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1.
Sci Rep ; 14(1): 570, 2024 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-38177237

RESUMO

Familial dysautonomia (FD) is a rare recessive neurodevelopmental disease caused by a splice mutation in the Elongator acetyltransferase complex subunit 1 (ELP1) gene. This mutation results in a tissue-specific reduction of ELP1 protein, with the lowest levels in the central and peripheral nervous systems (CNS and PNS, respectively). FD patients exhibit complex neurological phenotypes due to the loss of sensory and autonomic neurons. Disease symptoms include decreased pain and temperature perception, impaired or absent myotatic reflexes, proprioceptive ataxia, and progressive retinal degeneration. While the involvement of the PNS in FD pathogenesis has been clearly recognized, the underlying mechanisms responsible for the preferential neuronal loss remain unknown. In this study, we aimed to elucidate the molecular mechanisms underlying FD by conducting a comprehensive transcriptome analysis of neuronal tissues from the phenotypic mouse model TgFD9; Elp1Δ20/flox. This mouse recapitulates the same tissue-specific ELP1 mis-splicing observed in patients while modeling many of the disease manifestations. Comparison of FD and control transcriptomes from dorsal root ganglion (DRG), trigeminal ganglion (TG), medulla (MED), cortex, and spinal cord (SC) showed significantly more differentially expressed genes (DEGs) in the PNS than the CNS. We then identified genes that were tightly co-expressed and functionally dependent on the level of full-length ELP1 transcript. These genes, defined as ELP1 dose-responsive genes, were combined with the DEGs to generate tissue-specific dysregulated FD signature genes and networks. Within the PNS networks, we observed direct connections between Elp1 and genes involved in tRNA synthesis and genes related to amine metabolism and synaptic signaling. Importantly, transcriptomic dysregulation in PNS tissues exhibited enrichment for neuronal subtype markers associated with peptidergic nociceptors and myelinated sensory neurons, which are known to be affected in FD. In summary, this study has identified critical tissue-specific gene networks underlying the etiology of FD and provides new insights into the molecular basis of the disease.


Assuntos
Disautonomia Familiar , Humanos , Camundongos , Animais , Disautonomia Familiar/genética , Disautonomia Familiar/metabolismo , Disautonomia Familiar/patologia , Proteínas de Transporte/metabolismo , Sistema Nervoso Periférico/metabolismo , Células Receptoras Sensoriais/metabolismo , Perfilação da Expressão Gênica , Expressão Gênica
2.
Exp Physiol ; 109(1): 27-34, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37029664

RESUMO

Hereditary sensory and autonomic neuropathy type III (HSAN III), also known as familial dysautonomia or Riley-Day syndrome, results from an autosomal recessive genetic mutation that causes a selective loss of specific sensory neurones, leading to greatly elevated pain and temperature thresholds, poor proprioception, marked ataxia and disturbances in blood pressure control. Stretch reflexes are absent throughout the body, which can be explained by the absence of functional muscle spindle afferents - assessed by intraneural microelectrodes inserted into peripheral nerves in the upper and lower limbs. This also explains the greatly compromised proprioception at the knee joint, as assessed by passive joint-angle matching. Moreover, there is a tight correlation between loss of proprioceptive acuity at the knee and the severity of gait impairment. Surprisingly, proprioception is normal at the elbow, suggesting that participants are relying more on sensory cues from the overlying skin; microelectrode recordings have shown that myelinated tactile afferents in the upper and lower limbs appear to be normal. Nevertheless, the lack of muscle spindles does affect sensorimotor control in the upper limb: in addition to poor performance in the finger-to-nose test, manual performance in the Purdue pegboard task is much worse than in age-matched healthy controls. Unlike those rare individuals with large-fibre sensory neuropathy, in which both muscle spindle and cutaneous afferents are absent, those with HSAN III present as a means of assessing sensorimotor control following the selective loss of muscle spindle afferents.


