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, Tito Onyekweli, of the UDN Members of the UDN, David R. Adams, Cynthia J. Tifft, William A. Gahl, Lynne A. Wolfe, John Christodoulou, May Christine V. Malicdan

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3 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)49-57
Number of pages9
JournalMolecular Genetics and Metabolism
Issue number1
StatePublished - May 2020
Externally publishedYes


  • Early infantile epileptic encephalopathy 38
  • Endoplasmic reticulum
  • GPI-anchor synthesis
  • Rare disease

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Intramural
  • Research Support, N.I.H., Extramural

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    Davids, M., Menezes, M., Guo, Y., McLean, S. D., Hakonarson, H., Collins, F., Worgan, L., Billington, C. J., Maric, I., Littlejohn, R. O., Onyekweli, T., Members of the UDN, O. T. UDN., Adams, D. R., Tifft, C. J., Gahl, W. A., Wolfe, L. A., Christodoulou, J., & Malicdan, M. C. V. (2020). Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency. Molecular Genetics and Metabolism, 130(1), 49-57. https://doi.org/10.1016/j.ymgme.2020.02.005