Mariska Davids1, Minal Menezes2, Yiran Guo3, Scott D McLean4, Hakon Hakonarson3, Felicity Collins5, Lisa Worgan6, Charles J Billington1, Irina Maric7, Rebecca Okashah Littlejohn4, Tito Onyekweli1, David R Adams8, Cynthia J Tifft8, William A Gahl9, Lynne A Wolfe8, John Christodoulou10, May Christine V Malicdan11. 1. NIH Undiagnosed Diseases Program, Common Fund, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. 2. Genetic Metabolic Disorders Research Unit, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Child and Adolescent Health and Genomic Medicine, Sydney Medical School, Sydney University, Sydney, NSW, Australia. 3. Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. 4. Department of Clinical Genetics, The Children's Hospital of San Antonio, San Antonio, TX, USA. 5. Discipline of Child and Adolescent Health and Genomic Medicine, Sydney Medical School, Sydney University, Sydney, NSW, Australia; Department of Clinical Genetics, Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, NSW, Australia. 6. Department of Clinical Genetics, Liverpool Hospital, Liverpool, NSW, Australia. 7. Hematology Service, Clinical Center, NIH, Bethesda, MD, USA. 8. NIH Undiagnosed Diseases Program, Common Fund, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. 9. NIH Undiagnosed Diseases Program, Common Fund, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. 10. Genetic Metabolic Disorders Research Unit, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Child and Adolescent Health and Genomic Medicine, Sydney Medical School, Sydney University, Sydney, NSW, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Pediatrics, Melbourne Medical School, University of Melbourne, Melbourne, VIC, Australia. Electronic address: john.christodoulou@mcri.edu.au. 11. NIH Undiagnosed Diseases Program, Common Fund, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: malicdanm@mail.nih.gov.
Abstract
BACKGROUND: Mutations in the ARV1 Homolog, Fatty Acid Homeostasis Modulator (ARV1), have recently been described in association with early infantile epileptic encephalopathy 38. Affected individuals presented with epilepsy, ataxia, profound intellectual disability, visual impairment, and central hypotonia. In S. cerevisiae, Arv1 is thought to be involved in sphingolipid metabolism and glycophosphatidylinositol (GPI)-anchor synthesis. The function of ARV1 in human cells, however, has not been elucidated. METHODS: Mutations were discovered through whole exome sequencing and alternate splicing was validated on the cDNA level. Expression of the variants was determined by qPCR and Western blot. Expression of GPI-anchored proteins on neutrophils and fibroblasts was analyzed by FACS and immunofluorescence microscopy, respectively. RESULTS: Here we describe seven patients from two unrelated families with biallelic splice mutations in ARV1. The patients presented with early onset epilepsy, global developmental delays, profound hypotonia, delayed speech development, cortical visual impairment, and severe generalized cerebral and cerebellar atrophy. The splice variants resulted in decreased ARV1 expression and significant decreases in GPI-anchored protein on the membranes of neutrophils and fibroblasts, indicating that the loss of ARV1 results in impaired GPI-anchor synthesis. CONCLUSION: Loss of GPI-anchored proteins on our patients' cells confirms that the yeast Arv1 function of GPI-anchor synthesis is conserved in humans. Overlap between the phenotypes in our patients and those reported for other GPI-anchor disorders suggests that ARV1-deficiency is a GPI-anchor synthesis disorder. Crown
