RESUMEN
Charcot-Marie-Tooth disease 4H(CMT4H) is an autosomal recessive demyelinating form of CMT caused by FGD4/FRABIN mutations. CMT4H is characterized by early onset and slowly progressing motor and sensory deficits in the distal extremities, along with foot deformities. We describe a patient with CMT4H who presented with rapidly progressing flaccid quadriparesis during the postpartum period, which improved significantly with steroid therapy. Magnetic resonance imaging and ultrasonography demonstrated considerable nerve thickening with increased cross-sectional area in the peripheral nerves. A nerve biopsy revealed significant demyelination and myelin outfolding. This is the first report of an Indian patient with a novel homozygous nonsense c.1672C>T (p.Arg558Ter) mutation in the FGD4 gene, expanding the mutational and phenotypic spectrum of this disease.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth , Femenino , Humanos , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/patología , Proteínas de Microfilamentos/genética , Linaje , Mutación , Fenotipo , Factores de Intercambio de Guanina Nucleótido/genéticaRESUMEN
To explore the role of atorvastatin in regulating intraocular pressure (IOP) in glaucoma in vivo, and to investigate its related molecular pathway in vitro, an ocular hypertension model was generated by intravitreal injection of an adenoviral vector encoding transforming growth factor (TGF)ß2 in the right eye of BALB/cJ mice, while the left was treated with an empty control adenovirus. To determine its antiintraocular hypertension role, these induced hyperIOP mice were gavaged with atorvastatin (20 mg/kg/day). Furthermore, extracellular matrix (ECM) factors were examined in the primary human trabecular meshwork (HTM) cells followed atorvastatin (0~200 µM) treatment in vitro. Whole genome microarray was employed to identify potential therapeutic target molecules associated with ECM regulation. Unilateral murine ocular hypertension was induced, via intravitreal injection of the adenoviral vector carrying the human TGFß2 gene (Ad.hTGFß2226/228), raising IOP from 12±1.6 to 32.3±0.7 mmHg (n=6, P<0.05) at day 15, which plateaued from day 15 to 30. Atorvastatin administration from day 15 to 30 decreased IOP from 32.3±0.7 to 15.4±1.1 mmHg (n=6, P<0.05) at day 30. Additionally, atorvastatin administration changed the morphology of cultured HTM cells from an elongated and adherent morphology into rounded, less elongated and less adherent cells, accompanied with suppressed expression of ECM. Gene Ontology and Genome analysis revealed that FGD4 (FYVE, RhoGEF and PH domain containing 4) might be a key factor contributing to these changes. Our data demonstrated that atorvastatin reduced TGFß2induced ocular hypertension in vivo, perhaps via modifying cellular structure and decreasing ECM, using the FGD4 signaling pathway, as demonstrated in HTM cells. Our findings provide some useful information for the management of glaucoma, with statin therapy revealing a potential novel therapeutic pathway for glaucoma treatment.
Asunto(s)
Atorvastatina , Glaucoma , Proteínas de Microfilamentos , Hipertensión Ocular , Animales , Atorvastatina/farmacología , Células Cultivadas , Matriz Extracelular/metabolismo , Glaucoma/metabolismo , Presión Intraocular , Ratones , Proteínas de Microfilamentos/genética , Hipertensión Ocular/inducido químicamente , Hipertensión Ocular/tratamiento farmacológico , Hipertensión Ocular/metabolismo , Malla Trabecular/metabolismo , Factor de Crecimiento Transformador beta2/farmacologíaRESUMEN
Charcot-Marie-Tooth disease (CMT) is a hereditary sensory and motor peripheral neuropathy that is one of the most common inherited neurological diseases of humans and may be caused by mutations in a number of different genes. The subtype Charcot-Marie-Tooth disease type 4H (CMT4H) is caused by homozygous mutations in the FGD4 (FYVE, RhoGEF, and PH domain-containing 4) gene. A previous genome-wide association study involving 130,783 dairy cows found 6 novel variants, one of which was a homozygous splice site mutation in the FGD4 gene. Descendants of carriers were genotyped to identify 9 homozygous Holstein Friesian calves that were raised to maturity, of which 5 were euthanized and sampled for histopathology and electron microscopy at 2 and 2.5 years of age. Three control Holstein Friesian animals were raised with the calves and euthanized at the same time points. No macroscopic lesions consistent with CMT4H were seen at necropsy. Microscopically, peripheral nerves were hypercellular due to hyperplasia of S100-positive Schwann cells, and there was onion bulb formation, axonal degeneration with demyelination, and increased thickness of the endoneurium. On electron microscopy, decreased axonal density, onion bulb formations, myelin outfoldings, and increased numbers of mitochondria were present. These changes are consistent with those described in mouse models and humans with CMT4H, making these cattle a potential large animal model for CMT.
