Vermis Cerebeloso/metabolismo , Vermis Cerebeloso/patología , Cerebelo/metabolismo , Cerebelo/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Nucleares , Ataxias Espinocerebelosas/diagnóstico por imagen , Ataxias Espinocerebelosas/metabolismo , Ataxias Espinocerebelosas/patología
7.
BMC Med Inform Decis Mak ; 17(1): 159, 2017 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-29207981

RESUMEN

BACKGROUND: Electronic rating scales represent an important resource for standardized data collection. However, the ability to exploit reasoning on rating scale data is still limited. The objective of this work is to facilitate the integration of the semantics required to automatically interpret collections of standardized clinical data. We developed an electronic prototype for the Scale of the Assessment and Rating of Ataxia (SARA), broadly used in neurology. In order to address the modeling challenges of the SARA, we propose to combine the best performances from OpenEHR clinical archetypes, guidelines and ontologies. METHODS: A scaled-down version of the Human Phenotype Ontology (HPO) was built, extracting the terms that describe the SARA tests from free-text sources. This version of the HPO was then used as backbone to normalize the content of the SARA through clinical archetypes. The knowledge required to exploit reasoning on the SARA data was modeled as separate information-processing units interconnected via the defined archetypes. Each unit used the most appropriate technology to formally represent the required knowledge. RESULTS: Based on this approach, we implemented a prototype named SARA Management System, to be used for both the assessment of cerebellar syndrome and the production of a clinical synopsis. For validation purposes, we used recorded SARA data from 28 anonymous subjects affected by Spinocerebellar Ataxia Type 36 (SCA36). When comparing the performance of our prototype with that of two independent experts, weighted kappa scores ranged from 0.62 to 0.86. CONCLUSIONS: The combination of archetypes, phenotype ontologies and electronic information-processing rules can be used to automate the extraction of relevant clinical knowledge from plain scores of rating scales. Our results reveal a substantial degree of agreement between the results achieved by an ontology-aware system and the human experts.


Asunto(s)
Ataxia/diagnóstico , Registros Electrónicos de Salud , Guías como Asunto , Índice de Severidad de la Enfermedad , Terminología como Asunto , Ataxia/fisiopatología , Ontologías Biológicas , Humanos , Fenotipo
8.
Hum Mutat ; 37(10): 1106-9, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27363592

RESUMEN

The content of the 13th Mutation Detection meeting (Leiden, April 2015) is summarized in this report. Topics discussed at the meeting included current challenges of clinical NGS, advances in bioinformatics, data quality control, single cell analysis and RNA sequencing, among others. Social, ethical and regulatory challenges of genomic data handling and data sharing were the focus of an expert panel debate. The 14th International Symposium on Variants in the Genome will take place in Santiago de Compostela, June 5-8, 2017. http://isv.variome.org.


Asunto(s)
Variación Genética , Análisis de Secuencia de ADN/métodos , Análisis de Secuencia de ARN/métodos , Mapeo Cromosómico , Genoma Humano , Genómica/métodos , Humanos
9.
J Biol Chem ; 289(6): 3186-97, 2014 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-24356962

RESUMEN

The neurological disorders familial hemiplegic migraine type 2 (FHM2), alternating hemiplegia of childhood (AHC), and rapid-onset dystonia parkinsonism (RDP) are caused by mutations of Na(+),K(+)-ATPase α2 and α3 isoforms, expressed in glial and neuronal cells, respectively. Although these disorders are distinct, they overlap in phenotypical presentation. Two Na(+),K(+)-ATPase mutations, extending the C terminus by either 28 residues ("+28" mutation) or an extra tyrosine ("+Y"), are associated with FHM2 and RDP, respectively. We describe here functional consequences of these and other neurological disease mutations as well as an extension of the C terminus only by a single alanine. The dependence of the mutational effects on the specific α isoform in which the mutation is introduced was furthermore studied. At the cellular level we have characterized the C-terminal extension mutants and other mutants, addressing the question to what extent they cause a change of the intracellular Na(+) and K(+) concentrations ([Na(+)]i and [K(+)]i) in COS cells. C-terminal extension mutants generally showed dramatically reduced Na(+) affinity without disturbance of K(+) binding, as did other RDP mutants. No phosphorylation from ATP was observed for the +28 mutation of α2 despite a high expression level. A significant rise of [Na(+)]i and reduction of [K(+)]i was detected in cells expressing mutants with reduced Na(+) affinity and did not require a concomitant reduction of the maximal catalytic turnover rate or expression level. Moreover, two mutations that increase Na(+) affinity were found to reduce [Na(+)]i. It is concluded that the Na(+) affinity of the Na(+),K(+)-ATPase is an important determinant of [Na(+)]i.