Assuntos
Disautonomia Familiar , Fusos Musculares , Humanos , Fusos Musculares/fisiologia , Nervos Periféricos , Reflexo de Estiramento , Joelho
3.
Calcif Tissue Int ; 114(3): 222-227, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38030713

RESUMO

This combined retrospective and prospective study aimed to investigate the relationship between scoliosis, spinal bone mineral density (BMD), and truncal muscle strength in patients with familial dysautonomia (FD). A total of 79 FD patients (40 male, 39 female) aged 5-44 years were included. The severity of scoliosis, lumbar spine BMD (Z-score), and truncal muscle strength were assessed. Correlations were analyzed using Pearson's correlation coefficient. Inverse correlations were observed between scoliosis severity and BMD (r = - 0.328, p = 0.001), as indicated by increasingly negative Z-score values with worsening osteoporosis. There were also inverse correlations between scoliosis and truncal muscle strength (r = - 0.595, p < 0.001). The correlation between scoliosis and age was notable up to 22 years (r = 0.421, p = 0.01), but not in the older age group (22-44 years). Our study identified inverse correlations between osteoporosis and scoliosis, as well as between scoliosis and truncal muscle strength, in FD patients. These findings suggest that there may be a relationship between bone density, muscle strength, and the severity of spinal curvature in this population. While our results highlight the potential importance of early diagnosis and management of osteoporosis, and possibly the benefits of physical therapy to strengthen truncal muscles, further research is needed to determine the direct impact of these interventions on preventing the progression of scoliosis and its associated complications in FD patients. A long-term longitudinal study could provide more insights into these relationships and inform treatment strategies for FD patients.


Assuntos
Disautonomia Familiar , Osteoporose , Escoliose , Humanos , Masculino , Feminino , Idoso , Densidade Óssea/fisiologia , Disautonomia Familiar/complicações , Estudos Retrospectivos , Estudos Prospectivos , Estudos Longitudinais , Osteoporose/complicações , Vértebras Lombares , Força Muscular , Absorciometria de Fóton/métodos
4.
PLoS One ; 18(11): e0293800, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37943786

RESUMO

BACKGROUND: Children with familial dysautonomia (FD) are smaller and grow more slowly than the general population. It is unknown whether this abnormal growth is due to comorbidities that patients with FD live with, or if it is a direct effect of the disease-causing homozygous ELP-1 mutations. Here, we created growth curves for weight, height, and body mass index (BMI) in male and female children with FD to monitor the nutritional status of patients with FD. METHODS: We used the New York University (NYU) FD Registry which includes data from 680 individuals with FD who were followed longitudinally since birth. We generated sex-specific FD growth charts for three age ranges (birth to 36 months, 2 to 20 years, and 2 to 40 years) and compared them to the general population. We generated Kaplan-Meier curves to test the hypothesis that FD patients with low BMI had shorter survival than the rest of the cohort. RESULTS: Growth charts generated from 591 individuals with FD show that these patients grow more slowly, reach less height, and gain less weight than the general population. The impact of FD on height was more pronounced in girls than in boys. However, both groups showed markedly low weights, which resulted in low BMI. Low weight, but not height, is already evident at birth. In a subpopulation of FD patients, we found that treatment with growth hormone or spinal fusion surgery helped patients achieve the expected growth characteristic of FD patients, but these treatments did not lead FD patients to achieve the growth pattern of the general population. Contrary to our hypothesis, low BMI had no impact on patient survival. CONCLUSIONS: Pediatric patients with FD have lower height, weight, and BMI compared to the general pediatric population, but this does not appear to affect survival. Growth curves specific to the FD population are an important tool to monitor growth and nutritional status in pediatric patients with FD when the general population growth curves are of limited use.


