Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency

Mariska Davids; Minal Menezes; Yiran Guo; Scott D McLean; Hakon Hakonarson; Felicity Collins; Lisa Worgan; Charles J Billington Jr; Irina Maric; Rebecca Okashah Littlejohn; Tito Onyekweli; Members Of The Udn; David R Adams; Cynthia J Tifft; William A Gahl; Lynne A Wolfe; John Christodoulou; May Christine V Malicdan

doi:10.1016/j.ymgme.2020.02.005

Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency

Mol Genet Metab. 2020 May;130(1):49-57. doi: 10.1016/j.ymgme.2020.02.005. Epub 2020 Feb 10.

Authors

Mariska Davids¹, Minal Menezes², Yiran Guo³, Scott D McLean⁴, Hakon Hakonarson³, Felicity Collins⁵, Lisa Worgan⁶, Charles J Billington Jr¹, Irina Maric⁷, Rebecca Okashah Littlejohn⁴, Tito Onyekweli¹, Members Of The Udn⁸, David R Adams⁹, Cynthia J Tifft⁹, William A Gahl¹⁰, Lynne A Wolfe⁹, John Christodoulou¹¹, May Christine V Malicdan¹²

Affiliations

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 Undiagnosed Diseases Network, Common Fund, Office of the Director, 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.
¹⁰ 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.
¹¹ 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: [email protected].
¹² 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: [email protected].

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.

Keywords: Early infantile epileptic encephalopathy 38; Endoplasmic reticulum; GPI-anchor synthesis; Rare disease.

Publication types

Case Reports
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Abnormalities, Multiple / genetics*
Abnormalities, Multiple / physiopathology
Adolescent
Alternative Splicing / genetics
Carrier Proteins / genetics*
Carrier Proteins / metabolism*
Child, Preschool
Developmental Disabilities / genetics*
Developmental Disabilities / physiopathology
Epilepsy / genetics*
Epilepsy / physiopathology
Exome Sequencing
Female
Fibroblasts / metabolism
GPI-Linked Proteins / metabolism
Glycosylphosphatidylinositols / biosynthesis
Glycosylphosphatidylinositols / deficiency*
Homozygote
Humans
Infant
Infant, Newborn
Intellectual Disability / genetics*
Male
Membrane Proteins / genetics*
Membrane Proteins / metabolism*
Mutation
Neutrophils / metabolism
Pedigree

Substances

ARV1 protein, human
Carrier Proteins
GPI-Linked Proteins
Glycosylphosphatidylinositols
Membrane Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding