RESUMEN
Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses.
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Discapacidades del Desarrollo , Discapacidad Intelectual , Microcefalia , Animales , Niño , Preescolar , Femenino , Humanos , Masculino , Ratones , Chlorocebus aethiops , Células COS , Discapacidades del Desarrollo/genética , Células HEK293 , Discapacidad Intelectual/genética , Microcefalia/genética , Microcefalia/patología , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Neuronas/patología , Pez Cebra/genéticaRESUMEN
BACKGROUND: Biallelic ZBTB11 variants have previously been associated with an ultrarare subtype of autosomal recessive intellectual developmental disorder (MRT69). OBJECTIVE: The aim was to provide insights into the clinical and genetic characteristics of ZBTB11-related disorders (ZBTB11-RD), with a particular emphasis on progressive complex movement abnormalities. METHODS: Thirteen new and 16 previously reported affected individuals, ranging in age from 2 to 50 years, with biallelic ZBTB11 variants underwent clinical and genetic characterization. RESULTS: All patients exhibited a range of neurodevelopmental phenotypes with varying severity, encompassing ocular and neurological features. Eleven new patients presented with complex abnormal movements, including ataxia, dystonia, myoclonus, stereotypies, and tremor, and 7 new patients exhibited cataracts. Deep brain stimulation was successful in treating 1 patient with generalized progressive dystonia. Our analysis revealed 13 novel variants. CONCLUSIONS: This study provides additional insights into the clinical features and spectrum of ZBTB11-RD, highlighting the progressive nature of movement abnormalities in the background of neurodevelopmental phenotype. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
RESUMEN
Oxidative phosphorylation involves a complex multi-enzymatic mitochondrial machinery critical for proper functioning of the cell, and defects herein cause a wide range of diseases called "primary mitochondrial disorders" (PMDs). Mutations in about 400 nuclear and 37 mitochondrial genes have been documented to cause PMDs, which have an estimated birth prevalence of 1:5000. Here, we describe a 4-year-old female presenting from early childhood with psychomotor delay and white matter signal changes affecting several brain regions, including the brainstem, in addition to lactic and phytanic acidosis, compatible with Leigh syndrome, a genetically heterogeneous subgroup of PMDs. Whole genome sequencing of the family trio identified a homozygous 12.9 Kb deletion, entirely overlapping the NDUFA4 gene. Sanger sequencing of the breakpoints revealed that the genomic rearrangement was likely triggered by Alu elements flanking the gene. NDUFA4 encodes for a subunit of the respiratory chain Complex IV, whose activity was significantly reduced in the patient's fibroblasts. In one family, dysfunction of NDUFA4 was previously documented as causing mitochondrial Complex IV deficiency nuclear type 21 (MC4DN21, OMIM 619065), a relatively mild form of Leigh syndrome. Our finding confirms the loss of NDUFA4 function as an ultra-rare cause of Complex IV defect, clinically presenting as Leigh syndrome.
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Complejo I de Transporte de Electrón , Enfermedad de Leigh , Humanos , Enfermedad de Leigh/genética , Enfermedad de Leigh/patología , Femenino , Preescolar , Complejo IV de Transporte de Electrones/genética , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/patología , Linaje , Eliminación de SecuenciaRESUMEN
Strømme syndrome is an ultra-rare primary ciliopathy with clinical variability. The syndrome is caused by bi-allelic variants in CENPF, a protein with key roles in both chromosomal segregation and ciliogenesis. We report three unrelated patients with Strømme syndrome and, using high-throughput sequencing approaches, we identified novel pathogenic variants in CENPF, including one structural variant, giving a genetic diagnosis to the patients. Patient 1 was a premature baby who died at 26 days with congenital malformations affecting many organs including the brain, eyes, and intestine. She was homozygous for a donor splice variant in CENPF, NM_016343.3:c.1068+1G>A, causing skipping of exon 7, resulting in a frameshift. Patient 2 was a female with intestinal atresia, microcephaly, and a Peters anomaly. She had normal developmental milestones at the age of 7 years. She is compound heterozygous for CENPF NM_016343.3:c.5920dup and c.8991del, both frameshift. Patient 3 was a male with anomalies of the brain, eye, intestine, and kidneys. He was compound heterozygous for CENPF p.(Glu298Ter), and a 5323 bp deletion covering exon 1. CENPF exon 1 is flanked by repetitive sequences that may represent a site of a recurrent structural variation, which should be a focus in patients with Strømme syndrome of unknown etiology.