BACKGROUND: Mutations in the ARV1 Homolog, Fatty Acid Homeostasis Modulator (ARV1), have recently been described in association with early infantile epileptic encephalopathy 38. Affected individuals presented with epilepsy, ataxia, profound intellectual disability, visual impairment, and central hypotonia. In S. cerevisiae, Arv1 is thought to be involved in sphingolipid metabolism and glycophosphatidylinositol (GPI)-anchor synthesis. The function of ARV1 in human cells, however, has not been elucidated. METHODS: Mutations were discovered through whole exome sequencing and alternate splicing was validated on the cDNA level. Expression of the variants was determined by qPCR and Western blot. Expression of GPI-anchored proteins on neutrophils and fibroblasts was analyzed by FACS and immunofluorescence microscopy, respectively. RESULTS: Here we describe seven patients from two unrelated families with biallelic splice mutations in ARV1. The patients presented with early onset epilepsy, global developmental delays, profound hypotonia, delayed speech development, cortical visual impairment, and severe generalized cerebral and cerebellar atrophy. The splice variants resulted in decreased ARV1 expression and significant decreases in GPI-anchored protein on the membranes of neutrophils and fibroblasts, indicating that the loss of ARV1 results in impaired GPI-anchor synthesis. CONCLUSION: Loss of GPI-anchored proteins on our patients' cells confirms that the yeastArv1 function of GPI-anchor synthesis is conserved in humans. Overlap between the phenotypes in our patients and those reported for other GPI-anchor disorders suggests that ARV1-deficiency is a GPI-anchor synthesis disorder. Crown
Authors: Oriol Forés; Montserrat Arró; Albert Pahissa; Sergi Ferrero; Melody Germann; Joseph Stukey; Virginia McDonough; Joseph T Nickels; Narciso Campos; Albert Ferrer Journal: Biochim Biophys Acta Date: 2006-04-19
Authors: Antonio M Almeida; Yoshiko Murakami; D Mark Layton; Peter Hillmen; Gabrielle S Sellick; Yusuke Maeda; Stephen Richards; Scott Patterson; Ioannis Kotsianidis; Luigina Mollica; Dorothy H Crawford; Alastair Baker; Michael Ferguson; Irene Roberts; Richard Houlston; Taroh Kinoshita; Anastasios Karadimitris Journal: Nat Med Date: 2006-06-11 Impact factor: 53.440
Authors: Malcolm F Howard; Yoshiko Murakami; Alistair T Pagnamenta; Cornelia Daumer-Haas; Björn Fischer; Jochen Hecht; David A Keays; Samantha J L Knight; Uwe Kölsch; Ulrike Krüger; Steffen Leiz; Yusuke Maeda; Daphne Mitchell; Stefan Mundlos; John A Phillips; Peter N Robinson; Usha Kini; Jenny C Taylor; Denise Horn; Taroh Kinoshita; Peter M Krawitz Journal: Am J Hum Genet Date: 2014-01-16 Impact factor: 11.025
Authors: Periklis Makrythanasis; Mitsuhiro Kato; Maha S Zaki; Hirotomo Saitsu; Kazuyuki Nakamura; Federico A Santoni; Satoko Miyatake; Mitsuko Nakashima; Mahmoud Y Issa; Michel Guipponi; Audrey Letourneau; Clare V Logan; Nicola Roberts; David A Parry; Colin A Johnson; Naomichi Matsumoto; Hanan Hamamy; Eamonn Sheridan; Taroh Kinoshita; Stylianos E Antonarakis; Yoshiko Murakami Journal: Am J Hum Genet Date: 2016-03-17 Impact factor: 11.025
Authors: Biljana Ilkovski; Alistair T Pagnamenta; Gina L O'Grady; Taroh Kinoshita; Malcolm F Howard; Monkol Lek; Brett Thomas; Anne Turner; John Christodoulou; David Sillence; Samantha J L Knight; Niko Popitsch; David A Keays; Consuelo Anzilotti; Anne Goriely; Leigh B Waddell; Fabienne Brilot; Kathryn N North; Noriyuki Kanzawa; Daniel G Macarthur; Jenny C Taylor; Usha Kini; Yoshiko Murakami; Nigel F Clarke Journal: Hum Mol Genet Date: 2015-08-20 Impact factor: 6.150
Authors: Hilary C Martin; Grace E Kim; Alistair T Pagnamenta; Yoshiko Murakami; Gemma L Carvill; Esther Meyer; Richard R Copley; Andrew Rimmer; Giulia Barcia; Matthew R Fleming; Jack Kronengold; Maile R Brown; Karl A Hudspith; John Broxholme; Alexander Kanapin; Jean-Baptiste Cazier; Taroh Kinoshita; Rima Nabbout; David Bentley; Gil McVean; Sinéad Heavin; Zenobia Zaiwalla; Tony McShane; Heather C Mefford; Deborah Shears; Helen Stewart; Manju A Kurian; Ingrid E Scheffer; Edward Blair; Peter Donnelly; Leonard K Kaczmarek; Jenny C Taylor Journal: Hum Mol Genet Date: 2014-01-25 Impact factor: 6.150