The Experts below are selected from a list of 3510 Experts worldwide ranked by ideXlab platform
S. Gallati - One of the best experts on this subject based on the ideXlab platform.
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A novel mutation in BCS1L associated with deafness, Tubulopathy, growth retardation and microcephaly
European Journal of Pediatrics, 2016Co-Authors: C. B. Jackson, M. F. Bauer, A. Schaller, U. Kotzaeridou, A. Ferrarini, D. Hahn, H. Chehade, F. Barbey, C. Tran, S. GallatiAbstract:We report a novel homozygous missense mutation in the ubiquinol-cytochrome c reductase synthesis-like ( BCS1L ) gene in two consanguineous Turkish families associated with deafness, Fanconi syndrome (Tubulopathy), microcephaly, mental and growth retardation. All three patients presented with transitory metabolic acidosis in the neonatal period and development of persistent renal de Toni-Debré-Fanconi-type Tubulopathy, with subsequent rachitis, short stature, microcephaly, sensorineural hearing impairment, mild mental retardation and liver dysfunction. The novel missense mutation c.142A>G (p.M48V) in BCS1L is located at a highly conserved region associated with sorting to the mitochondria. Biochemical analysis revealed an isolated complex III deficiency in skeletal muscle not detected in fibroblasts. Native polyacrylamide gel electrophoresis (PAGE) revealed normal super complex formation, but a shift in mobility of complex III most likely caused by the absence of the BCS1L-mediated insertion of Rieske Fe/S protein into complex III. These findings expand the phenotypic spectrum of BCS1L mutations, highlight the importance of biochemical analysis of different primary affected tissue and underline that neonatal lactic acidosis with multi-organ involvement may resolve after the newborn period with a relatively spared neurological outcome and survival into adulthood. Conclusion : Mutation screening for BCS1L should be considered in the differential diagnosis of severe (proximal) Tubulopathy in the newborn period. What is Known: • Mutations in BCS1L cause mitochondrial complex III deficiencies . • Phenotypic presentations of defective BCS1L range from Bjornstad to neonatal GRACILE syndrome . What is New: • Description of a novel homozygous mutation in BCS1L with transient neonatal acidosis and persistent de Toni-Debré-Fanconi-type Tubulopathy . • The long survival of patients with phenotypic presentation of severe complex III deficiency is uncommon.
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A novel mutation in BCS1L associated with deafness, Tubulopathy, growth retardation and microcephaly.
European journal of pediatrics, 2015Co-Authors: C. B. Jackson, M. F. Bauer, A. Schaller, U. Kotzaeridou, A. Ferrarini, D. Hahn, H. Chehade, F. Barbey, C. Tran, S. GallatiAbstract:We report a novel homozygous missense mutation in the ubiquinol-cytochrome c reductase synthesis-like (BCS1L) gene in two consanguineous Turkish families associated with deafness, Fanconi syndrome (Tubulopathy), microcephaly, mental and growth retardation. All three patients presented with transitory metabolic acidosis in the neonatal period and development of persistent renal de Toni-Debre-Fanconi-type Tubulopathy, with subsequent rachitis, short stature, microcephaly, sensorineural hearing impairment, mild mental retardation and liver dysfunction. The novel missense mutation c.142A>G (p.M48V) in BCS1L is located at a highly conserved region associated with sorting to the mitochondria. Biochemical analysis revealed an isolated complex III deficiency in skeletal muscle not detected in fibroblasts. Native polyacrylamide gel electrophoresis (PAGE) revealed normal super complex formation, but a shift in mobility of complex III most likely caused by the absence of the BCS1L-mediated insertion of Rieske Fe/S protein into complex III. These findings expand the phenotypic spectrum of BCS1L mutations, highlight the importance of biochemical analysis of different primary affected tissue and underline that neonatal lactic acidosis with multi-organ involvement may resolve after the newborn period with a relatively spared neurological outcome and survival into adulthood.
Markus Reichold - One of the best experts on this subject based on the ideXlab platform.