Assuntos
Disautonomia Familiar , Recém-Nascido , Humanos , Criança , Masculino , Feminino , Pré-Escolar , Índice de Massa Corporal , Peso Corporal , Disautonomia Familiar/genética , Estado Nutricional , Magreza , Redução de Peso , Estatura
5.
Sci Rep ; 13(1): 18600, 2023 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-37903840

RESUMO

Familial dysautonomia (FD) is a rare neurodevelopmental and neurodegenerative disease caused by a splicing mutation in the Elongator Acetyltransferase Complex Subunit 1 (ELP1) gene. The reduction in ELP1 mRNA and protein leads to the death of retinal ganglion cells (RGCs) and visual impairment in all FD patients. Currently patient symptoms are managed, but there is no treatment for the disease. We sought to test the hypothesis that restoring levels of Elp1 would thwart the death of RGCs in FD. To this end, we tested the effectiveness of two therapeutic strategies for rescuing RGCs. Here we provide proof-of-concept data that gene replacement therapy and small molecule splicing modifiers effectively reduce the death of RGCs in mouse models for FD and provide pre-clinical foundational data for translation to FD patients.


Assuntos
Disautonomia Familiar , Doenças Neurodegenerativas , Camundongos , Animais , Humanos , Células Ganglionares da Retina/metabolismo , Disautonomia Familiar/genética , Disautonomia Familiar/terapia , Disautonomia Familiar/metabolismo , Doenças Neurodegenerativas/metabolismo , Splicing de RNA , Terapia Genética , Fatores de Elongação da Transcrição/genética , Fatores de Elongação da Transcrição/metabolismo
6.
Clin Auton Res ; 33(3): 269-280, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37204536

RESUMO

Familial dysautonomia (FD) is an autosomal recessive hereditary sensory and autonomic neuropathy (HSAN, type 3) expressed at birth with profound sensory loss and early death. The FD founder mutation in the ELP1 gene arose within the Ashkenazi Jews in the sixteenth century and is present in 1:30 Jews of European ancestry. The mutation yield a tissue-specific skipping of exon 20 and a loss of function of the elongator-1 protein (ELP1), which is essential for the development and survival of neurons. Patients with FD produce variable amounts of ELP1 in different tissues, with the brain producing mostly mutant transcripts. Patients have excessive blood pressure variability due to the failure of the IXth and Xth cranial nerves to carry baroreceptor signals. Neurogenic dysphagia causes frequent aspiration leading to chronic pulmonary disease. Characteristic hyperadrenergic "autonomic crises" consisting of brisk episodes of severe hypertension, tachycardia, skin blotching, retching, and vomiting occur in all patients. Progressive features of the disease include retinal nerve fiber loss and blindness, and proprioceptive ataxia with severe gait impairment. Chemoreflex failure may explain the high frequency of sudden death in sleep. Although 99.5% of patients are homozygous for the founder mutation, phenotypic severity varies, suggesting that modifier genes impact expression. Medical management is currently symptomatic and preventive. Disease-modifying therapies are close to clinical testing. Endpoints to measure efficacy have been developed, and the ELP1 levels are a good surrogate endpoint for target engagement. Early intervention may be critical for treatment to be successful.


Assuntos
Disautonomia Familiar , Recém-Nascido , Humanos , Neurônios , Mutação
7.
Clin Auton Res ; 33(2): 87-92, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36735101

RESUMO

OBJECTIVE: Familial dysautonomia (FD) is a rare inherited autosomal recessive disorder with abnormal somatosensory, enteric, and afferent autonomic neurons. We aimed to define the incidence of gastrointestinal bleeding and its associated risk factors in patients with FD. METHODS: In this retrospective case-control study, we identified all episodes of gastrointestinal bleeding in patients with FD, occurring over four decades (January 1980-December 2017), using the New York University FD registry. RESULTS: We identified 104 episodes of gastrointestinal bleeding occurring in 60 patients with FD. The estimated incidence rate of gastrointestinal bleeds in the FD population rate was 4.20 episodes per 1000 person-years. We compared the 60 cases with 94 age-matched controls. Bleeding in the upper gastrointestinal tract from gastric and duodenal ulcers occurred most frequently (64 bleeds, 75.6%). Patients were more likely to have a gastrostomy (G)-tube and a Nissen fundoplication [odds ratio (OR) 3.73, 95% confidence interval (CI) 1.303-13.565] than controls. The mean time from G-tube placement to first gastrointestinal bleed was 7.01 years. The mean time from Nissen fundoplication to bleed was 7.01 years. Cases and controls had similar frequency of intake of nonsteroidal antiinflammatory drugs (NSAID) and selective serotonin reuptake inhibitors (SSRI). CONCLUSION: The incidence of gastrointestinal bleeding in the pediatric FD population was estimated to be 4.20 per 1000 person-years, 21 times higher than in the general pediatric population (0.2 per 1000 person-years). Patients with FD with a G-tube and a Nissen fundoplication had a higher risk of a subsequent gastrointestinal bleeding.


