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1.
J Med Genet ; 61(3): 244-249, 2024 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-37857482

RESUMEN

BACKGROUND: The neurodevelopmental prognosis of anomalies of the corpus callosum (ACC), one of the most frequent brain malformations, varies extremely, ranging from normal development to profound intellectual disability (ID). Numerous genes are known to cause syndromic ACC with ID, whereas the genetics of ACC without ID remains poorly deciphered. METHODS: Through a collaborative work, we describe here ZEB1, a gene previously involved in an ophthalmological condition called type 3 posterior polymorphous corneal dystrophy, as a new dominant gene of ACC. We report a series of nine individuals with ACC (including three fetuses terminated due to ACC) carrying a ZEB1 heterozygous loss-of-function (LoF) variant, identified by exome sequencing. RESULTS: In five cases, the variant was inherited from a parent with a normal corpus callosum, which illustrates the incomplete penetrance of ACC in individuals with an LoF in ZEB1. All patients reported normal schooling and none of them had ID. Neuropsychological assessment in six patients showed either normal functioning or heterogeneous cognition. Moreover, two patients had a bicornuate uterus, three had a cardiovascular anomaly and four had macrocephaly at birth, which suggests a larger spectrum of malformations related to ZEB1. CONCLUSION: This study shows ZEB1 LoF variants cause dominantly inherited ACC without ID and extends the extraocular phenotype related to this gene.


Asunto(s)
Discapacidad Intelectual , Malformaciones del Sistema Nervioso , Recién Nacido , Femenino , Humanos , Cuerpo Calloso , Agenesia del Cuerpo Calloso/genética , Malformaciones del Sistema Nervioso/genética , Discapacidad Intelectual/genética , Cognición , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética
2.
J Med Genet ; 61(2): 103-108, 2024 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-37879892

RESUMEN

The Aristaless-related homeobox (ARX) gene is located on the X chromosome and encodes a transcription factor that is essential for brain development. While the clinical spectrum of ARX-related disorders is well described in males, from X linked lissencephaly with abnormal genitalia syndrome to syndromic and non-syndromic intellectual disability (ID), its phenotypic delineation in females is incomplete. Carrier females in ARX families are usually asymptomatic, but ID has been reported in some of them, as well as in others with de novo variants. In this study, we collected the clinical and molecular data of 10 unpublished female patients with de novo ARX pathogenic variants and reviewed the data of 63 females from the literature with either de novo variants (n=10), inherited variants (n=33) or variants of unknown inheritance (n=20). Altogether, the clinical spectrum of females with heterozygous pathogenic ARX variants is broad: 42.5% are asymptomatic, 16.4% have isolated agenesis of the corpus callosum (ACC) or mild symptoms (learning disabilities, autism spectrum disorder, drug-responsive epilepsy) without ID, whereas 41% present with a severe phenotype (ie, ID or developmental and epileptic encephalopathy (DEE)). The ID/DEE phenotype was significantly more prevalent in females carrying de novo variants (75%, n=15/20) versus in those carrying inherited variants (27.3%, n=9/33). ACC was observed in 66.7% (n=24/36) of females who underwent a brain MRI. By refining the clinical spectrum of females carrying ARX pathogenic variants, we show that ID is a frequent sign in females with this X linked condition.


Asunto(s)
Trastorno del Espectro Autista , Discapacidad Intelectual , Masculino , Humanos , Femenino , Genes Homeobox , Proteínas de Homeodominio/genética , Trastorno del Espectro Autista/genética , Mutación/genética , Factores de Transcripción/genética , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Fenotipo , Agenesia del Cuerpo Calloso/genética
3.
Brain ; 143(12): 3564-3573, 2020 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-33242881