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The salt-wasting phenotype of EAST syndrome, a disease with multifaceted symptoms linked to the KCNJ10 K^+ channel
Pflügers Archiv - European Journal of Physiology, 2011Co-Authors: Sascha Bandulik, Detlef Bockenhauer, Anselm A. Zdebik, Katharina Schmidt, Evelyn Humberg, Robert Kleta, Richard Warth, Markus ReicholdAbstract:Mutations in the K^+ channel gene KCNJ10 (Kir4.1) cause the autosomal recessive EAST syndrome which is characterized by epilepsy, ataxia, sensorineural deafness, and a salt-wasting Tubulopathy. The renal salt-wasting pathology of EAST syndrome is caused by transport defects in the distal convoluted tubule where KCNJ10 plays a pivotal role as a basolateral K^+ channel. This review on EAST syndrome outlines the molecular aspects of the physiology and pathophysiology of KCNJ10 in the distal convoluted tubule.
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Epilepsy, ataxia, sensorineural deafness, Tubulopathy, and KCNJ10 mutations.
The New England journal of medicine, 2009Co-Authors: Detlef Bockenhauer, Sally Feather, Horia Stanescu, Sascha Bandulik, Anselm A. Zdebik, Markus Reichold, Jonathan Tobin, E Lieberer, Christina Sterner, Guida LandouréAbstract:Background Five children from two consanguineous families presented with epilepsy beginning in infancy and severe ataxia, moderate sensorineural deafness, and a renal salt-losing Tubulopathy with normotensive hypokalemic metabolic alkalosis. We investigated the genetic basis of this autosomal recessive disease, which we call the EAST syndrome (the presence of epilepsy, ataxia, sensorineural deafness, and Tubulopathy). Methods Whole-genome linkage analysis was performed in the four affected children in one of the families. Newly identified mutations in a potassium-channel gene were evaluated with the use of a heterologous expression system. Protein expression and function were further investigated in genetically modified mice. Results Linkage analysis identified a single significant locus on chromosome 1q23.2 with a lod score of 4.98. This region contained the KCNJ10 gene, which encodes a potassium channel expressed in the brain, inner ear, and kidney. Sequencing of this candidate gene revealed homozygous ...
Nathalie Godefroid - One of the best experts on this subject based on the ideXlab platform.
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Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness
Journal of the American Society of Nephrology, 2021Co-Authors: Karl P. Schlingmann, Aparna Renigunta, Ewout J. Hoorn, Anna-lena Forst, Vijay Renigunta, Velko Atanasov, Sinthura Mahendran, Tahsin Stefan Barakat, Valentine Gillion, Nathalie GodefroidAbstract:BackgroundThe transepithelial transport of electrolytes, solutes, and water in the kidney is a well-orchestrated process involving numerous membrane transport systems. Basolateral potassium channels in tubular cells not only mediate potassium recycling for proper Na+,K+-ATPase function but are also involved in potassium and pH sensing. Genetic defects in KCNJ10 cause EAST/SeSAME syndrome, characterized by renal salt wasting with hypokalemic alkalosis associated with epilepsy, ataxia, and sensorineural deafness.MethodsA candidate gene approach and whole-exome sequencing determined the underlying genetic defect in eight patients with a novel disease phenotype comprising a hypokalemic Tubulopathy with renal salt wasting, disturbed acid-base homeostasis, and sensorineural deafness. Electrophysiologic studies and surface expression experiments investigated the functional consequences of newly identified gene variants.ResultsWe identified mutations in the KCNJ16 gene encoding KCNJ16, which along with KCNJ15 and KCNJ10, constitutes the major basolateral potassium channel of the proximal and distal tubules, respectively. Coexpression of mutant KCNJ16 together with KCNJ15 or KCNJ10 in Xenopus oocytes significantly reduced currents.ConclusionsBiallelic variants in KCNJ16 were identified in patients with a novel disease phenotype comprising a variable proximal and distal Tubulopathy associated with deafness. Variants affect the function of heteromeric potassium channels, disturbing proximal tubular bicarbonate handling as well as distal tubular salt reabsorption.