Assuntos
Disautonomia Familiar , Humanos , Criança , Disautonomia Familiar/complicações , Disautonomia Familiar/epidemiologia , Estudos de Casos e Controles , Estudos Retrospectivos , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/complicações , Inibidores Seletivos de Recaptação de Serotonina
8.
Am J Hum Genet ; 110(3): 531-547, 2023 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-36809767

RESUMO

Familial dysautonomia (FD) is a rare neurodegenerative disease caused by a splicing mutation in elongator acetyltransferase complex subunit 1 (ELP1). This mutation leads to the skipping of exon 20 and a tissue-specific reduction of ELP1, mainly in the central and peripheral nervous systems. FD is a complex neurological disorder accompanied by severe gait ataxia and retinal degeneration. There is currently no effective treatment to restore ELP1 production in individuals with FD, and the disease is ultimately fatal. After identifying kinetin as a small molecule able to correct the ELP1 splicing defect, we worked on its optimization to generate novel splicing modulator compounds (SMCs) that can be used in individuals with FD. Here, we optimize the potency, efficacy, and bio-distribution of second-generation kinetin derivatives to develop an oral treatment for FD that can efficiently pass the blood-brain barrier and correct the ELP1 splicing defect in the nervous system. We demonstrate that the novel compound PTC258 efficiently restores correct ELP1 splicing in mouse tissues, including brain, and most importantly, prevents the progressive neuronal degeneration that is characteristic of FD. Postnatal oral administration of PTC258 to the phenotypic mouse model TgFD9;Elp1Δ20/flox increases full-length ELP1 transcript in a dose-dependent manner and leads to a 2-fold increase in functional ELP1 in the brain. Remarkably, PTC258 treatment improves survival, gait ataxia, and retinal degeneration in the phenotypic FD mice. Our findings highlight the great therapeutic potential of this novel class of small molecules as an oral treatment for FD.


Assuntos
Disautonomia Familiar , Doenças Neurodegenerativas , Degeneração Retiniana , Camundongos , Animais , Disautonomia Familiar/genética , Cinetina , Marcha Atáxica , Administração Oral
9.
Nat Commun ; 14(1): 218, 2023 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-36639365

RESUMO

Familial dysautonomia (FD) is a rare genetic neurologic disorder caused by impaired neuronal development and progressive degeneration of both the peripheral and central nervous systems. FD is monogenic, with >99.4% of patients sharing an identical point mutation in the elongator acetyltransferase complex subunit 1 (ELP1) gene, providing a relatively simple genetic background in which to identify modifiable factors that influence pathology. Gastrointestinal symptoms and metabolic deficits are common among FD patients, which supports the hypothesis that the gut microbiome and metabolome are altered and dysfunctional compared to healthy individuals. Here we show significant differences in gut microbiome composition (16 S rRNA gene sequencing of stool samples) and NMR-based stool and serum metabolomes between a cohort of FD patients (~14% of patients worldwide) and their cohabitating, healthy relatives. We show that key observations in human subjects are recapitulated in a neuron-specific Elp1-deficient mouse model, and that cohousing mutant and littermate control mice ameliorates gut microbiome dysbiosis, improves deficits in gut transit, and reduces disease severity. Our results provide evidence that neurologic deficits in FD alter the structure and function of the gut microbiome, which shifts overall host metabolism to perpetuate further neurodegeneration.