Asunto(s)
Trastornos Distónicos/metabolismo , Migraña con Aura/metabolismo , Mutación Missense , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Animales , Células COS , Chlorocebus aethiops , Trastornos Distónicos/genética , Humanos , Transporte Iónico/genética , Migraña con Aura/genética , Potasio/metabolismo , Estructura Terciaria de Proteína , Ratas , Sodio/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/genética
10.
Am J Med Genet B Neuropsychiatr Genet ; 168B(1): 54-65, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25349034

RESUMEN

Certain mitochondrial DNA (mtDNA) variants and haplogroups have been found to be associated with neurological disorders. Several studies have suggested that mtDNA variation could have an etiologic role in these disorders by affecting the ATP production on high-energy demanding organs, such as the brain. We have analyzed 15 mtDNA SNPs (mtSNPs) in five cohorts of cases presenting Alzheimer disease (AD), Parkinson disease (PD), and migraine, and in controls, to evaluate the role mtDNA variation in disease risk. Association tests were undertaken both for mtSNPs and mitochondrial haplogroups. No significant association was detected for any mtSNP or haplogroup in AD and PD cohorts. Two mtSNPs were associated with one migraine cohort after correcting for multiple tests, namely, T4216C and G13708A and haplogroup J (FDR q-value = 0.02; Santiago's cohort). However, this association was not confirmed in a second replication migraine series. A review of the literature reveals the existence of inconsistent findings and methodological shortcomings affecting a large proportion of mtDNA association studies on AD, PD, and migraine. A detailed inspection of the literature highlights the need for performing more rigorous methodological and statistical standards in mtDNA genetic association studies aimed to avoid false positive results of association between mtDNA variants and neurological diseases.


Asunto(s)
Enfermedad de Alzheimer/genética , ADN Mitocondrial/genética , Trastornos Migrañosos/genética , Mitocondrias/genética , Enfermedad de Parkinson/genética , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genética , España
12.
Neurogenetics ; 14(1): 11-22, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23334463

RESUMEN

Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient's disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41% of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation.


Asunto(s)
Enfermedades de los Ganglios Basales/genética , Calcinosis/genética , Mutación , Enfermedades Neurodegenerativas/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo III/genética , Adulto , Anciano , Secuencia de Aminoácidos , Estudios de Cohortes , Análisis Mutacional de ADN , Familia , Femenino , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Modelos Biológicos , Datos de Secuencia Molecular , Mutación/fisiología , Estudios Retrospectivos
13.
Front Mol Neurosci ; 16: 1078634, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37008782

RESUMEN

Niemann Pick disease type C (NPC) is an autosomal recessive neurodegenerative lysosomal disorder characterized by an accumulation of lipids in different organs. Clinical manifestations can start at any age and include hepatosplenomegaly, intellectual impairment, and cerebellar ataxia. NPC1 is the most common causal gene, with over 460 different mutations with heterogeneous pathological consequences. We generated a zebrafish NPC1 model by CRISPR/Cas9 carrying a homozygous mutation in exon 22, which encodes the end of the cysteine-rich luminal loop of the protein. This is the first zebrafish model with a mutation in this gene region, which is frequently involved in the human disease. We observed a high lethality in npc1 mutants, with all larvae dying before reaching the adult stage. Npc1 mutant larvae were smaller than wild type (wt) and their motor function was impaired. We observed vacuolar aggregations positive to cholesterol and sphingomyelin staining in the liver, intestine, renal tubules and cerebral gray matter of mutant larvae. RNAseq comparison between npc1 mutants and controls showed 284 differentially expressed genes, including genes with functions in neurodevelopment, lipid exchange and metabolism, muscle contraction, cytoskeleton, angiogenesis, and hematopoiesis. Lipidomic analysis revealed significant reduction of cholesteryl esters and increase of sphingomyelin in the mutants. Compared to previously available zebrafish models, our model seems to recapitulate better the early onset forms of the NPC disease. Thus, this new model of NPC will allow future research in the cellular and molecular causes/consequences of the disease and on the search for new treatments.