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Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness.
Journal of the American Society of Nephrology : JASN, 2021Co-Authors: Karl P. Schlingmann, Aparna Renigunta, Ewout J. Hoorn, Anna-lena Forst, Vijay Renigunta, Velko Atanasov, Sinthura Mahendran, Tahsin Stefan Barakat, Valentine Gillion, Nathalie GodefroidAbstract:The transepithelial transport of electrolytes, solutes, and water in the kidney is a well-orchestrated process involving numerous membrane transport systems. Basolateral potassium channels in tubular cells not only mediate potassium recycling for proper Na+,K+-ATPase function but are also involved in potassium and pH sensing. Genetic defects in KCNJ10 cause EAST/SeSAME syndrome, characterized by renal salt wasting with hypokalemic alkalosis associated with epilepsy, ataxia, and sensorineural deafness. A candidate gene approach and whole-exome sequencing determined the underlying genetic defect in eight patients with a novel disease phenotype comprising a hypokalemic Tubulopathy with renal salt wasting, disturbed acid-base homeostasis, and sensorineural deafness. Electrophysiologic studies and surface expression experiments investigated the functional consequences of newly identified gene variants. We identified mutations in the KCNJ16 gene encoding KCNJ16, which along with KCNJ15 and KCNJ10, constitutes the major basolateral potassium channel of the proximal and distal tubules, respectively. Coexpression of mutant KCNJ16 together with KCNJ15 or KCNJ10 in Xenopus oocytes significantly reduced currents. Biallelic variants in KCNJ16 were identified in patients with a novel disease phenotype comprising a variable proximal and distal Tubulopathy associated with deafness. Variants affect the function of heteromeric potassium channels, disturbing proximal tubular bicarbonate handling as well as distal tubular salt reabsorption. Copyright © 2021 by the American Society of Nephrology.
Hannsjörg W. Seyberth - One of the best experts on this subject based on the ideXlab platform.
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hypokalemic salt losing Tubulopathy with chronic renal failure and sensorineural deafness
Pediatrics, 2001Co-Authors: Nikola Jeck, Stephan C Reinalter, Thomas Henne, Wolfgang Marg, Rudolf Mallmann, Katharina Pasel, Martin Vollmer, Gunter Klaus, Andreas Leonhardt, Hannsjörg W. SeyberthAbstract:Objective. To characterize a rare inherited hypokalemic salt-losing Tubulopathy with linkage to chromosome 1p31. Methods. We conducted a retrospective analysis of the clinical data for 7 patients in whom cosegregation of the disease with chromosome 1p31 had been demonstrated. In addition, in 1 kindred, prenatal diagnosis in the second child was established, allowing a prospective clinical evaluation. Results. Clinical presentation of the patients was homogeneous and included premature birth attributable to polyhydramnios, severe renal salt loss, normotensive hyperreninemia, hypokalemic alkalosis, and excessive hyperprostaglandin E-uria, which suggested the diagnosis of hyperprostaglandin E syndrome/antenatal Bartter syndrome. However, the response to indomethacin was only poor, accounting for a more severe variant of the disease. The patients invariably developed chronic renal failure. The majority had extreme growth retardation, and motor development was markedly delayed. In addition, all patients turned out to be deaf. Conclusion. The hypokalemic salt-losing Tubulopathy with chronic renal failure and sensorineural deafness represents not only genetically but also clinically a disease entity distinct from hyperprostaglandin E syndrome/antenatal Bartter syndrome. A pleiotropic effect of a single gene defect is most likely causative for syndromic hearing loss.