Assuntos
Disautonomia Familiar , Microbioma Gastrointestinal , Humanos , Camundongos , Animais , Disautonomia Familiar/genética , Disbiose/metabolismo , Neurônios/metabolismo , Sistema Nervoso Central/metabolismo
10.
Nat Commun ; 13(1): 7032, 2022 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-36396637

RESUMO

Familial dysautonomia (FD), a rare neurodevelopmental and neurodegenerative disorder affects the sympathetic and sensory nervous system. Although almost all patients harbor a mutation in ELP1, it remains unresolved exactly how function of sympathetic neurons (symNs) is affected; knowledge critical for understanding debilitating disease hallmarks, including cardiovascular instability or dysautonomic crises, that result from dysregulated sympathetic activity. Here, we employ the human pluripotent stem cell (hPSC) system to understand symN disease mechanisms and test candidate drugs. FD symNs are intrinsically hyperactive in vitro, in cardiomyocyte co-cultures, and in animal models. We report reduced norepinephrine transporter expression, decreased intracellular norepinephrine (NE), decreased NE re-uptake, and excessive extracellular NE in FD symNs. SymN hyperactivity is not a direct ELP1 mutation result, but may connect to NET via RAB proteins. We found that candidate drugs lowered hyperactivity independent of ELP1 modulation. Our findings may have implications for other symN disorders and may allow future drug testing and discovery.


Assuntos
Disautonomia Familiar , Animais , Humanos , Disautonomia Familiar/genética , Disautonomia Familiar/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Neurônios/metabolismo , Norepinefrina/metabolismo , Mutação
11.
Am J Hum Genet ; 109(8): 1534-1548, 2022 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-35905737

RESUMO

Familial dysautonomia (FD) is a currently untreatable, neurodegenerative disease caused by a splicing mutation (c.2204+6T>C) that causes skipping of exon 20 of the elongator complex protein 1 (ELP1) pre-mRNA. Here, we used adeno-associated virus serotype 9 (AAV9-U1-FD) to deliver an exon-specific U1 (ExSpeU1) small nuclear RNA, designed to cause inclusion of ELP1 exon 20 only in those cells expressing the target pre-mRNA, in a phenotypic mouse model of FD. Postnatal systemic and intracerebral ventricular treatment in these mice increased the inclusion of ELP1 exon 20. This also augmented the production of functional protein in several tissues including brain, dorsal root, and trigeminal ganglia. Crucially, the treatment rescued most of the FD mouse mortality before one month of age (89% vs 52%). There were notable improvements in ataxic gait as well as renal (serum creatinine) and cardiac (ejection fraction) functions. RNA-seq analyses of dorsal root ganglia from treated mice and human cells overexpressing FD-ExSpeU1 revealed only minimal global changes in gene expression and splicing. Overall then, our data prove that AAV9-U1-FD is highly specific and will likely be a safe and effective therapeutic strategy for this debilitating disease.


Assuntos
Disautonomia Familiar , Doenças Neurodegenerativas , Animais , Modelos Animais de Doenças , Disautonomia Familiar/genética , Éxons/genética , Humanos , Camundongos , Doenças Neurodegenerativas/genética , Precursores de RNA/genética , Splicing de RNA/genética , RNA Nuclear Pequeno/genética , RNA Nuclear Pequeno/metabolismo
13.
Hum Mol Genet ; 31(20): 3521-3538, 2022 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-35708500