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Atresia Intestinal , Microcefalia , Niño , Femenino , Humanos , Lactante , Masculino , Segmento Anterior del Ojo , Atresia Intestinal/genética , Microcefalia/genética , MutaciónRESUMEN
RNA polymerase I transcribes ribosomal DNA to produce precursor 47S rRNA. Post-transcriptional processing of this rRNA generates mature 28S, 18S and 5.8S rRNAs, which form the ribosomes, together with 5S rRNA, assembly factors and ribosomal proteins. We previously reported a homozygous variant in the catalytic subunit of RNA polymerase I, POLR1A, in two brothers with leukodystrophy and progressive course. However, the disease mechanism remained unknown. In this report, we describe another missense variant POLR1A NM_015425.3:c.1925C>A; p.(Thr642Asn) in homozygosity in two unrelated patients. Patient 1 was a 16-year-old male and Patient 2 was a 2-year-old female. Both patients manifested neurological deficits, with brain MRIs showing hypomyelinating leukodystrophy and cerebellar atrophy; and in Patient 1 additionally with hypointensity of globi pallidi and small volume of the basal ganglia. Patient 1 had progressive disease course, leading to death at the age of 16.5 years. Extensive in vitro experiments in fibroblasts from Patient 1 documented that the mutated POLR1A led to aberrant rRNA processing and degradation, and abnormal nucleolar homeostasis. Proteomics data analyses and further in vitro experiments documented abnormal protein homeostasis, and endoplasmic reticulum stress responses. We confirm that POLR1A biallelic variants cause neurodegenerative disease, expand the knowledge of the clinical phenotype of the disorder, and provide evidence for possible pathological mechanisms leading to POLR1A-related leukodystrophy.
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Enfermedades Neurodegenerativas , ARN Polimerasa I , Masculino , Femenino , Humanos , ARN Polimerasa I/genética , ARN Polimerasa I/metabolismo , Enfermedades Neurodegenerativas/genética , Proteostasis , ARN Ribosómico/metabolismo , Ribosomas , Procesamiento Postranscripcional del ARNRESUMEN
PURPOSE: Brain monoamine vesicular transport disease is an infantile-onset movement disorder that mimics cerebral palsy. In 2013, the homozygous SLC18A2 variant, p.Pro387Leu, was first reported as a cause of this rare disorder, and dopamine agonists were efficient for treating affected individuals from a single large family. To date, only 6 variants have been reported. In this study, we evaluated genotype-phenotype correlations in individuals with biallelic SLC18A2 variants. METHODS: A total of 42 affected individuals with homozygous SLC18A2 variant alleles were identified. We evaluated genotype-phenotype correlations and the missense variants in the affected individuals based on the structural modeling of rat VMAT2 encoded by Slc18a2, with cytoplasm- and lumen-facing conformations. A Caenorhabditis elegans model was created for functional studies. RESULTS: A total of 19 homozygous SLC18A2 variants, including 3 recurrent variants, were identified using exome sequencing. The affected individuals typically showed global developmental delay, hypotonia, dystonia, oculogyric crisis, and autonomic nervous system involvement (temperature dysregulation/sweating, hypersalivation, and gastrointestinal dysmotility). Among the 58 affected individuals described to date, 16 (28%) died before the age of 13 years. Of the 17 patients with p.Pro237His, 9 died, whereas all 14 patients with p.Pro387Leu survived. Although a dopamine agonist mildly improved the disease symptoms in 18 of 21 patients (86%), some affected individuals with p.Ile43Phe and p.Pro387Leu showed milder phenotypes and presented prolonged survival even without treatment. The C. elegans model showed behavioral abnormalities. CONCLUSION: These data expand the phenotypic and genotypic spectra of SLC18A2-related disorders.