15.
Hum Mutat ; 33(9): 1311-4, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22890789

RESUMEN

The importance for research and clinical utility of mutation databases, as well as the issues and difficulties entailed in their construction, is discussed within the Human Variome Project. While general principles and standards can apply to most human diseases, some specific questions arise when dealing with the nature of genetic neurological disorders. So far, publically accessible mutation databases exist for only about half of the genes causing neurogenetic disorders; and a considerable work is clearly still needed to optimize their content. The current landscape, main challenges, some potential solutions, and future perspectives on genetic databases for disorders of the nervous system are reviewed in this special issue of Human Mutation on neurogenetics.


Asunto(s)
Bases de Datos Genéticas , Genoma Humano , Enfermedades del Sistema Nervioso/genética , Biología Computacional/métodos , Estudios de Asociación Genética , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Heterogeneidad Genética , Humanos , Almacenamiento y Recuperación de la Información/métodos , Mutación
16.
Hum Mutat ; 33(9): 1315-23, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22753388

RESUMEN

Hereditary spastic paraplegias (HSPs) constitute a heterogeneous group of neurological disorders, characterized primarily by progressive spasticity and weakness of the lower limbs. HSPs are caused by mutations in multiple genes (at least 48 loci and 28 causative genes). The clinical spectrum of HSPs is wide and important differences have been reported between patients with distinct mutations in the same gene, or even between different family members bearing the same mutation. Many patients with HSP present clinical deficits related to the involvement of neuronal systems other than corticospinal tracts, namely, peripheral nerves, sensory, or cerebellar pathways. These cases may be difficult to differentiate from other neurological diseases (e.g., hereditary ataxias), also genetically and clinically heterogeneous. As an illustration of how overlapping this genotype-phenotype relationship is, and the difficulties that it brings upon the development of neurogenetic algorithms and databases, we review the main clinical and genetic features of HSPs, and summarize reports on cases of triplet-repeat spinocerebellar ataxias that can mimic HSP phenotypes. This complex scenario makes the necessity of high-quality, curated mutation databases even more urgent, in order to develop adequate diagnostic guidelines, correct interpretation of genetic testing, and appropriate genetic counseling.


Asunto(s)
Estudios de Asociación Genética/métodos , Paraplejía Espástica Hereditaria/genética , Repeticiones de Trinucleótidos , Algoritmos , Ataxina-3 , Bases de Datos Genéticas , Sitios Genéticos , Humanos , Mutación , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Fenotipo , Proteínas Represoras/genética , Paraplejía Espástica Hereditaria/diagnóstico , Degeneraciones Espinocerebelosas/diagnóstico , Degeneraciones Espinocerebelosas/genética
17.
Hum Mutat ; 33(11): 1513-9, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22753370

RESUMEN

The Human Variome Project (http://www.humanvariomeproject.org) is an international effort aiming to systematically collect and share information on all human genetic variation. The two main pillars of this effort are gene/disease-specific databases and a network of Human Variome Project Country Nodes. The latter are nationwide efforts to document the genomic variation reported within a specific population. The development and successful operation of the Human Variome Project Country Nodes are of utmost importance to the success of Human Variome Project's aims and goals because they not only allow the genetic burden of disease to be quantified in different countries, but also provide diagnosticians and researchers access to an up-to-date resource that will assist them in their daily clinical practice and biomedical research, respectively. Here, we report the discussions and recommendations that resulted from the inaugural meeting of the International Confederation of Countries Advisory Council, held on 12th December 2011, during the 2011 Human Variome Project Beijing Meeting. We discuss the steps necessary to maximize the impact of the Country Node effort for developing regional and country-specific clinical genetics resources and summarize a few well-coordinated genetic data collection initiatives that would serve as paradigms for similar projects.


Asunto(s)
Variación Genética , Genoma Humano , Proyecto Genoma Humano , Guías como Asunto , Proyecto Genoma Humano/economía , Proyecto Genoma Humano/ética , Proyecto Genoma Humano/legislación & jurisprudencia , Humanos , Cooperación Internacional , Sistema de Registros , Programas Informáticos
18.
Muscle Nerve ; 46(6): 961-4, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23225389