RESUMO

Recent research on familial dysautonomia (FD) has focused on the development of therapeutics that facilitate the production of the correctly spliced, exon 20-containing, transcript in cells and individuals bearing the splice-altering, FD-causing mutation in the elongator acetyltransferase complex subunit I (ELP1) gene. We report here the ability of carnosol, a diterpene present in plant species of the Lamiaceae family, including rosemary, to enhance the cellular presence of the correctly spliced ELP1 transcript in FD patient-derived fibroblasts by upregulating transcription of the ELP1 gene and correcting the aberrant splicing of the ELP1 transcript. Carnosol treatment also elevates the level of the RNA binding motif protein 24 (RBM24) and RNA binding motif protein 38 (RBM38) proteins, two multifunctional RNA-binding proteins. Transfection-mediated expression of either of these RNA binding motif (RBMs) facilitates the inclusion of exon 20 sequence into the transcript generated from a minigene-bearing ELP1 genomic sequence containing the FD-causing mutation. Suppression of the carnosol-mediated induction of either of these RBMs, using targeting siRNAs, limited the carnosol-mediated inclusion of the ELP1 exon 20 sequence. Carnosol treatment of FD patient peripheral blood mononuclear cells facilitates the inclusion of exon 20 into the ELP1 transcript. The increased levels of the ELP1 and RBM38 transcripts and the alternative splicing of the sirtuin 2 (SIRT2) transcript, a sentinel for exon 20 inclusion in the FD-derived ELP1 transcript, are observed in RNA isolated from whole blood of healthy adults following the ingestion of carnosol-containing rosemary extract. These findings and the excellent safety profile of rosemary together justify an expedited clinical study of the impact of carnosol on the FD patient population.


Assuntos
Disautonomia Familiar , Rosmarinus , Fatores de Elongação da Transcrição/metabolismo , Abietanos/farmacologia , Acetiltransferases , Adulto , Proteínas de Transporte/genética , Disautonomia Familiar/tratamento farmacológico , Disautonomia Familiar/genética , Disautonomia Familiar/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo , RNA , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Rosmarinus/genética , Rosmarinus/metabolismo , Sirtuína 2/metabolismo , Fatores de Elongação da Transcrição/genética
14.
Elife ; 112022 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-35713404

RESUMO

Familial dysautonomia (FD) is a sensory and autonomic neuropathy caused by mutations in elongator complex protein 1 (ELP1). FD patients have small trigeminal nerves and impaired facial pain and temperature perception. These signals are relayed by nociceptive neurons in the trigeminal ganglion, a structure that is composed of both neural crest- and placode-derived cells. Mice lacking Elp1 in neural crest derivatives ('Elp1 CKO') are born with small trigeminal ganglia, suggesting Elp1 is important for trigeminal ganglion development, yet the function of Elp1 in this context is unknown. We demonstrate that Elp1, expressed in both neural crest- and placode-derived neurons, is not required for initial trigeminal ganglion formation. However, Elp1 CKO trigeminal neurons exhibit abnormal axon outgrowth and deficient target innervation. Developing nociceptors expressing the receptor TrkA undergo early apoptosis in Elp1 CKO, while TrkB- and TrkC-expressing neurons are spared, indicating Elp1 supports the target innervation and survival of trigeminal nociceptors. Furthermore, we demonstrate that specific TrkA deficits in the Elp1 CKO trigeminal ganglion reflect the neural crest lineage of most TrkA neurons versus the placodal lineage of most TrkB and TrkC neurons. Altogether, these findings explain defects in cranial gangliogenesis that may lead to loss of facial pain and temperature sensation in FD.


Assuntos
Disautonomia Familiar , Animais , Disautonomia Familiar/genética , Disautonomia Familiar/metabolismo , Dor Facial/metabolismo , Camundongos , Crista Neural/metabolismo , Neurônios/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Gânglio Trigeminal
15.
Dis Model Mech ; 15(5)2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35481599

RESUMO

Cardiovascular instability and a blunted respiratory drive in hypoxic conditions are hallmark features of the genetic sensory and autonomic neuropathy, familial dysautonomia (FD). FD results from a mutation in the gene ELP1, the encoded protein of which is a scaffolding subunit of the six-subunit Elongator complex. In mice, we and others have shown that Elp1 is essential for the normal development of neural crest-derived dorsal root ganglia sensory neurons. Whether Elp1 is also required for development of ectodermal placode-derived visceral sensory receptors, which are required for normal baroreception and chemosensory responses, has not been investigated. Using mouse models for FD, we here show that the entire circuitry underlying baroreception and chemoreception is impaired due to a requirement for Elp1 in the visceral sensory neuron ganglia, as well as for normal peripheral target innervation, and in their central nervous system synaptic partners in the medulla. Thus, Elp1 is required in both placode- and neural crest-derived sensory neurons, and its reduction aborts the normal development of neuronal circuitry essential for autonomic homeostasis and interoception. This article has an associated First Person interview with the first author of the paper.