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Encefalopatías , Distonía , Trastornos del Movimiento , Humanos , Animales , Ratas , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Transporte Vesicular de Monoaminas/genética , Proteínas de Transporte Vesicular de Monoaminas/metabolismo , Trastornos del Movimiento/genética , Aminas , Encéfalo/metabolismoRESUMEN
Bi-allelic pathogenic variants in ZBTB11 have been associated with intellectual developmental disorder, autosomal recessive 69 (MRT69; OMIM 618383). We report five patients from three families with novel, bi-allelic variants in ZBTB11. We have expanded the clinical phenotype of MRT69, documenting varied severity of atrophy affecting different brain regions and described combined malonic and methylmalonic aciduria as a biochemical manifestation. As ZBTB11 encodes for a transcriptional regulator, we performeded chromatin immunoprecipitation-sequencing targeting ZBTB11 in fibroblasts from patients and controls. Chromatin immunoprecipitation-sequencing revealed binding of wild-type ZBTB11 to promoters in 238 genes, among which genes encoding proteins involved in mitochondrial functions and RNA processing are over-represented. Mutated ZBTB11 showed reduced binding to 61 of the targeted genes, indicating that the variants act as loss of function. Most of these genes are related to mitochondrial functions. Transcriptome analysis of the patient fibroblasts revealed dysregulation of mitochondrial functions. In addition, we uncovered that reduced binding of the mutated ZBTB11 to ACSF3 leads to decreased ACSF3 transcript level, explaining combined malonic and methylmalonic aciduria. Collectively, these results expand the clinical spectrum of ZBTB11-related neurological disease and give insight into the pathophysiology in which the dysfunctional ZBTB11 affect mitochondrial functions and RNA processing contributing to the neurological and biochemical phenotypes.
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Errores Innatos del Metabolismo de los Aminoácidos , Errores Innatos del Metabolismo , Malformaciones del Sistema Nervioso , Errores Innatos del Metabolismo de los Aminoácidos/genética , Encéfalo , Humanos , Errores Innatos del Metabolismo/genéticaRESUMEN
PURPOSE: Gabriele-de Vries syndrome (GADEVS) is a rare genetic disorder characterized by developmental delay and/or intellectual disability, hypotonia, feeding difficulties, and distinct facial features. To refine the phenotype and to better understand the molecular basis of the syndrome, we analyzed clinical data and performed genome-wide DNA methylation analysis of a series of individuals carrying a YY1 variant. METHODS: Clinical data were collected for 13 individuals not yet reported through an international call for collaboration. DNA was collected for 11 of these individuals and 2 previously reported individuals in an attempt to delineate a specific DNA methylation signature in GADEVS. RESULTS: Phenotype in most individuals overlapped with the previously described features. We described 1 individual with atypical phenotype, heterozygous for a missense variant in a domain usually not involved in individuals with YY1 pathogenic missense variations. We also described a specific peripheral blood DNA methylation profile associated with YY1 variants. CONCLUSION: We reported a distinct DNA methylation episignature in GADEVS. We expanded the clinical profile of GADEVS to include thin/sparse hair and cryptorchidism. We also highlighted the utility of DNA methylation episignature analysis for classification of variants of unknown clinical significance.
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Discapacidad Intelectual , Trastornos del Neurodesarrollo , Metilación de ADN/genética , Genoma , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Masculino , Trastornos del Neurodesarrollo/genética , Fenotipo , SíndromeRESUMEN
The Angry Puppet Syndrome is a crime novel about a clandestine liaison between the pharmaceutical industry, academia, the criminal justice system and government agencies. The story is based on a rare side effect from medication, intermittent explosive disorder, which is an organic behavioural disorder.
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Crimen , Derecho Penal , HumanosRESUMEN
CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.
