دورية أكاديمية
Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome.
| العنوان: | Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome. |
|---|---|
| المؤلفون: | Cousin MA; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA., Veale EL; Medway School of Pharmacy, University of Kent and University of Greenwich, Central Avenue, Anson Building, Central Avenue, Chatham Maritime, ME4 4, Kent, TB, ME4 4 TB, UK., Dsouza NR; Bioinformatics Research and Development Laboratory, Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI, USA., Tripathi S; Bioinformatics Research and Development Laboratory, Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI, USA., Holden RG; Medway School of Pharmacy, University of Kent and University of Greenwich, Central Avenue, Anson Building, Central Avenue, Chatham Maritime, ME4 4, Kent, TB, ME4 4 TB, UK., Arelin M; Department for Women and Child Health, Hospital for Children and Adolescents, University Hospitals, University of Leipzig, Leipzig, Germany., Beek G; Children's Hospital of Minnesota, Minneapolis, MN, USA., Bekheirnia MR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Beygo J; Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Bhambhani V; Children's Hospital of Minnesota, Minneapolis, MN, USA., Bialer M; Division of Medical Genetics, Northwell Health, Manhasset, NY, USA., Bigoni S; Medical Genetics Unit, Department of Medical Sciences, Ferrara University, Ferrara, Italy., Boelman C; Division of Neurology, BC Children's Hospital, Vancouver, British Columbia, Canada., Carmichael J; Oxford Centre for Genomic Medicine, ACE Building, Nuffield Orthopaedic centre, Oxford University Hospitals NHS Foundation Trust, Windmill road, Headington, Oxford, OX3 7HE, UK., Courtin T; Département of Genetics, APHP, Hôpital Pitié-Salpêtrière, Sorbonne Université, Paris, France., Cogne B; CHU Nantes, Service de génétique médicale, Nantes, France., Dabaj I; CHU de Rouen, Service de Néonatologie, Réanimation pédiatrique, Neuropédiatrie et éducation fonctionnelle de l'enfant, INSERM U 1245, ED497, 76000, Rouen, France.; APHP, Hôpital Raymond Poincaré, Hôpitaux Universitaires Paris Ile-de-France Ouest, Pôle pédiatrique, Service de Pédiatrie, Centre de Reference Nord-Est-Ile de France, 92380, Garches, France., Doummar D; APHP, Department of Neuropediatrics, National Reference Center for Neurogenetic Disorders, Hôpital Armand-Trousseau, GHUEP, Paris, France., Fazilleau L; Service de Néonatologie, CHU de Caen, Caen, France., Ferlini A; Medical Genetics Unit, Department of Medical Sciences, Ferrara University, Ferrara, Italy., Gavrilova RH; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA., Graham JM Jr; Department of Pediatrics, Harbor-UCLA Medical Center, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA., Haack TB; Centre for Rare Diseases, University of Tübingen, Tübingen, Germany.; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Juusola J; GeneDx, 207 Perry Parkway, Gaithersburg, MD, USA., Kant SG; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.; Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands., Kayani S; Departments of Pediatrics and Neurology, University of Texas Southwestern Medical Center and Children's Health, Dallas, TX, USA., Keren B; APHP, Département de Génétique et Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, 75651, Paris, France., Ketteler P; Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.; Pediatrics III, Pediatric Oncology and Hematology, University Hospital Essen, Essen, Germany., Klöckner C; Institute of Human Genetics, University of Leipzig Medical Center, 04103, Leipzig, Germany., Koopmann TT; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands., Kruisselbrink TM; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA., Kuechler A; Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Lambert L; Service de Genetique Clinique, CHRU de