Assuntos
Proteínas de Transporte , Disautonomia Familiar , Animais , Proteínas de Transporte/metabolismo , Sistema Nervoso Central/metabolismo , Disautonomia Familiar/genética , Gânglios Espinais/metabolismo , Humanos , Camundongos , Crista Neural/metabolismo
16.
Hum Mol Genet ; 31(11): 1776-1787, 2022 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34908112

RESUMO

Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease caused by a splicing mutation in the gene encoding Elongator complex protein 1 (ELP1, also known as IKBKAP). This mutation results in tissue-specific skipping of exon 20 with a corresponding reduction of ELP1 protein, predominantly in the central and peripheral nervous system. Although FD patients have a complex neurological phenotype caused by continuous depletion of sensory and autonomic neurons, progressive visual decline leading to blindness is one of the most problematic aspects of the disease, as it severely affects their quality of life. To better understand the disease mechanism as well as to test the in vivo efficacy of targeted therapies for FD, we have recently generated a novel phenotypic mouse model, TgFD9; IkbkapΔ20/flox. This mouse exhibits most of the clinical features of the disease and accurately recapitulates the tissue-specific splicing defect observed in FD patients. Driven by the dire need to develop therapies targeting retinal degeneration in FD, herein, we comprehensively characterized the progression of the retinal phenotype in this mouse, and we demonstrated that it is possible to correct ELP1 splicing defect in the retina using the splicing modulator compound (SMC) BPN-15477.


Assuntos
Disautonomia Familiar , Peptídeos e Proteínas de Sinalização Intracelular , Doenças Neurodegenerativas , Doenças do Nervo Óptico , Células Ganglionares da Retina , Animais , Modelos Animais de Doenças , Disautonomia Familiar/patologia , Humanos , Camundongos , Doenças Neurodegenerativas/patologia , Doenças do Nervo Óptico/patologia , Células Ganglionares da Retina/patologia
17.
J Genet Genomics ; 49(7): 654-665, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-34896608

RESUMO

Familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy, is caused by a mutation in the Elongator complex protein 1 (ELP1) gene that leads to a tissue-specific reduction of ELP1 protein. Our work to generate a phenotypic mouse model for FD headed to the discovery that homozygous deletion of the mouse Elp1 gene leads to embryonic lethality prior to mid-gestation. Given that FD is caused by a reduction, not loss, of ELP1, we generated two new mouse models by introducing different copy numbers of the human FD ELP1 transgene into the Elp1 knockout mouse (Elp1-/-) and observed that human ELP1 expression rescues embryonic development in a dose-dependent manner. We then conducted a comprehensive transcriptome analysis in mouse embryos to identify genes and pathways whose expression correlates with the amount of ELP1. We found that ELP1 is essential for the expression of genes responsible for nervous system development. Further, gene length analysis of the differentially expressed genes showed that the loss of Elp1 mainly impacts the expression of long genes and that by gradually restoring Elongator, their expression is progressively rescued. Finally, through evaluation of co-expression modules, we identified gene sets with unique expression patterns that depended on ELP1 expression.