Asunto(s)
Enfermedades de los Bovinos , Enfermedad de Charcot-Marie-Tooth , Animales , Bovinos , Enfermedades de los Bovinos/genética , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/patología , Enfermedad de Charcot-Marie-Tooth/veterinaria , Femenino , Estudio de Asociación del Genoma Completo/veterinaria , Proteínas de Microfilamentos , MutaciónRESUMEN
Charcot-Marie-Tooth disease type 4H (CMT4H) is an autosomal recessive inherited demyelinating neuropathy caused by an FYVE, RhoGEF, and a PH domain-containing protein 4 (FGD4) gene mutation. CMT4H is characterized by an early onset, slow progression, scoliosis, distal muscle atrophy, and foot deformities. We herein present sibling cases of CMT4H with a homozygous mutation in the FGD4 gene. Both patients exhibited cauda equina thickening on magnetic resonance imaging, which had not been reported among the previous CMT4H cases. This is the first report of CMT4H with a homozygous FGD4 c.1730G>A (p.Arg577Gln) mutation showing mild progression and cauda equina thickening.
Asunto(s)
Cauda Equina , Enfermedad de Charcot-Marie-Tooth , Enfermedad de Charcot-Marie-Tooth/diagnóstico por imagen , Enfermedad de Charcot-Marie-Tooth/genética , Humanos , Proteínas de Microfilamentos/genética , Mutación , Linaje , Fenotipo , HermanosRESUMEN
Background: Chemotherapy-related adverse events may restrain taxane/cisplatin administration as a regimen for patients with esophageal squamous cell carcinoma. Genetic polymorphisms may contribute to adverse event susceptibility. Method & results: The authors genotyped ten SNPs from five genes (rs1045642, rs2032582 and rs3213619 of ABCB1; rs2231137 and rs2231142 of ABCG2; rs246221 of ABCC1; rs3740066 of ABCC2; and rs10771973, rs12296975 and rs1239829 of FGD4) in 219 patients with esophageal squamous cell carcinoma treated with taxane/cisplatin. Patients with severe toxicities were compared with those with minor or no adverse events by unconditional logistic regression models and semi-Bayesian shrinkage. After adjustment for age and sex, with the null prior, FGD4 rs1239829 was statistically significantly related to grade 3-4 leukopenia (odds ratio [95% CI] in dominant model = 1.77 [1.04-3.03]). Conclusion: The minor allele of FGD4 rs1239829 was related to grade 3-4 leukopenia in patients with esophageal squamous cell carcinoma treated with taxane/cisplatin, with unclear biological mechanism.
Lay abstract Taxane/cisplatin is the main chemotherapy regimen in patients with esophageal squamous cell carcinoma in China. Many patients suffer from neurotoxicity or bone marrow suppression, such as decreased white blood cells. Higher-grade adverse events, in particular, usually result in chemotherapy dose reduction or treatment termination. Researchers explored the associations between genetics and chemotherapy toxicity and found that the genetic variant (SNP rs1239829) of the gene FGD4 was related to serious white blood cell decline in patients with esophageal squamous cell carcinoma who were treated with the taxane/cisplatin regimen.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Esofágicas/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Leucopenia/epidemiología , Proteínas de Microfilamentos/genética , Polimorfismo Genético , Adulto , Anciano , Anciano de 80 o más Años , Teorema de Bayes , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Estudios de Casos y Controles , China/epidemiología , Cisplatino/administración & dosificación , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Estudios de Seguimiento , Humanos , Leucopenia/inducido químicamente , Leucopenia/genética , Leucopenia/patología , Masculino , Persona de Mediana Edad , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Taxoides/administración & dosificaciónRESUMEN
BACKGROUND: MiRNAs play important roles in the development of ovarian cancer, activation of primitive follicles, follicular development, oocyte maturation and ovulation. In the present study, we investigated the specific role of miR-23a in cov434 cells. RESULTS: Downregulation of miR-23a was observed in serum of PCOS patients compared with the healthy control, suggesting the inhibitory effect of miR-23a in PCOS. MiR-23a was positively correlated with Body Mass Index (BMI) and negatively correlated with Luteinizing hormone (LH), Testostrone (T), Glucose (Glu) and Insulin (INS) of PCOS patients. MiR-23a mimic inhibited the proliferation and promoted apoptosis of human cov434 cells. In addition, flow cytometry assay confirmed that miR-23a blocked cell cycle on G0/G1 phase. MiR-23a inhibitor showed opposite results. Furthermore, double luciferase reporter assay proved that miR-23a could bind to the 3'UTR of FGD4 directly through sites predicted on Target Scan. FGD4 level was significantly suppressed by miR-23a mimic, but was significantly enhanced by miR-23a inhibitor. We further proved that miR-23a increased the expression of activated CDC42 (GTP bround) and p-PAK-1, suggesting that miR-23a induced cell cycle arrest through CDC42/PAK1 pathway. CONCLUSIONS: In conclusion, our study reveals that miR-23a participates in the regulation of proliferation and apoptosis of cov434 cells through target FGD4, and may play a role in the pathophysiology of PCOS.
Asunto(s)
MicroARNs/genética , Proteínas de Microfilamentos/genética , Síndrome del Ovario Poliquístico/genética , Transducción de Señal , Regiones no Traducidas 3' , Adulto , Apoptosis , Estudios de Casos y Controles , Puntos de Control del Ciclo Celular , Línea Celular , Proliferación Celular , Regulación hacia Abajo , Femenino , Humanos , Fosforilación , Proteína de Unión al GTP cdc42/metabolismo , Quinasas p21 Activadas/metabolismoRESUMEN
BACKGROUND: Mutations in the FGD4 gene cause an autosomal recessive demyelinating peripheral neuropathy referred to as CMT4H, characterized by its onset in infancy or early-childhood and its slow progression. METHODS: The clinical and genetic status of two patients with CMT4H was studied, performing genetic testing with a panel of genes and analysing FGD4 mRNA expression by quantitative PCR. RESULTS: Two novel FGD4 variants (c.514delG and c.2211dupA) were identified in two mildly affected Spanish siblings with CMT4H, and with disease onset in late adolescence/adulthood (one of them remaining asymptomatic at 20). On examination, foot deformity was observed without weakness or sensory involvement, and in the muscles of the lower extremities magnetic resonance imaging showed no fat replacement. Further analysis of FGD4 expression in peripheral blood suggested that neither mutation affected splicing, nor did they affect the dosage of FGD4 mRNA (compared to a healthy control). It was predicted that each allele would produce a truncated protein, p.Ala172Glnfs*28 (c.514delG) and p.Ala738Serfs*5 (c.2211dupA), the latter containing all the functional domains of the native protein. CONCLUSIONS: The conservation of functional domains in the proteins produced from the FGD4 gene of two patients with CMT4H, could explain both the milder phenotype and the later disease onset in these patients. These results expand the clinical and mutational spectrum of FGD4-related peripheral neuropathies.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Mutación del Sistema de Lectura , Proteínas de Microfilamentos/genética , Fenotipo , Adolescente , Alelos , Femenino , Humanos , Masculino , Linaje , Hermanos , Adulto JovenRESUMEN
Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of taxane treatment during chemotherapy. Identifying predictive biomarkers of CIPN would allow physicians to alter treatment given to patients according to a personal risk of developing this condition. The current literature on CIPN biomarkers is reviewed, identifying biomarkers which have been found to be significantly related to CIPN. Three genetic biomarkers are identified (ARHGEF10 rs9657362, CYP2C8 rs11572080/rs10509681 and FGD4 rs10771973) which have been found to act as predictive CIPN biomarkers in multiple studies. Possible mechanisms underlying the relationship between these single nucleotide polymorphisms and CIPN development are explored. The biomarkers identified in this study should be investigated further to generate predictive biomarkers that may be used in a clinical setting.