Nancy, F-54000, Vandoeuvre-les-Nancy, France.; Unite INSERM N-GERE UMR_S 1256, Université de Lorraine, Faculté de Médecine, 9 avenue de la Forêt de Haye, CS 50184, Vandoeuvre-les-Nancy, France., Latypova X; CHU Nantes, Service de génétique médicale, Nantes, France., Lebel RR; Section of Medical Genetics, SUNY Upstate University Hospital, Syracuse, NY, USA., Leduc MS; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Leonardi E; Molecular Genetics of Neurodevelopmental Disorders, Department of Woman and Child Health, University of Padova, Padua, Italy.; Pediatric Research Institute, Città della Speranza, Padova, Italy., Lewis AM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Liew W; Department of Paediatric Medicine, KK Women's and Children's Hospital, Mount Elizabeth Hospital, Singapore, Singapore., Machol K; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Hospital, Houston, TX, USA., Mardini S; Division of Plastic and Reconstructive Surgery, Mayo Clinic, Rochester, MN, USA., McWalter K; GeneDx, 207 Perry Parkway, Gaithersburg, MD, USA., Mignot C; APHP, Département de Génétique et Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, 75651, Paris, France., McLaughlin J; Division of Medical Genetics, Northwell Health, Manhasset, NY, USA., Murgia A; Molecular Genetics of Neurodevelopmental Disorders, Department of Woman and Child Health, University of Padova, Padua, Italy.; Pediatric Research Institute, Città della Speranza, Padova, Italy., Narayanan V; Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ, USA., Nava C; APHP, Département de Génétique et Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, 75651, Paris, France., Neuser S; Institute of Human Genetics, University of Leipzig Medical Center, 04103, Leipzig, Germany., Nizon M; CHU Nantes, Service de génétique médicale, Nantes, France., Ognibene D; Medical Genetics Unit, Department of Medical Sciences, Ferrara University, Ferrara, Italy., Park J; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Platzer K; Institute of Human Genetics, University of Leipzig Medical Center, 04103, Leipzig, Germany., Poirsier C; Department of Genetics, Reims University Hospital, Reims, France., Radtke M; Institute of Human Genetics, University of Leipzig Medical Center, 04103, Leipzig, Germany., Ramsey K; Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ, USA., Runke CK; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA., Guillen Sacoto MJ; GeneDx, 207 Perry Parkway, Gaithersburg, MD, USA., Scaglia F; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Hospital, Houston, TX, USA.; Joint BCM-CUHK Center of Medical Genetics, Shatin, Hong Kong SAR., Shinawi M; Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MT, USA., Spranger S; Practice of Human Genetics, Bremen, Germany., Tan ES; Department of Paediatric Medicine, KK Women's and Children's Hospital, Mount Elizabeth Hospital, Singapore, Singapore., Taylor J; Oxford Centre for Genomic Medicine, ACE Building, Nuffield Orthopaedic centre, Oxford University Hospitals NHS Foundation Trust, Windmill road, Headington, Oxford, OX3 7HE, UK., Trentesaux AS; Service de Néonatologie, CHU de Caen, Caen, France., Vairo F; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA., Willaert R; GeneDx, 207 Perry Parkway, Gaithersburg, MD, USA., Zadeh N; Genetics Center, Orange, CA, USA.; Division of Medical Genetics, CHOC Children's Hospital, Orange, CA, USA., Urrutia R; Bioinformatics Research and Development Laboratory, Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.; Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA., Babovic-Vuksanovic D; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA., Zimmermann MT; Bioinformatics Research and Development Laboratory, Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI, USA. mtzimmermann@mcw.edu.; Clinical and Translational Sciences Institute, Medical College of Wisconsin, Human