RESUMEN

KCNN2 encodes the small conductance calcium-activated potassium channel 2 (SK2). Rodent models with spontaneous Kcnn2 mutations show abnormal gait and locomotor activity, tremor and memory deficits, but human disorders related to KCNN2 variants are largely unknown. Using exome sequencing, we identified a de novo KCNN2 frameshift deletion in a patient with learning disabilities, cerebellar ataxia and white matter abnormalities on brain MRI. This discovery prompted us to collect data from nine additional patients with de novo KCNN2 variants (one nonsense, one splice site, six missense variants and one in-frame deletion) and one family with a missense variant inherited from the affected mother. We investigated the functional impact of six selected variants on SK2 channel function using the patch-clamp technique. All variants tested but one, which was reclassified to uncertain significance, led to a loss-of-function of SK2 channels. Patients with KCNN2 variants had motor and language developmental delay, intellectual disability often associated with early-onset movement disorders comprising cerebellar ataxia and/or extrapyramidal symptoms. Altogether, our findings provide evidence that heterozygous variants, likely causing a haploinsufficiency of the KCNN2 gene, lead to novel autosomal dominant neurodevelopmental movement disorders mirroring phenotypes previously described in rodents.


Asunto(s)
Trastornos del Movimiento/genética , Trastornos del Neurodesarrollo/genética , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/genética , Adolescente , Adulto , Ataxia Cerebelosa/genética , Ataxia Cerebelosa/psicología , Niño , Preescolar , Fenómenos Electrofisiológicos , Exoma , Mutación del Sistema de Lectura , Variación Genética , Haploinsuficiencia , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/psicología , Discapacidades para el Aprendizaje/genética , Discapacidades para el Aprendizaje/psicología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Trastornos del Movimiento/psicología , Mutación Missense/genética , Trastornos del Neurodesarrollo/psicología , Técnicas de Placa-Clamp , Sustancia Blanca/anomalías , Sustancia Blanca/diagnóstico por imagen , Adulto Joven
4.
Neurobiol Dis ; 136: 104709, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31843706

RESUMEN

Corpus callosum agenesis (CCA) is a brain malformation associated with a wide clinical spectrum including intellectual disability (ID) and an etiopathological complexity. We identified a novel missense G424R mutation in the X-linked p21-activated kinase 3 (PAK3) gene in a boy presenting with severe ID, microcephaly and CCA and his fetal sibling with CCA and severe hydrocephaly. PAK3 kinase is known to control synaptic plasticity and dendritic spine dynamics but its implication is less characterized in brain ontogenesis. In order to identify developmental functions of PAK3 impacted by mutations responsible for CCA, we compared the biochemical and biological effects of three PAK3 mutations localized in the catalytic domain. These mutations include two "severe" G424R and K389N variants (responsible for severe ID and CCA) and the "mild" A365E variant (responsible for nonsyndromic mild ID). Whereas they suppressed kinase activity, only the two severe variants displayed normal protein stability. Furthermore, they increased interactions between PAK3 and the guanine exchange factor αPIX/ARHGEF6, disturbed adhesion point dynamics and cell spreading, and severely impacted cell migration. Our findings highlight new molecular defects associated with mutations responsible for severe clinical phenotypes with developmental brain defects.


Asunto(s)
Agenesia del Cuerpo Calloso/genética , Movimiento Celular/fisiología , Discapacidad Intelectual/genética , Mutación/genética , Índice de Severidad de la Enfermedad , Quinasas p21 Activadas/genética , Agenesia del Cuerpo Calloso/complicaciones , Agenesia del Cuerpo Calloso/diagnóstico por imagen , Secuencia de Aminoácidos , Animales , Células COS , Niño , Chlorocebus aethiops , Células HEK293 , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/diagnóstico por imagen , Masculino , Linaje , Estructura Secundaria de Proteína , Quinasas p21 Activadas/química
5.
Brain ; 141(11): 3160-3178, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30351409

RESUMEN

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: one adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.