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Hereditary hypokalemic salt-losing tubulopathies
Channelopathies, 2000Co-Authors: Nikola Jeck, Martin Konrad, Hannsjörg W. SeyberthAbstract:Publisher Summary The combination of autosomal recessively transmitted hypokalemic alkalosis and normotensive hyperalsosteronism is termed as Bartter syndrome. Three main phenotypical variants of this syndrome are described in this chapter: the classical Batter syndrome; the hypomagnesemic hypocalciuric, Gitelman syndrome; and the antenatal, hypercalciuric hyperprostaglandin E syndrome. The chapter describes the clinical features, genetics, pathogenesis, diagnosis, and therapy of the three variants. The hypocalciuric hypomagnesemic Gitelman syndrome is described functionally as a thiazide-like salt-losing Tubulopathy (TSLT) because renal salt is relatively mild in this disorder. Affected individuals present fatigue, muscle weakness, tetany, carpopedal spasms, obstipation, chondrocalcinosis, and small stature. Hyperprostaglandin E syndrome is described as a furosemide-like salt-losing Tubulopathy (FSLT). The onset of this disorder is typically prenatal. Fetal polyuria leads to the development of a polyhydraminos around the fifth month of pregnancy, which naturally results in premature birth. Classic Bartter syndrome with intermediate clinical features is classified as Bartter-like salt-losing Tubulopathy (BSLT). This disorder is characterized by hypokalemic alkalosis. Four causative genes have been identified each indicating different mechanisms for disease pathogenesis. In two of the genes, SLC12A1 and KCNJ1 , encoding the NA-K-2Cl cotranspoter type 2 and the inwardly rectifying potassium channel ROMK, loss of function mutations are found that exert urine concentration disturbances corresponding to the diuretic effects of furosemide. Mutations in the third gene, SLC12A3 , encoding the NaCl cotranspoter of the distal convoluted tubule, resemble thiazide effects, while the phenotype due to defective chloride channel C1C-Kb can mimic both diuretic substances.
Sascha Bandulik - One of the best experts on this subject based on the ideXlab platform.
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The salt-wasting phenotype of EAST syndrome, a disease with multifaceted symptoms linked to the KCNJ10 K^+ channel
Pflügers Archiv - European Journal of Physiology, 2011Co-Authors: Sascha Bandulik, Detlef Bockenhauer, Anselm A. Zdebik, Katharina Schmidt, Evelyn Humberg, Robert Kleta, Richard Warth, Markus ReicholdAbstract:Mutations in the K^+ channel gene KCNJ10 (Kir4.1) cause the autosomal recessive EAST syndrome which is characterized by epilepsy, ataxia, sensorineural deafness, and a salt-wasting Tubulopathy. The renal salt-wasting pathology of EAST syndrome is caused by transport defects in the distal convoluted tubule where KCNJ10 plays a pivotal role as a basolateral K^+ channel. This review on EAST syndrome outlines the molecular aspects of the physiology and pathophysiology of KCNJ10 in the distal convoluted tubule.
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Epilepsy, ataxia, sensorineural deafness, Tubulopathy, and KCNJ10 mutations.
The New England journal of medicine, 2009Co-Authors: Detlef Bockenhauer, Sally Feather, Horia Stanescu, Sascha Bandulik, Anselm A. Zdebik, Markus Reichold, Jonathan Tobin, E Lieberer, Christina Sterner, Guida LandouréAbstract:Background Five children from two consanguineous families presented with epilepsy beginning in infancy and severe ataxia, moderate sensorineural deafness, and a renal salt-losing Tubulopathy with normotensive hypokalemic metabolic alkalosis. We investigated the genetic basis of this autosomal recessive disease, which we call the EAST syndrome (the presence of epilepsy, ataxia, sensorineural deafness, and Tubulopathy). Methods Whole-genome linkage analysis was performed in the four affected children in one of the families. Newly identified mutations in a potassium-channel gene were evaluated with the use of a heterologous expression system. Protein expression and function were further investigated in genetically modified mice. Results Linkage analysis identified a single significant locus on chromosome 1q23.2 with a lod score of 4.98. This region contained the KCNJ10 gene, which encodes a potassium channel expressed in the brain, inner ear, and kidney. Sequencing of this candidate gene revealed homozygous ...
