Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of end-stage renal failure. Identification of single-gene causes of SRNS has generated some insights into its pathogenesis; however, additional genes and disease mechanisms remain obscure, and SRNS continues to be treatment refractory. Here we have identified 6 different mutations in coenzyme Q 10 biosynthesis monooxygenase 6 (COQ6) in 13 individuals from 7 families by homozygosity mapping. Each mutation was linked to early-onset SRNS with sensorineural deafness. The deleterious effects of these human COQ6 mutations were validated by their lack of complementation in coq6-deficient yeast. Furthermore, knockdown of Coq6 in podocyte cell lines and coq6 in zebrafish embryos caused apoptosis that was partially reversed by coenzyme Q 10 treatment. In rats, COQ6 was located within cell processes and the Golgi apparatus of renal glomerular podocytes and in stria vascularis cells of the inner ear, consistent with an oto-renal disease phenotype. These data suggest that coenzyme Q 10 -related forms of SRNS and hearing loss can be molecularly identified and potentially treated.
BackgroundMutations in about 50 genes have been identified as monogenic causes of nephrotic syndrome, a frequent cause of CKD. These genes delineated the pathogenetic pathways and rendered significant insight into podocyte biology.MethodsWe used whole-exome sequencing to identify novel monogenic causes of steroid-resistant nephrotic syndrome (SRNS). We analyzed the functional significance of an SRNS-associated gene in vitro and in podocyte-like Drosophila nephrocytes.ResultsWe identified hemizygous missense mutations in the gene TBC1D8B in five families with nephrotic syndrome. Coimmunoprecipitation assays indicated interactions between TBC1D8B and active forms of RAB11. Silencing TBC1D8B in HEK293T cells increased basal autophagy and exocytosis, two cellular functions that are independently regulated by RAB11. This suggests that TBC1D8B plays a regulatory role by inhibiting endogenous RAB11. Coimmunoprecipitation assays showed TBC1D8B also interacts with the slit diaphragm protein nephrin, and colocalizes with it in immortalized cell lines. Overexpressed murine Tbc1d8b with patient-derived mutations had lower affinity for endogenous RAB11 and nephrin compared with wild-type Tbc1d8b protein. Knockdown of Tbc1d8b in Drosophila impaired function of the podocyte-like nephrocytes, and caused mistrafficking of Sns, the Drosophila ortholog of nephrin. Expression of Rab11 RNAi in nephrocytes entailed defective delivery of slit diaphragm protein to the membrane, whereas RAB11 overexpression revealed a partial phenotypic overlap to Tbc1d8b loss of function.ConclusionsNovel mutations in TBC1D8B are monogenic causes of SRNS. This gene inhibits RAB11. Our findings suggest that RAB11-dependent vesicular nephrin trafficking plays a role in the pathogenesis of nephrotic syndrome.
The aim of this study was to assess the association between metabolic control, microalbuminuria, and diabetic nephropathy with ambulatory blood pressure monitoring (ABPM) in normotensive individuals with type 1 diabetes mellitus (DM). ABPM was undertaken in 68 normotensive type 1 diabetic patients with a mean age of 14.4+/-4.2 years. Microalbuminuria was diagnosed on the basis of a urinary albumin excretion rate grater than 20 microg/min in two of the three 24-h urine collections. Hypertension (HT) frequency was greater in the microalbuminuric patients than normoalbuminuric patients (54 vs 17.54%, p=0.05) with ABPM. Microalbuminuric patients had a higher diastolic pressure burden than normoalbuminuric patients. There were no differences in systolic and diastolic dips between the two groups. Diastolic pressure loads in all periods showed a significant correlation with duration of diabetes, mean HbA1c from the onset of diabetes, and level of microalbuminuria. Nocturnal dipping was reduced in 41.2% of the patients. In the normoalbuminuric group 41.1% and in the microalbuminuric group 63.6% were nondippers. Our data demonstrate higher 24-h and daytime diastolic blood pressure load and loss of nocturnal dip in type 1 diabetic adolescents and children. High diastolic blood pressure burden in diabetic patients could represent a risk for nephropathy.
Gene polymorphism of IL-6 -174 G>C is a risk factor for PCOS in Turkish patients. IL-6 gene polymorphisms are not related to NO, MDA, and SH levels in PCOS. Our negative results in risks factors of CV disorders can probably be explained by the fact that metabolic parameters and endothelial systems of patients may not yet be affected in this short period of time.
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