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ARN Polimerasas Dirigidas por ADN/genética , Enfermedades del Sistema Endocrino/genética , Trastornos del Crecimiento/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Enfermedades Mitocondriales/genética , Adolescente , Adulto , Variación Biológica Poblacional , Niño , Preescolar , Estudios de Cohortes , Estudios Transversales , Enfermedades del Sistema Endocrino/epidemiología , Enfermedades del Sistema Endocrino/etiología , Femenino , Heterogeneidad Genética , Trastornos del Crecimiento/epidemiología , Trastornos del Crecimiento/etiología , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/complicaciones , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/epidemiología , Humanos , Hipogonadismo/epidemiología , Hipogonadismo/etiología , Lactante , Recién Nacido , Masculino , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/epidemiología , Mutación , ARN Polimerasa III/genética , Estudios Retrospectivos , Adulto JovenRESUMEN
Ciliopathies are clinically and genetically heterogeneous diseases. We studied three patients from two independent families presenting with features of Joubert syndrome: abnormal breathing pattern during infancy, developmental delay/intellectual disability, cerebellar ataxia, molar tooth sign on magnetic resonance imaging scans, and polydactyly. We identified biallelic loss-of-function (LOF) variants in CBY1, segregating with the clinical features of Joubert syndrome in the families. CBY1 localizes to the distal end of the mother centriole, contributing to the formation and function of cilia. In accordance with the clinical and mutational findings in the affected individuals, we demonstrated that depletion of Cby1 in zebrafish causes ciliopathy-related phenotypes. Levels of CBY1 transcript were found reduced in the patients compared with controls, suggesting degradation of the mutated transcript through nonsense-mediated messenger RNA decay. Accordingly, we could detect CBY1 protein in fibroblasts from controls, but not from patients by immunofluorescence. Furthermore, we observed reduced ability to ciliate, increased ciliary length, and reduced levels of the ciliary proteins AHI1 and ARL13B in patient fibroblasts. Our data show that CBY1 LOF-variants cause a ciliopathy with features of Joubert syndrome.
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Anomalías Múltiples/genética , Proteínas Portadoras/genética , Cerebelo/anomalías , Ciliopatías/genética , Anomalías del Ojo/genética , Enfermedades Renales Quísticas/genética , Mutación/genética , Proteínas Nucleares/genética , Retina/anomalías , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/patología , Adolescente , Animales , Cerebelo/diagnóstico por imagen , Cerebelo/patología , Niño , Preescolar , Cilios/metabolismo , Cilios/patología , Ciliopatías/diagnóstico por imagen , Ciliopatías/patología , Anomalías del Ojo/diagnóstico por imagen , Anomalías del Ojo/patología , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Homocigoto , Humanos , Lactante , Recién Nacido , Enfermedades Renales Quísticas/diagnóstico por imagen , Enfermedades Renales Quísticas/patología , Imagen por Resonancia Magnética , Masculino , Linaje , Fenotipo , Retina/diagnóstico por imagen , Retina/patología , Receptor Smoothened/metabolismo , Adulto Joven , Pez Cebra/genéticaRESUMEN
BACKGROUND: Joubert syndrome (JBTS) is a genetically heterogeneous group of neurodevelopmental syndromes caused by primary cilia dysfunction. Usually the neurological presentation starts with abnormal neonatal breathing followed by muscular hypotonia, psychomotor delay, and cerebellar ataxia. Cerebral MRI shows mid- and hindbrain anomalies including the molar tooth sign. We report a male patient with atypical presentation of Joubert syndrome type 23, thus expanding the phenotype. CASE PRESENTATION: Clinical features were consistent with JBTS already from infancy, yet the syndrome was not suspected before cerebral MRI later in childhood showed the characteristic molar tooth sign and ectopic neurohypophysis. From age 11 years seizures developed and after few years became increasingly difficult to treat, also related to inadequate compliance to therapy. He died at 23 years of sudden unexpected death in epilepsy (SUDEP). The genetic diagnosis remained elusive for many years, despite extensive genetic testing. We reached the genetic diagnosis by performing whole genome sequencing of the family trio and analyzing the data with the combination of one analysis pipeline for single nucleotide variants (SNVs)/indels and one for structural variants (SVs). This lead to the identification of the most common variant detected in patients with JBTS23 (OMIM# 616490), rs534542684, in compound heterozygosity with a 8.3 kb deletion in KIAA0586, not previously reported. CONCLUSIONS: We describe for the first time ectopic neurohypophysis and SUDEP in JBTS23, expanding the phenotype of this condition and raising the attention on the possible severity of the epilepsy in this disease. We also highlight the diagnostic power of WGS, which efficiently detects SNVs/indels and in addition allows the identification of SVs.