Assuntos
Proteínas de Transporte , Disautonomia Familiar , Animais , Proteínas de Transporte/genética , Modelos Animais de Doenças , Disautonomia Familiar/genética , Disautonomia Familiar/metabolismo , Expressão Gênica , Homozigoto , Humanos , Camundongos , Deleção de Sequência
18.
Pharmacoepidemiol Drug Saf ; 31(2): 128-140, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34245206

RESUMO

PURPOSE: Patients with the autosomal recessive disorder of familial dysautonomia typically exhibit exacerbated adverse side effects to many common drugs. We aimed to catalog these adverse effects - with a focus on common drugs that are frequently administered to FD patients and compare their incidences to those within the general population. METHODS: We used data of 595 FD patients from an international database with information on drugs received and adverse effects. To investigate the molecular causes of reported differences in drug responses in FD patients, we used expression microarrays to compare the mRNA expression profiles in peripheral blood leukocytes of FD patients (n = 12) and healthy individuals (n = 10). RESULTS: Several drug classes, including cholinergics, anti-cholinergics, anti-convulsants, methylxanthines, SSRIs, and antibiotics caused either unreported symptoms or elevated rates of adverse events in FD patients. FD patients experienced different or more frequent adverse side effects than the general population in 31/123 drugs. These side effects included blood cell dyscrasias, amenorrhea, gastrointestinal bleeding, and bronchospasm. New findings include enhanced reaction of FD patients to H2 antagonist agents and to serotonin receptor agonists. We also detected eight genes differentially expressed between FD patients and healthy individuals that may underlie the differential drug responses of FD patients. CONCLUSION: We provide evidence that suggests the use of several common drugs should be discontinued or reduced in FD patients.


Assuntos
Disautonomia Familiar , Preparações Farmacêuticas , Proteínas de Transporte , Disautonomia Familiar/epidemiologia , Disautonomia Familiar/genética , Feminino , Humanos , Fatores de Elongação da Transcrição
19.
Nat Commun ; 12(1): 5878, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620845

RESUMO

Microtubule (MT)-based transport is an evolutionary conserved process finely tuned by posttranslational modifications. Among them, α-tubulin acetylation, primarily catalyzed by a vesicular pool of α-tubulin N-acetyltransferase 1 (Atat1), promotes the recruitment and processivity of molecular motors along MT tracks. However, the mechanism that controls Atat1 activity remains poorly understood. Here, we show that ATP-citrate lyase (Acly) is enriched in vesicles and provide Acetyl-Coenzyme-A (Acetyl-CoA) to Atat1. In addition, we showed that Acly expression is reduced upon loss of Elongator activity, further connecting Elongator to Atat1 in a pathway regulating α-tubulin acetylation and MT-dependent transport in projection neurons, across species. Remarkably, comparable defects occur in fibroblasts from Familial Dysautonomia (FD) patients bearing an autosomal recessive mutation in the gene coding for the Elongator subunit ELP1. Our data may thus shine light on the pathophysiological mechanisms underlying FD.


Assuntos
ATP Citrato (pro-S)-Liase/metabolismo , Transporte Axonal/fisiologia , ATP Citrato (pro-S)-Liase/genética , Acetilcoenzima A/metabolismo , Acetilação , Acetiltransferases/genética , Animais , Transporte Axonal/genética , Drosophila melanogaster , Disautonomia Familiar/metabolismo , Feminino , Fibroblastos/metabolismo , Humanos , Larva , Masculino , Camundongos , Microtúbulos/metabolismo , Processamento de Proteína Pós-Traducional , Tubulina (Proteína)/metabolismo
20.
Stem Cell Res ; 55: 102495, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34419746

RESUMO

Familial Dysautonomia (FD) is an autosomal recessive congenital neuropathy affecting the development and function of the peripheral nervous system. FD causing gene is IKBKAP, encoding IkappaB kinase complex-associated protein also named elongator complex like protein 1 (IKAP/ELP1). The most common mutation (IVS20 + 6 T > C) causes an exon 20 skipping, leading to a truncated protein. We report the generation of two induced pluripotent stem cell lines from an FD patient with a homozygous mutation in ELP1 and his heterozygous healthy family relative. Both lines highly express pluripotency markers, can differentiate into the three germ layers, retain the disease-causing mutation and display normal karyotypes.


Assuntos
Disautonomia Familiar , Células-Tronco Pluripotentes Induzidas , Proteínas de Transporte/genética , Disautonomia Familiar/genética , Heterozigoto , Humanos , Mutação
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