Evidence map›Paper›PMID 32165008›Full record

ArticleMolecular genetics and metabolism2020

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, Irina Maric, Rebecca Okashah Littlejohn and 8 more

Registry-linked trialOpen access · greenAbstract readCase Reports
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular genetics and metabolism, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02450851 (Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network), which is not on this map. Cited by 13 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
13citing papers in PubMed, 1 pooled it
2.2field-weighted citation impact, top 10% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT02450851 recruitingnot on this map

Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network

TypeobservationalSponsorNational Human Genome Research Institute (NHGRI)Ran2015 to 2028Enrolled20,000ConditionsGenetic Disease
3 · Its place in the literature

Who cites it

13 citing papers in PubMed, 1 synthesis or guideline pooled it, 23 citations in OpenAlex.

  1. Pooled it
  2. Insights intomSphere · 2026
    Article
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  13. Arv1; a "Mover and Shaker" of Subcellular Lipids.Contact (Thousand Oaks (Ventura County, Calif.))
    Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors at 9 institutions in 2 countries.

Mariska DavidsNIH Undiagnosed Diseases Program, Common Fund, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Minal MenezesGenetic 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.
Yiran GuoCenter for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Scott D McLeanDepartment of Clinical Genetics, The Children's Hospital of San Antonio, San Antonio, TX, USA.
Hakon HakonarsonCenter for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Felicity CollinsDiscipline 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.
Lisa WorganDepartment of Clinical Genetics, Liverpool Hospital, Liverpool, NSW, Australia.
Charles J BillingtonNIH Undiagnosed Diseases Program, Common Fund, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Irina MaricHematology Service, Clinical Center, NIH, Bethesda, MD, USA.
Rebecca Okashah LittlejohnDepartment of Clinical Genetics, The Children's Hospital of San Antonio, San Antonio, TX, USA.
Tito OnyekweliNIH Undiagnosed Diseases Program, Common Fund, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Members Of The UdnUndiagnosed Diseases Network, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
David R AdamsNIH 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.
Cynthia J TifftNIH 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.
William A GahlNIH 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.
Lynne A WolfeNIH 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.
John ChristodoulouGenetic 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.
May Christine V MalicdanNIH 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.
National Human Genome Research Institute · USNational Institutes of Health · USChildren's Hospital of Philadelphia · USChildren's Hospital of San Antonio · USUniversity of Sydney · AULiverpool Hospital · AUMurdoch Children's Research Institute · AUNational Institutes of Health Clinical Center · USOffice of the Director · US

Funding

Human Biochemical GeneticsZ01HG000215 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI GAHL, WILLIAM ALLEN · 2003 to 2008
$10.2M
Heterogenity in Patients with Congenital GlycosylatioinZ01HG000100 · NHGRI · HUMAN GENOME RESEARCH · PI GAHL, WILLIAM ALLEN · 1997 to 2007
$297k
Intramural NIH HHS Z01 HG000100Intramural NIH HHS Z01 HG000215
6 · The paper itself

Abstract

backgroundMutations 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.

methodsMutations 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.

resultsHere 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.

conclusionLoss 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.

Indexed as

Abnormalities, MultipleAdolescentAlternative SplicingCarrier ProteinsChild, PreschoolDevelopmental DisabilitiesEpilepsyExome SequencingFemaleFibroblastsGlycosylphosphatidylinositolsGPI-Linked ProteinsHomozygoteHumansInfantInfant, NewbornARV1 protein, humanCarrier ProteinsGlycosylphosphatidylinositolsGPI-Linked ProteinsMembrane ProteinsEarly infantile epileptic encephalopathy 38Endoplasmic reticulumGPI-anchor synthesisRare disease

Identifiers

PMID32165008
PMCPMC7303973
OpenAlexW3005905307

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.