Asunto(s)
Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/genética , Polimorfismo de Nucleótido Simple , Marcadores Genéticos , Humanos , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/metabolismo , Valor Predictivo de las PruebasRESUMEN
Charcot-Marie-Tooth disease type 4H (CMT4H) is a rare variant of autosomal recessive hereditary neuropathy. It is caused by FGD4 mutations and characterized by early infantile onset, slowly progressive distal muscle weakness, scoliosis, and myelin outfoldings visible in nerve biopsy samples. Here, we report a 65-year-old male born to consanguineous parents, who carries a novel homozygous FGD4 c.724C>T nonsense mutation. He developed lower limb weakness in his teens, which progressed slowly and was accompanied by diplopia, bilateral hearing loss, and erectile dysfunction from his twenties. At the age of 65, he was wheelchair-bound and had mild scoliosis, bilateral ophthalmoplegia, facial muscle weakness, inner ear hearing loss, distal-dominant weakness, and sensory disturbance, but no cognitive deterioration. Magnetic resonance imaging revealed enlarged bilateral trigeminal and facial nerves. Accordingly, we believe that this mutation causes slowly progressive sensorimotor neuropathy with apparent cranial nerve involvement, thereby further expanding the clinical spectrum of CMT4H.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Proteínas de Microfilamentos/genética , Mutación/genética , Anciano , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Predisposición Genética a la Enfermedad , Humanos , Masculino , Linaje , Fenotipo , Nervio Sural/patologíaRESUMEN
Charcot-Marie-Tooth disease type 4H (CMT4H) is an autosomal recessive demyelinating subtype of peripheral enuropathies caused by mutations in the FGD4 gene. Most CMT4H patients are in consanguineous Mediterranean families characterized by early onset and slow progression. We identified two CMT4H patients from a Korean CMT cohort, and performed a detailed genetic and clinical analysis in both cases. Both patients from nonconsanguineous families showed characteristic clinical manifestations of CMT4H including early onset, scoliosis, areflexia, and slow disease progression. Exome sequencing revealed novel compound heterozygous mutations in FGD4 as the underlying cause in both families (p.Arg468Gln and c.1512-2A>C in FC73, p.Met345Thr and c.2043+1G>A (p.Trp663Trpfs*30) in FC646). The missense mutations were located in highly conserved RhoGEF and PH domains which were predicted to be pathogenic in nature by in silico modeling. The CMT4H occurrence frequency was calculated to 0.7% in the Korean demyelinating CMT patients. This study is the first report of CMT4H in Korea. FGD4 assay could be considered as a means of molecular diagnosis for sporadic cases of demyelinating CMT with slow progression.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Proteínas de Microfilamentos/genética , Secuencia de Aminoácidos , Pueblo Asiatico/genética , Análisis Mutacional de ADN , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación , Linaje , República de Corea , Adulto JovenRESUMEN
Charcot-Marie-Tooth disease type 4H (CMT4H) is an autosomal recessive demyelinating neuropathy. It presents as infancy or early childhood-onset neuropathy associated with FGD4 mutations. Clinically it causes predominantly distal muscle weakness. On nerve biopsy examination, myelin outfoldings are seen. The previous case reports have been from regions bordering the Mediterranean, as well as a family from Northern Ireland. This paper presents the detailed clinical course of the first reported case of CMT4H in a Japanese woman. The patient showed mild weakness without scoliosis and a severe sensory disturbance; her functional impairment was less severe than the previously published cases. In addition, a novel homozygous FGD4 c.837-1G>A mutation was identified in this patient.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Proteínas de Microfilamentos/genética , Mutación/genética , Enfermedad de Charcot-Marie-Tooth/patología , Femenino , Humanos , Japón , Fibras Nerviosas Mielínicas/patología , Fibras Nerviosas Mielínicas/ultraestructura , Nervio Sural/patología , Nervio Sural/ultraestructura , Adulto JovenRESUMEN
Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogenous group of disorders. Useful classifi cation is still clinical and electrophysiological classifi cation that divides CMT into CMT type 1 - demyelinating form and CMT type 2 - axonal form. An intermediate type is also increasingly being determined. Inheritance can be autosomal dominant, X-linked and autosomal recessive (AR). In this review, we will focus on the clinical and/or electrophysiological findings and molecular genetics of ARCMT1 (CMT4). Ten genes, GDAP1, MTMR2, MTMR13, SH3TC2, NDRG1, EGR2, PRX, CTDP1, FGD4 and SAC3 have been identifi ed in the CMT4A, CMT4B1, CMT4B2, CMT4C, CMT4D, CMT4E, CMT4F, CCFDN, CMT4H and CMT4J types, respectively. In addition, susceptibility locus on chromosome 10q23 has been found for CMT4G disease. Molecular genetics of demyelinating ARCMT are large disabilities of proteins in Schwann cells and their functions (transcriptional factor, protein transport, protein sorting, intra/extra cellular compartments, signal transduction, cell division, and cell differentiation). It has been rising necessary requirements to defi ne clinical and genetic subtypes of the ARCMT1, prevent from disease, give reproductive and genetic counselling, and develop methods for reducing and clear disease risk factor.