Asunto(s)
Epilepsia Generalizada/genética , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/genética , Mutación/genética , Canales de Potasio/genética , Espasmos Infantiles/genética , Adolescente , Adulto , Anciano , Animales , Células CHO , Niño , Preescolar , Cricetulus , Estimulación Eléctrica , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Masculino , Potenciales de la Membrana/genética , Persona de Mediana Edad , Modelos Moleculares , Mutagénesis Sitio-Dirigida/métodos , Adulto Joven
6.
Hum Mutat ; 39(1): 23-39, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29068161

RESUMEN

The deleted in colorectal cancer (DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus-specific LOVD (https://databases.lovd.nl/shared/genes/DCC).


Asunto(s)
Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Genes DCC , Estudios de Asociación Genética , Mutación , Fenotipo , Agenesia del Cuerpo Calloso , Secuencia de Aminoácidos , Sitios de Unión , Secuencia Conservada , Bases de Datos Genéticas , Humanos , Imagen por Resonancia Magnética , Modelos Moleculares , Netrina-1/química , Netrina-1/metabolismo , Unión Proteica , Conformación Proteica , Dominios Proteicos/genética , Síndrome
7.
J Inherit Metab Dis ; 41(3): 447-456, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29423831

RESUMEN

BACKGROUND: In 2009, untargeted metabolomics led to the delineation of a new clinico-biological entity called cerebellar ataxia with elevated cerebrospinal free sialic acid, or CAFSA. In order to elucidate CAFSA, we applied sequentially targeted and untargeted omic approaches. METHODS AND RESULTS: First, we studied five of the six CAFSA patients initially described. Besides increased CSF free sialic acid concentrations, three patients presented with markedly decreased 5-methyltetrahydrofolate (5-MTHF) CSF concentrations. Exome sequencing identified a homozygous POLG mutation in two affected sisters, but failed to identify a causative gene in the three sporadic patients with high sialic acid but low 5-MTHF. Using targeted mass spectrometry, we confirmed that free sialic acid was increased in the CSF of a third known POLG-mutated patient. We then pursued pathophysiological analyses of CAFSA using mass spectrometry-based metabolomics on CSF from two sporadic CAFSA patients as well as 95 patients with an unexplained encephalopathy and 39 controls. This led to the identification of a common metabotype between the two initial CAFSA patients and three additional patients, including one patient with Kearns-Sayre syndrome. Metabolites of the CSF metabotype were positioned in a reconstruction of the human metabolic network, which highlighted the proximity of the metabotype with acetyl-CoA and carnitine, two key metabolites regulating mitochondrial energy homeostasis. CONCLUSION: Our genetic and metabolomics analyses suggest that CAFSA is a heterogeneous entity related to mitochondrial DNA alterations either through POLG mutations or a mechanism similar to what is observed in Kearns-Sayre syndrome.


Asunto(s)
Ataxia Cerebelosa/diagnóstico , Genómica/métodos , Metabolómica/métodos , Ácido N-Acetilneuramínico/líquido cefalorraquídeo , Tetrahidrofolatos/líquido cefalorraquídeo , Adulto , Estudios de Casos y Controles , Ataxia Cerebelosa/líquido cefalorraquídeo , Ataxia Cerebelosa/genética , Ataxia Cerebelosa/metabolismo , Análisis Mutacional de ADN , ADN Polimerasa gamma/genética , ADN Mitocondrial/análisis , Femenino , Humanos , Masculino , Espectrometría de Masas , Hermanos , Tetrahidrofolatos/análisis , Secuenciación del Exoma/métodos
8.
Hum Genet ; 136(4): 463-479, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28283832

RESUMEN

Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.


Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 1 , Ribonucleoproteínas Nucleares Heterogéneas/genética , Mutación , Trastornos del Neurodesarrollo/genética , Fenotipo , Proteínas Represoras/genética , Humanos
9.
J Med Genet ; 53(8): 511-22, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-26989088

RESUMEN

OBJECTIVE: We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype-phenotype correlations. METHODS: We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed. RESULTS: We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3' and 5' exons. Seizures in patients with mutations in exons 4-5 were more pharmacoresponsive than in patients with mutations in exons 8-15. CONCLUSIONS: SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers.

