Ute I Scholl1, Haatal B Dave2, Ming Lu1, Anita Farhi1, Carol Nelson-Williams1, James A Listman2, Richard P Lifton3,4. 1. Departments of Genetics and Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, 300 Cedar Street, New Haven, CT, 06510, USA. 2. Department of Pediatrics, SUNY Upstate Medical University, 750 E. Adams St., Syracuse, NY, 13210, USA. 3. Departments of Genetics and Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, 300 Cedar Street, New Haven, CT, 06510, USA. richard.lifton@yale.edu. 4. Departments of Genetics and Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, 333 Cedar St., SHM I308, New Haven, CT, 06510, USA. richard.lifton@yale.edu.
Abstract
BACKGROUND: Mutations in the K(+) channel KCNJ10 (Kir4.1) cause an autosomal recessive syndrome featuring seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME). Kir4.1 localizes to the basolateral membrane of the renal distal convoluted tubule, and its loss of function mimics renal features of Gitelman syndrome, with hypokalemic alkalosis, hypomagnesemia, and hypocalciuria. Presentation early in life due to seizures provides an opportunity to investigate the development of the electrolyte defect with age. METHODS: We used DNA sequencing, electrophysiology, confocal imaging, and biochemistry to identify a new KCNJ10 mutation in a previously unreported family and determine its impact on channel function. We examined medical records to follow the development of electrolyte disorders with age. RESULTS: The four affected members were all homozygous for a novel T57I mutation that confers biochemical loss-of-function. Electrolytes in affected children were normal in the first years of life but showed significant worsening with age, resulting in clinically significant defects at age 5-8 years. Similar findings were seen in other SeSAME patients. CONCLUSIONS: These findings provide evidence for a delayed activity of salt reabsorption by the distal convoluted tubule and suggest an explanation for the delayed clinical presentation of subjects with Gitelman syndrome.
BACKGROUND: Mutations in the K(+) channel KCNJ10 (Kir4.1) cause an autosomal recessive syndrome featuring seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME). Kir4.1 localizes to the basolateral membrane of the renal distal convoluted tubule, and its loss of function mimics renal features of Gitelman syndrome, with hypokalemic alkalosis, hypomagnesemia, and hypocalciuria. Presentation early in life due to seizures provides an opportunity to investigate the development of the electrolyte defect with age. METHODS: We used DNA sequencing, electrophysiology, confocal imaging, and biochemistry to identify a new KCNJ10 mutation in a previously unreported family and determine its impact on channel function. We examined medical records to follow the development of electrolyte disorders with age. RESULTS: The four affected members were all homozygous for a novel T57I mutation that confers biochemical loss-of-function. Electrolytes in affected children were normal in the first years of life but showed significant worsening with age, resulting in clinically significant defects at age 5-8 years. Similar findings were seen in other SeSAMEpatients. CONCLUSIONS: These findings provide evidence for a delayed activity of salt reabsorption by the distal convoluted tubule and suggest an explanation for the delayed clinical presentation of subjects with Gitelman syndrome.
Authors: D B Simon; F E Karet; J Rodriguez-Soriano; J H Hamdan; A DiPietro; H Trachtman; S A Sanjad; R P Lifton Journal: Nat Genet Date: 1996-10 Impact factor: 38.330
Authors: D N Cruz; D B Simon; C Nelson-Williams; A Farhi; K Finberg; L Burleson; J R Gill; R P Lifton Journal: Hypertension Date: 2001-06 Impact factor: 10.190
Authors: Maria D Lalioti; Junhui Zhang; Heather M Volkman; Kristopher T Kahle; Kristin E Hoffmann; Hakan R Toka; Carol Nelson-Williams; David H Ellison; Richard Flavell; Carmen J Booth; Yin Lu; David S Geller; Richard P Lifton Journal: Nat Genet Date: 2006-09-10 Impact factor: 38.330
Authors: Ute I Scholl; Murim Choi; Tiewen Liu; Vincent T Ramaekers; Martin G Häusler; Joanne Grimmer; Sheldon W Tobe; Anita Farhi; Carol Nelson-Williams; Richard P Lifton Journal: Proc Natl Acad Sci U S A Date: 2009-03-16 Impact factor: 11.205
Authors: D B Simon; C Nelson-Williams; M J Bia; D Ellison; F E Karet; A M Molina; I Vaara; F Iwata; H M Cushner; M Koolen; F J Gainza; H J Gitleman; R P Lifton Journal: Nat Genet Date: 1996-01 Impact factor: 38.330
Authors: A Bettinelli; M G Bianchetti; E Girardin; A Caringella; M Cecconi; A C Appiani; L Pavanello; R Gastaldi; C Isimbaldi; G Lama Journal: J Pediatr Date: 1992-01 Impact factor: 4.406
Authors: Matias Morin; Anna-Lena Forst; Paula Pérez-Torre; Adriano Jiménez-Escrig; Verónica Barca-Tierno; Eva García-Galloway; Richard Warth; Jose Luis Lopez-Sendón Moreno; Miguel Angel Moreno-Pelayo Journal: Neurogenetics Date: 2020-02-15 Impact factor: 2.660
Authors: Mario Van Poucke; Kimberley Stee; Sofie F M Bhatti; An Vanhaesebrouck; Leslie Bosseler; Luc J Peelman; Luc Van Ham Journal: Eur J Hum Genet Date: 2016-12-14 Impact factor: 4.246