Research Center, Milwaukee, Wl, USA. mtzimmermann@mcw.edu.; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA. mtzimmermann@mcw.edu., Mathie A; Medway School of Pharmacy, University of Kent and University of Greenwich, Central Avenue, Anson Building, Central Avenue, Chatham Maritime, ME4 4, Kent, TB, ME4 4 TB, UK. a.a.mathie@kent.ac.uk.; School of Engineering, Arts, Science and Technology, University of Suffolk, Ipswich, UK. a.a.mathie@kent.ac.uk., Klee EW; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA. klee.eric@mayo.edu.; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA. klee.eric@mayo.edu.; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA. klee.eric@mayo.edu. |
| المصدر: | Genome medicine [Genome Med] 2022 Jun 13; Vol. 14 (1), pp. 62. Date of Electronic Publication: 2022 Jun 13. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: BioMed Central Country of Publication: England NLM ID: 101475844 Publication Model: Electronic Cited Medium: Internet ISSN: 1756-994X (Electronic) Linking ISSN: 1756994X NLM ISO Abbreviation: Genome Med Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [London] : BioMed Central |
| مواضيع طبية MeSH: | Intellectual Disability*/genetics , Potassium Channels, Tandem Pore Domain*/genetics , Potassium Channels, Tandem Pore Domain*/metabolism, Genotype ; Humans ; Muscle Hypotonia ; Mutation ; Phenotype |
| مستخلص: | Background: Genomics enables individualized diagnosis and treatment, but large challenges remain to functionally interpret rare variants. To date, only one causative variant has been described for KCNK9 imprinting syndrome (KIS). The genotypic and phenotypic spectrum of KIS has yet to be described and the precise mechanism of disease fully understood. Methods: This study discovers mechanisms underlying KCNK9 imprinting syndrome (KIS) by describing 15 novel KCNK9 alterations from 47 KIS-affected individuals. We use clinical genetics and computer-assisted facial phenotyping to describe the phenotypic spectrum of KIS. We then interrogate the functional effects of the variants in the encoded TASK3 channel using sequence-based analysis, 3D molecular mechanic and dynamic protein modeling, and in vitro electrophysiological and functional methodologies. Results: We describe the broader genetic and phenotypic variability for KIS in a cohort of individuals identifying an additional mutational hotspot at p.Arg131 and demonstrating the common features of this neurodevelopmental disorder to include motor and speech delay, intellectual disability, early feeding difficulties, muscular hypotonia, behavioral abnormalities, and dysmorphic features. The computational protein modeling and in vitro electrophysiological studies discover variability of the impact of KCNK9 variants on TASK3 channel function identifying variants causing gain and others causing loss of conductance. The most consistent functional impact of KCNK9 genetic variants, however, was altered channel regulation. Conclusions: This study extends our understanding of KIS mechanisms demonstrating its complex etiology including gain and loss of channel function and consistent loss of channel regulation. These data are rapidly applicable to diagnostic strategies, as KIS is not identifiable from clinical features alone and thus should be molecularly diagnosed. Furthermore, our data suggests unique therapeutic strategies may be needed to address the specific functional consequences of KCNK9 variation on channel function and regulation. (© 2022. The Author(s).) |