10.
PLoS Genet ; 10(9): e1004580, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25188300

RESUMEN

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.


Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/genética , Trastornos del Conocimiento/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Estudios de Casos y Controles , Niño , Cognición/fisiología , Variaciones en el Número de Copia de ADN/genética , Femenino , Humanos , Discapacidad Intelectual/genética , Masculino , Neuronas/fisiología , Sinapsis/genética
11.
Am J Hum Genet ; 92(2): 238-44, 2013 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-23332916

RESUMEN

Spastic paraplegia 46 refers to a locus mapped to chromosome 9 that accounts for a complicated autosomal-recessive form of hereditary spastic paraplegia (HSP). With next-generation sequencing in three independent families, we identified four different mutations in GBA2 (three truncating variants and one missense variant), which were found to cosegregate with the disease and were absent in controls. GBA2 encodes a microsomal nonlysosomal glucosylceramidase that catalyzes the conversion of glucosylceramide to free glucose and ceramide and the hydrolysis of bile acid 3-O-glucosides. The missense variant was also found at the homozygous state in a simplex subject in whom no residual glucocerebrosidase activity of GBA2 could be evidenced in blood cells, opening the way to a possible measurement of this enzyme activity in clinical practice. The overall phenotype was a complex HSP with mental impairment, cataract, and hypogonadism in males associated with various degrees of corpus callosum and cerebellar atrophy on brain imaging. Antisense morpholino oligonucleotides targeting the zebrafish GBA2 orthologous gene led to abnormal motor behavior and axonal shortening/branching of motoneurons that were rescued by the human wild-type mRNA but not by applying the same mRNA containing the missense mutation. This study highlights the role of ceramide metabolism in HSP pathology.


Asunto(s)
Neuronas Motoras/patología , Paraplejía Espástica Hereditaria/enzimología , Paraplejía Espástica Hereditaria/genética , Proteínas de Pez Cebra/genética , beta-Glucosidasa/genética , Adolescente , Adulto , Anciano , Animales , Encéfalo/patología , Niño , Preescolar , Familia , Femenino , Glucosilceramidasa , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mutación/genética , Neuroimagen , Linaje , Adulto Joven , Pez Cebra
12.
Amino Acids ; 47(12): 2647-58, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26215737

RESUMEN

Cationic amino acid transporters (CATs) mediate the entry of L-type cationic amino acids (arginine, ornithine and lysine) into the cells including neurons. CAT-3, encoded by the SLC7A3 gene on chromosome X, is one of the three CATs present in the human genome, with selective expression in brain. SLC7A3 is highly intolerant to variation in humans, as attested by the low frequency of deleterious variants in available databases, but the impact on variants in this gene in humans remains undefined. In this study, we identified a missense variant in SLC7A3, encoding the CAT-3 cationic amino acid transporter, on chromosome X by exome sequencing in two brothers with autism spectrum disorder (ASD). We then sequenced the SLC7A3 coding sequence in 148 male patients with ASD and identified three additional rare missense variants in unrelated patients. Functional analyses of the mutant transporters showed that two of the four identified variants cause severe or moderate loss of CAT-3 function due to altered protein stability or abnormal trafficking to the plasma membrane. The patient with the most deleterious SLC7A3 variant had high-functioning autism and epilepsy, and also carries a de novo 16p11.2 duplication possibly contributing to his phenotype. This study shows that rare hypomorphic variants of SLC7A3 exist in male individuals and suggest that SLC7A3 variants possibly contribute to the etiology of ASD in male subjects in association with other genetic factors.