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Anomalías Múltiples/genética , Proteínas de Ciclo Celular/genética , Cerebelo/anomalías , Muerte Súbita/patología , Epilepsia/genética , Anomalías del Ojo/genética , Enfermedades Renales Quísticas/genética , Retina/anomalías , Anomalías Múltiples/mortalidad , Anomalías Múltiples/patología , Adulto , Cerebelo/patología , Niño , Muerte Súbita/epidemiología , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/mortalidad , Discapacidades del Desarrollo/patología , Epilepsia/mortalidad , Epilepsia/patología , Anomalías del Ojo/mortalidad , Anomalías del Ojo/patología , Femenino , Heterocigoto , Humanos , Mutación INDEL , Enfermedades Renales Quísticas/mortalidad , Enfermedades Renales Quísticas/patología , Masculino , Neurohipófisis/metabolismo , Neurohipófisis/patología , Retina/patología , Secuenciación Completa del Genoma , Adulto JovenAsunto(s)
Proteínas de Unión al ADN/genética , Homocigoto , Mutación , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , Fenotipo , Pulgar/anomalías , Factores de Transcripción/genética , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Niño , Bandeo Cromosómico , Electroencefalografía , Facies , Femenino , Humanos , Imagen por Resonancia Magnética , SíndromeRESUMEN
NAME OF THE DISEASE (SYNONYMS): Stromme syndrome.Jejunal atresia with microcephaly and ocular anomalies.Apple peel syndrome with microcephaly and ocular anomalies.Ciliopathy phenotype.Primary microcephaly and intellectual disability.OMIM# of the disease 243605.Name of the analysed genes or DNA/chromosome segments CENPF.OMIM# of the gene(s) 600236.Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in CENPF genes in diagnostic, prenatal settings, and for risk assessment in relatives.
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Proteínas Cromosómicas no Histona/genética , Anomalías del Ojo/genética , Pruebas Genéticas/métodos , Atresia Intestinal/genética , Microcefalia/genética , Proteínas de Microfilamentos/genética , Anomalías del Ojo/diagnóstico , Pruebas Genéticas/normas , Humanos , Atresia Intestinal/diagnóstico , Microcefalia/diagnóstico , Mutación , Fenotipo , Sensibilidad y EspecificidadRESUMEN
AIM: To investigate if potassium citrate, a mild alkaline compound, can prevent metabolic acidosis in children with epilepsy treated with the ketogenic diet without reducing antiepileptic efficacy. METHOD: In this prospective controlled study, we investigated the frequency of initial uncompensated metabolic acidosis in 51 participants. There were 22 participants with and 29 without potassium citrate supplementation. The ketogenic diet was used as add-on treatment to children with drug resistant epilepsy. We also estimated the proportion of participants with a greater than 50% seizure reduction after 7 months. RESULTS: None of the 22 participants (15 males, seven females; median age 1y 7mo, interquartile range [IQR] 3y 3mo) with, and 10 of 29 (12 males, 17 females; median age 6y 1mo, IQR 4y 8mo) without potassium citrate developed metabolic acidosis (odds ratio=0.04, 95% CI 0.00-0.75 [p<0.01]); median pH 7.32 vs 7.24; [p<0.001]), and median bicarbonate 19.7mmol/L vs 14.0mmol/L (p<0.001). The number of seizures was reduced by more than 50% in 9 of 22 with potassium citrate and 8 of 29 participants without potassium citrate, 7 months after introducing a ketogenic diet (p=0.4). INTERPRETATION: In the ketogenic diet, potassium citrate supplementation can prevent metabolic acidosis, without reducing antiepileptic efficacy. WHAT THIS PAPER ADDS: Citrate supplementation prevents metabolic acidosis in children treated with a ketogenic diet. Efficacy of the ketogenic diet is not affected by supplementation with citrate. Citrate supplementation does not affect beta-hydroxybuturate concentration. Potassium citrate reduces the time needed to reach an optimal ketogenic ratio. This article is commented on by Schoeler on page 8 of this issue.