RESUMEN

INTRODUCTION: Multiple endocrine neoplasia type 2 (MEN 2) is an uncommon autosomal dominant cancer syndrome which can be associated with nerve conduction abnormalities. METHODS: A 14-year-old boy with a family history of consanguinity developed progressive gait clumsiness, pes cavus, hypotonia, and mucosal tumors of the lips and tongue since the age of 3 years. At age 11 years, he was diagnosed with an hereditary motor neuropathy (Charcot-Marie-Tooth syndrome). RESULTS: Physical examination revealed a Marfanoid habitus, mucocutaneous verrucous tumors, thyroid nodules, and cervical adenopathy. Genetic testing demonstrated the p.M918T mutation in the RET gene, and blood tests showed elevated levels of calcitonin. CONCLUSIONS: Clinical suspicion in MEN2 is crucial for early diagnosis and subsequent therapy. Mucosal neuroma and a Marfanoid habitus are especially useful. Other neurologic manifestations should not disguise the endocrine disorder, because early diagnosis and treatment of medullary thyroid carcinoma determines the prognosis.


Asunto(s)
Deformidades Congénitas de las Extremidades/etiología , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades de la Lengua/etiología , Adolescente , Humanos , Deformidades Congénitas de las Extremidades/genética , Masculino , Neoplasia Endocrina Múltiple Tipo 2b/complicaciones , Neoplasia Endocrina Múltiple Tipo 2b/genética , Neoplasia Endocrina Múltiple Tipo 2b/patología , Enfermedades del Sistema Nervioso Periférico/genética
19.
Cephalalgia ; 32(14): 1076-80, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22908361

RESUMEN

BACKGROUND: Migraine is a prevalent neurological disorder with a complex genetic background characterized by recurrent episodes of headache. The disease is subclassified into migraine with aura (MA) and migraine without aura (MO). Many association studies have been performed to date to identify genetic risk variants for common migraine, most of them focusing on selected candidate genes, with variable and often inconsistent results. Recently, a clinic-based genome-wide association study for migraine reported a functionally relevant risk variant (SNP rs1835740), involved in glutamate homeostasis, which showed a significant association with MA. We aimed to replicate this finding in a clinic-based study of a Spanish cohort with MA and MO patients. METHODS: We genotyped SNP rs1835740 in a Spanish sample of 1521 patients and 1379 screened controls and performed a case-control association study. CONCLUSION: No association was found between the assayed SNP and any of the clinical groups considered.


Asunto(s)
Cromosomas Humanos Par 8/genética , Estudio de Asociación del Genoma Completo , Migraña con Aura/genética , Migraña sin Aura/genética , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Moléculas de Adhesión Celular/genética , Niño , Preescolar , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Ácido Glutámico/metabolismo , Humanos , Masculino , Proteínas de la Membrana , Persona de Mediana Edad , Migraña con Aura/epidemiología , Migraña con Aura/etnología , Migraña sin Aura/epidemiología , Migraña sin Aura/etnología , Proteínas de Unión al ARN , Reproducibilidad de los Resultados , Riesgo , España/epidemiología , Adulto Joven
20.
Am J Med Genet B Neuropsychiatr Genet ; 159B(1): 94-103, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22162417

RESUMEN

The transient receptor potential (TRP) superfamily of non-selective cationic channels are involved in several processes plausibly relevant to migraine pathophysiology, including multimodal sensory and pain perception, central and peripheral sensitization, and regulation of calcium homeostasis. With the aim of identifying single nucleotide polymorphisms (SNPs) in TRP genes that may confer increased genetic susceptibility to migraine, we carried out a case-control genetic association study with replication, including a total of 1,040 cases and 1,037 controls. We genotyped 149 SNPs covering 14 TRP genes with known brain expression. The two-stage study comprised samples of 555 and 485 Spanish, Caucasian patients, selected according to the ICHD-II criteria for the diagnosis of migraine without aura (MO) or migraine with aura (MA). In the discovery sample, 19 SNPs in ten TRP genes showed nominal association (P < 0.05) with MO, MA, or overall migraine. In the replication sample, nominal association was confirmed for TRPV3 rs7217270 in MA and TRPV1 rs222741 in the overall migraine group. Risk haplotypes were identified for seven of the genes showing nominal association in the discovery set, but none of them was replicated. The present findings suggest that members of the vanilloid TRPV subfamily of receptors contribute to the genetic susceptibility to migraine in the Spanish population.


Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Trastornos Migrañosos/genética , Polimorfismo de Nucleótido Simple/genética , Canales Catiónicos TRPV/genética , Adulto , Estudios de Casos y Controles , Femenino , Marcadores Genéticos , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Migraña con Aura/genética , Reproducibilidad de los Resultados , Programas Informáticos , España , Canales Catiónicos TRPM/genética
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