Asunto(s)
Sistemas de Transporte de Aminoácidos Básicos/genética , Trastorno del Espectro Autista/genética , Secuencia de Aminoácidos , Animales , Biotinilación , Encéfalo/metabolismo , Membrana Celular/metabolismo , Niño , Cromosomas Humanos X/genética , Epilepsia/complicaciones , Epilepsia/genética , Frecuencia de los Genes , Humanos , Pérdida de Heterocigocidad , Masculino , Conformación Molecular , Datos de Secuencia Molecular , Mutación , Mutación Missense , Oocitos/metabolismo , Linaje , Fenotipo , Xenopus laevis
13.
Neurobiol Dis ; 48(3): 299-308, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22801083

RESUMEN

Hereditary spastic paraplegias (HSPs) are rare neurological conditions caused by degeneration of the long axons of the cerebrospinal tracts, leading to locomotor impairment and additional neurological symptoms. There are more than 40 different causative genes, 24 of which have been identified, including SPG11 and SPG15 mutated in complex clinical forms. Since the vast majority of the causative mutations lead to loss of function of the corresponding proteins, we made use of morpholino-oligonucleotide (MO)-mediated gene knock-down to generate zebrafish models of both SPG11 and SPG15 and determine how invalidation of the causative genes (zspg11 and zspg15) during development might contribute to the disease. Micro-injection of MOs targeting each gene caused locomotor impairment and abnormal branching of spinal cord motor neurons at the neuromuscular junction. More severe phenotypes with abnormal tail developments were also seen. Moreover, partial depletion of both proteins at sub-phenotypic levels resulted in the same phenotypes, suggesting for the first time, in vivo, a genetic interaction between these genes. In conclusion, the zebrafish orthologues of the SPG11 and SPG15 genes are important for proper development of the axons of spinal motor neurons and likely act in a common pathway to promote their proper path finding towards the neuromuscular junction.


Asunto(s)
Axones/metabolismo , Neuronas Motoras/metabolismo , Neurogénesis/fisiología , Proteínas de Pez Cebra/metabolismo , Pez Cebra/embriología , Animales , Proteínas Portadoras/metabolismo , Embrión no Mamífero , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Proteínas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Homología de Secuencia de Aminoácido , Pez Cebra/metabolismo
14.
Mov Disord ; 27(10): 1295-8, 2012 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-22777947

RESUMEN

BACKGROUND: Thiamine transporter-2 deficiency, a condition resulting from mutations in the SLC19A3 gene, has been described in patients with subacute dystonia and striatal necrosis. The condition responds extremely well to treatment with biotin and has thus been named biotin-responsive basal ganglia disease. Recently, this deficiency has also been related to Wernicke's-like encephalopathy and atypical infantile spasms, showing heterogeneous responses to biotin and/or thiamine. METHODS: Two Spanish siblings with a biotin-responsive basal ganglia disease phenotype and mutations in SLC19A3 presented with acute episodes of generalized dystonia, rigidity, and symmetrical lesions involving the striatum, midline nuclei of the thalami, and the cortex of cerebral hemispheres as shown by magnetic resonance imaging. RESULTS: The clinical features resolved rapidly after thiamine administration. CONCLUSIONS: Despite the rarity of thiamine transporter-2 deficiency, it should be suspected in patients with acute dystonia and basal ganglia injury, as thiamine can halt disease evolution and prevent further episodes. © 2012 Movement Disorder Society.


Asunto(s)
Enfermedades de los Ganglios Basales/complicaciones , Enfermedades de los Ganglios Basales/genética , Trastornos Distónicos/etiología , Proteínas de Transporte de Membrana/deficiencia , Adolescente , Alanina/análogos & derivados , Alanina/metabolismo , Ganglios Basales/metabolismo , Ganglios Basales/patología , Preescolar , Colina/metabolismo , Trastornos Distónicos/genética , Femenino , Humanos , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Masculino , Proteínas de Transporte de Membrana/genética , Hermanos
16.
Mol Cell Neurosci ; 47(3): 191-202, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21545838