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Acidosis/prevención & control , Dieta Cetogénica , Epilepsia Refractaria/dietoterapia , Evaluación de Resultado en la Atención de Salud , Citrato de Potasio/farmacología , Niño , Preescolar , Dieta Cetogénica/efectos adversos , Suplementos Dietéticos , Femenino , Humanos , Lactante , Masculino , Citrato de Potasio/administración & dosificaciónAsunto(s)
Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/diagnóstico , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/genética , Proteínas Serina-Treonina Quinasas/genética , Niño , Biología Computacional , Resultado Fatal , Femenino , Humanos , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/complicaciones , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/fisiopatología , Linaje , Secuenciación Completa del GenomaRESUMEN
BACKGROUND: Thyroid hormones (TH) are essential for brain development and function. The TH transporters monocarboxylate transporter 8 (MCT8) and organic anion transporter1 C1 (OATP1C1) facilitate the transport of TH across the blood-brain barrier and into glia and neuronal cells in the brain. Loss of MCT8 function causes Allan-Herndon-Dudley syndrome (AHDS, OMIM 300523) characterized by severe intellectual and motor disability due to cerebral hypothyroidism. Here, the first patient with loss of OATP1C1 function is described. The patient is a 15.5-year-old girl with normal development in the first year of life, who gradually developed dementia with spasticity and intolerance to cold. Brain imaging demonstrated gray and white matter degeneration and severe glucose hypometabolism. METHODS: Exome sequencing of the patient and parents was performed to identify the disease-causing mutation, and the effect of the mutation was studied through a panel of in vitro experiments, including thyroxine uptake studies, immunoblotting, and immunocytochemistry. Furthermore, the clinical effects of treatment with the triiodothyronine analogue triiodothyroacetic acid (Triac) are described. RESULTS: Exome sequencing identified a homozygous missense mutation in OATP1C1, changing the highly conserved aspartic acid 252 to asparagine (D252N). In vitro, the mutated OATP1C1 displays impaired plasma membrane localization and decreased cellular thyroxine uptake. After treatment with Triac, the clinical condition improved in several domains. CONCLUSIONS: This is the first report of human OATP1C1 deficiency compatible with brain-specific hypothyroidism and neurodegeneration.
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Encéfalo/metabolismo , Mutación Missense , Degeneración Nerviosa/genética , Transportadores de Anión Orgánico/genética , Adolescente , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Femenino , Humanos , Degeneración Nerviosa/diagnóstico por imagen , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Transportadores de Anión Orgánico/metabolismo , Secuenciación del ExomaRESUMEN
Transforming growth factor (TGF)-ß1 (encoded by TGFB1) is the prototypic member of the TGF-ß family of 33 proteins that orchestrate embryogenesis, development and tissue homeostasis1,2. Following its discovery 3 , enormous interest and numerous controversies have emerged about the role of TGF-ß in coordinating the balance of pro- and anti-oncogenic properties4,5, pro- and anti-inflammatory effects 6 , or pro- and anti-fibrinogenic characteristics 7 . Here we describe three individuals from two pedigrees with biallelic loss-of-function mutations in the TGFB1 gene who presented with severe infantile inflammatory bowel disease (IBD) and central nervous system (CNS) disease associated with epilepsy, brain atrophy and posterior leukoencephalopathy. The proteins encoded by the mutated TGFB1 alleles were characterized by impaired secretion, function or stability of the TGF-ß1-LAP complex, which is suggestive of perturbed bioavailability of TGF-ß1. Our study shows that TGF-ß1 has a critical and nonredundant role in the development and homeostasis of intestinal immunity and the CNS in humans.
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Encefalopatías/complicaciones , Encefalopatías/genética , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/genética , Factor de Crecimiento Transformador beta1/genética , Análisis Mutacional de ADN , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/patología , Masculino , Linaje , Índice de Severidad de la EnfermedadRESUMEN
Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.