Association of genetic variants in NEDD4L with blood pressure responses to dietary salt and potassium intake / 西安交通大学学报(医学版)

【Objective】 4-like protein with down-regulated expression and development in neural precursor cells (NEDD4L) plays an important role in blood pressure (BP) regulation and sodium homeostasis by regulating epithelial sodium channel protein. In this study, we aimed to explore the relationship of NEDD4L gene polymorphisms with BP responses to sodium and potassium intake. 【Methods】 In 2004, 514 subjects from 124 families in Meixian County, Shaanxi Province, were recruited to establish a salt-sensitive hypertension study cohort. All the subjects received a 3-day baseline survey, a 7-day low-salt diet, a 7-day high-salt diet, and finally a 7-day high-salt and potassium supplementation. Their BP was measured and peripheral blood samples were collected at different intervention periods. The 14 gene polymorphisms of NEDD4L gene were genotyped and analyzed by MassARRAY platform. 【Results】 BP decreased on a low-salt diet, and significantly increased on a high-salt diet, and decreased again after potassium supplementation. NEDD4L SNPs rs74408486 were significantly associated with systolic BP, diastolic BP and mean arterial pressure responses to the low-salt diet. SNPs rs292449 and rs2288775 were significantly associated with pulse pressure response to the high-salt diet. In addition, SNPs rs563283 and rs292449 were significantly associated with diastolic BP, mean arterial pressure, and pulse pressure responses to high-salt and potassium supplementation diet. 【Conclusion】 NEDD4L gene polymorphisms were significantly associated with BP responses to sodium and potassium intake, suggesting that NEDD4L gene may be involved in the development of salt sensitivity and potassium sensitivity.

PTPRN mediates endocytosis of NaV1.2 sodium chan-nels and suppresses epileptogenesis in mice / 中国药理学与毒理学杂志

Epilepsy is a disorder of the brain charac-terized by abnormal neuron excitability.However,the underlying molecular mechanism of neuron excitability modulation remains elusive.With the help of bioinformatic methods,we have identified receptor-type tyrosine-pro-tein phosphatase-like N(PTPRN)as a critical gene dur-ing epileptogenesis.PTPRN recruits NEDD4L ubiquitin E3 ligase to NaV1.2 sodium channels,facilitating NEDD4L-mediated ubiquitination and endocytosis.Knockout of PTPRN endows hippocampal granule cells with augmented depolarization currents and higher intrinsic excitability,which is reflected by increased seizure susceptibility of transgenic mice.On the contrary,reduced neuron excit-ability and decreased seizure susceptibility are observed after PTPRN overexpression.Meanwhile,we find that a 133 aa fragment recaptures modulation effect of PTPRN full-length,and this fragment shows therapeutic potential towards epilepsy caused by NaV1.2 gain of function vari-ants.In brief,our results demonstrate PTPRN playsa criti-calroleinregulatingneuronexcitability,providing a poten-tial therapeutic approach for epilepsy.

Clinical and genetic analysis of a patient with periventricular nodular heterotopia 7 caused by NEDD4L gene variant / 中华医学遗传学杂志

Objective@#To explore the genetic basis of a patient featuring global developmental delay, intellectual disability, cleft palate, seizures and hypotonia.@*Methods@#Clinical examination and laboratory tests were carried out. Peripheral blood samples were obtained from the patient and his parents. Whole genomic DNA was extracted and subjected to next generation sequencing. Candidate variation was analyzed by using bioinformatic software and validated by Sanger sequencing.@*Results@#The proband was found to carry a heterozygous c. 2117T>C (p.Leu706Pro) variant of the NEDD4L gene, which was a de novo variant validated by Sanger sequencing and predicted to be likely pathogenic according to the American College of Medical Genetics Guidelines.@*Conclusion@#The heterozygous variant of c. 2117T>C (p.Leu706Pro) of the NEDD4L gene probably underlies the disorders in the patient.