RESUMEN

Truncating mutations in the SPG11 and SPG15 genes cause complicated spastic paraplegia, severe neurological conditions due to loss of the functions of spatacsin and spastizin, respectively. We developed specific polyclonal anti-spatacsin (SPG11) and anti-spastizin (SPG15) antisera, which we then used to explore the intracellular and tissue localizations of these proteins. We observed expression of both proteins in human and rat central nervous system, which was particularly strong in cortical and spinal motor neurons as well as in retina. Both proteins were also expressed ubiquitously and strongly in embryos. In cultured cells, these two proteins had similar diffuse punctate, cytoplasmic and sometimes nuclear (spastizin) distributions. They partially co-localized with multiple organelles, particularly with protein-trafficking vesicles, endoplasmic reticulum and microtubules. Spastizin was also found at the mitochondria surface. This first study of the endogenous expression of spatacsin and spastizin shows similarities in their expression patterns that could account for their overlapping clinical phenotypes and involvement in a common protein complex.


Asunto(s)
Proteínas Portadoras/metabolismo , Citoplasma/metabolismo , Neuronas Motoras/metabolismo , Proteínas/metabolismo , Animales , Proteínas Portadoras/genética , Línea Celular Tumoral , Células Cultivadas , Citoplasma/genética , Humanos , Ratones , Proteínas/genética , Ratas , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/metabolismo
17.
Nat Commun ; 13(1): 6570, 2022 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-36323681

RESUMEN

Disease gene discovery on chromosome (chr) X is challenging owing to its unique modes of inheritance. We undertook a systematic analysis of human chrX genes. We observe a higher proportion of disorder-associated genes and an enrichment of genes involved in cognition, language, and seizures on chrX compared to autosomes. We analyze gene constraints, exon and promoter conservation, expression, and paralogues, and report 127 genes sharing one or more attributes with known chrX disorder genes. Using machine learning classifiers trained to distinguish disease-associated from dispensable genes, we classify 247 genes, including 115 of the 127, as having high probability of being disease-associated. We provide evidence of an excess of variants in predicted genes in existing databases. Finally, we report damaging variants in CDK16 and TRPC5 in patients with intellectual disability or autism spectrum disorders. This study predicts large-scale gene-disease associations that could be used for prioritization of X-linked pathogenic variants.


Asunto(s)
Trastorno del Espectro Autista , Discapacidad Intelectual , Humanos , Cromosomas Humanos X/genética , Genes Ligados a X , Discapacidad Intelectual/genética , Trastorno del Espectro Autista/genética , Bases de Datos Genéticas
18.
Eur J Paediatr Neurol ; 33: 121-124, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-34174751

RESUMEN

BACKGROUND: Variants in SCN1A gene, encoding the voltage-gated sodium channel Nav1.1, are associated with distinct epilepsy syndromes ranging from the relatively benign genetic epilepsy with febrile seizures plus (GEFS+) to Dravet syndrome, a severe developmental and epileptic encephalopathy (DEE). Most SCN1A pathogenic variants are heterozygous changes inherited in a dominant or de novo inheritance and many cause a loss-of-function of one allele. To date, recessive inheritance has been suggested in only two families with affected children harboring homozygous SCN1A missense variants while their heterozygous parents were asymptomatic. The aim of this report is to describe two additional families in which affected individuals have biallelic SCN1A variants possibly explaining their phenotype. METHODS AND RESULTS: We report two novel homozygous SCN1A missense variants in two patients from related parents. Both patients had fever-sensitive epilepsy beginning in the first months of life, followed by afebrile seizures, without severe cognitive impairment. Parents were asymptomatic. Next generation sequencing excluded a pathogenic variant in other genes involved in DEE. Estimation of pathogenicity scores by in-silico tools suggests that the impact of these SCN1A variants is less damaging than that of dominant pathogenic variants. CONCLUSION: This study provides additional evidence that homozygous variants in SCN1A can cause GEFS+. This recessive inheritance would imply that hypomorphic variants may not necessarily cause epilepsy at the heterozygous state but may decrease the seizure threshold when combined.