| References: | PLoS One. 2011 Jan 28;6(1):e15827. (PMID: 21297978) Genet Med. 2015 May;17(5):405-24. (PMID: 25741868) Biophys J. 2009 Jul 8;97(1):50-8. (PMID: 19580743) Nucleic Acids Res. 2009 Jul;37(Web Server issue):W510-4. (PMID: 19429685) Nat Methods. 2010 Apr;7(4):248-9. (PMID: 20354512) Hum Mutat. 2015 Oct;36(10):928-30. (PMID: 26220891) Nat Genet. 2019 Jan;51(1):88-95. (PMID: 30531870) Bioinformatics. 2000 Jun;16(6):566-7. (PMID: 10980157) Nat Med. 2019 Jan;25(1):60-64. (PMID: 30617323) Mol Syst Biol. 2011 Oct 11;7:539. (PMID: 21988835) J Mol Graph. 1996 Feb;14(1):33-8, 27-8. (PMID: 8744570) Nucleic Acids Res. 2003 Jul 1;31(13):3316-9. (PMID: 12824316) Physiol Rev. 2010 Apr;90(2):559-605. (PMID: 20393194) Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W382-8. (PMID: 15980494) Nature. 2020 May;581(7809):434-443. (PMID: 32461654) BMC Biol. 2012 Oct 02;10:82. (PMID: 23031578) Science. 2012 Jan 27;335(6067):436-41. (PMID: 22282805) Genet Med. 2019 Jul;21(7):1611-1620. (PMID: 30504930) Am J Hum Genet. 2008 Aug;83(2):193-9. (PMID: 18678320) Nucleic Acids Res. 2000 Jan 1;28(1):235-42. (PMID: 10592235) Nucleic Acids Res. 2016 Jul 8;44(W1):W356-60. (PMID: 27131359) BMC Bioinformatics. 2008 Jan 23;9:40. (PMID: 18215316) Neuroscientist. 2018 Aug;24(4):368-380. (PMID: 29542386) Bioinformatics. 2011 Jun 15;27(12):1711-2. (PMID: 21505037) Genome Med. 2020 Dec 2;12(1):103. (PMID: 33261662) J Comput Chem. 2005 Dec;26(16):1781-802. (PMID: 16222654) Bioinformatics. 2006 Nov 1;22(21):2695-6. (PMID: 16940322) J Physiol. 2009 Oct 15;587(Pt 20):4769-83. (PMID: 19703964) Genome Res. 2007 Dec;17(12):1723-30. (PMID: 18055845) Cereb Cortex. 2014 Apr;24(4):1017-29. (PMID: 23236211) Science. 2012 Jan 27;335(6067):432-6. (PMID: 22282804) J Neurosci. 2001 Oct 1;21(19):7491-505. (PMID: 11567039) Nat Genet. 2018 Aug;50(8):1161-1170. (PMID: 30038395) J Comput Chem. 2008 Aug;29(11):1859-65. (PMID: 18351591) Brain Res. 2011 Oct 6;1416:69-79. (PMID: 21885038) Protein Sci. 2018 Jan;27(1):112-128. (PMID: 28836357) Eur J Med Genet. 2020 Jan;63(1):103619. (PMID: 30690205) J Pharmacol Exp Ther. 2007 Dec;323(3):924-34. (PMID: 17875609) Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10037-41. (PMID: 11517324) Bioinformatics. 2021 Jun 16;37(10):1367-1375. (PMID: 33226070) J Biol Chem. 2000 Mar 31;275(13):9340-7. (PMID: 10734076) Nat Commun. 2020 Jan 24;11(1):480. (PMID: 31980599) Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17546-51. (PMID: 19805135) Nucleic Acids Res. 2019 Jan 8;47(D1):D886-D894. (PMID: 30371827) J Biomol NMR. 1996 Dec;8(4):477-86. (PMID: 9008363) J Biol Chem. 2000 Jun 2;275(22):16650-7. (PMID: 10747866) Mol Pharmacol. 2014 Mar;85(3):397-407. (PMID: 24342771) Genet Med. 2021 Mar;23(3):498-507. (PMID: 33144682) Genome Res. 2001 May;11(5):863-74. (PMID: 11337480) Nat Methods. 2014 Apr;11(4):361-2. (PMID: 24681721) J Physiol. 2007 Jan 15;578(Pt 2):377-85. (PMID: 17068099) Nature. 2020 Jun;582(7812):443-447. (PMID: 32499642) Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3422-7. (PMID: 16492788) Annu Rev Pharmacol Toxicol. 2021 Jan 6;61:401-420. (PMID: 32679007) Am J Med Genet A. 2016 Oct;170(10):2632-7. (PMID: 27151206) Biophys J. 2007 Mar 1;92(5):1503-11. (PMID: 17158570) Nucleic Acids Res. 2013 Jul;41(Web Server issue):W597-600. (PMID: 23671338) Pharmacol Rev. 2005 Dec;57(4):527-40. (PMID: 16382106) Bioinformatics. 2014 Sep 1;30(17):i505-11. (PMID: 25161240) J Physiol. 2019 Feb;597(4):1087-1101. (PMID: 30365877) Curr Opin Genet Dev. 2020 Dec;65:69-75. (PMID: 32599522) Science. 1998 Apr 3;280(5360):69-77. (PMID: 9525859) Mol Pharmacol. 2007 Jun;71(6):1666-75. (PMID: 17374744) |
| فهرسة مساهمة: | Keywords: Computational protein modeling; Electrophysiology; KCNK9 imprinting syndrome; Neurodevelopmental disorder; TASK3 channel |
| المشرفين على المادة: | 0 (KCNK9 protein, human) 0 (Potassium Channels, Tandem Pore Domain) |
| تواريخ الأحداث: | Date Created: 20220613 Date Completed: 20220615 Latest Revision: 20220716 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC9195326 |
| DOI: | 10.1186/s13073-022-01064-4 |
| PMID: | 35698242 |
| قاعدة البيانات: | MEDLINE |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 1756-994X |
|---|---|
| DOI: | 10.1186/s13073-022-01064-4 |