Asunto(s)
Canal de Sodio Activado por Voltaje NAV1.1/genética , Epilepsias Mioclónicas/genética , Síndromes Epilépticos , Humanos , Mutación , Fenotipo , Convulsiones Febriles/genética
19.
Front Neurol ; 11: 641, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32793093

RESUMEN

Introduction: Impulse control disorders (ICDs) frequently complicate dopamine agonist (DA) therapy in Parkinson's disease (PD). There is growing evidence of a high heritability for ICDs in the general population and in PD. Variants on genes belonging to the reward pathway have been shown to account for part of this heritability. We aimed to identify new pathways associated with ICDs in PD. Methods: Thirty-six Parkinsonian patients on DA therapy with (n = 18) and without ICDs (n = 18) matched on age at PD's onset, and gender was selected to represent the most extreme phenotypes of their category. Exome sequencing was performed, and variants with a strong functional impact in brain-expressed genes were selected. Allele frequencies and their distribution in genes and pathways were analyzed with single variant and SKAT-O tests. The 10 most associated variants, genes, and pathways were retained for replication in the Parkinson's progression markers initiative (PPMI) cohort. Results: None of markers tested passed the significance threshold adjusted for multiple comparisons. However, the "Adenylate cyclase activating" pathway, one of the top associated pathways in the discovery data set (p = 1.6 × 10-3) was replicated in the PPMI cohort and was significantly associated with ICDs in a post hoc pooled analysis (combined p-value 3.3 × 10-5). Two of the 10 most associated variants belonged to genes implicated in cAMP and ERK signaling (rs34193571 in RasGRF2, p = 5 × 10-4; rs1877652 in PDE2A, p = 8 × 10-4) although non-significant after Bonferroni correction. Conclusion: Our results suggest that genes implicated in the signaling pathways linked to G protein-coupled receptors participate to genetic susceptibility to ICDs in PD.

20.
Nat Commun ; 11(1): 2441, 2020 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-32415109

RESUMEN

KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynamics. We report three missense variants and one duplication in KIF21B in individuals with neurodevelopmental disorders associated with brain malformations, including corpus callosum agenesis (ACC) and microcephaly. We demonstrate, in vivo, that the expression of KIF21B missense variants specifically recapitulates patients' neurodevelopmental abnormalities, including microcephaly and reduced intra- and inter-hemispheric connectivity. We establish that missense KIF21B variants impede neuronal migration through attenuation of kinesin autoinhibition leading to aberrant KIF21B motility activity. We also show that the ACC-related KIF21B variant independently perturbs axonal growth and ipsilateral axon branching through two distinct mechanisms, both leading to deregulation of canonical kinesin motor activity. The duplication introduces a premature termination codon leading to nonsense-mediated mRNA decay. Although we demonstrate that Kif21b haploinsufficiency leads to an impaired neuronal positioning, the duplication variant might not be pathogenic. Altogether, our data indicate that impaired KIF21B autoregulation and function play a critical role in the pathogenicity of human neurodevelopmental disorder.


Asunto(s)
Cinesinas/genética , Actividad Motora , Mutación/genética , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/fisiopatología , Animales , Axones/metabolismo , Movimiento Celular , Proliferación Celular , Corteza Cerebral/embriología , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Femenino , Regulación del Desarrollo de la Expresión Génica , Células HEK293 , Humanos , Masculino , Ratones , Mutación Missense/genética , Red Nerviosa/patología , Red Nerviosa/fisiopatología , Neuronas/metabolismo , Tamaño de los Órganos , Organogénesis/genética , Linaje , ARN Mensajero/genética , ARN Mensajero/metabolismo , Pez Cebra/anatomía & histología , Pez Cebra/genética
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