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

doi:10.1016/j.ymgme.2020.02.005

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

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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.

Original language	English (US)
Pages (from-to)	49-57
Number of pages	9
Journal	Molecular Genetics and Metabolism
Volume	130
Issue number	1
DOIs	https://doi.org/10.1016/j.ymgme.2020.02.005
State	Published - May 2020
Externally published	Yes

Bibliographical note

Funding Information:
The authors would like to thank all patients and their families for their participation in this research. We also thank Yan Huang for establishing primary fibroblast cultures and for sample preparations. This research was in part supported by the Intramural Research Program of the National Human Genome Research Institute and the NIH Office of the Director's Common Fund . The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government‘s Operational Infrastructure Support Program . Whole Exome Sequencing of two case samples (Family II) and Sanger validation of eight samples, including relevant bioinformatics data analysis was supported by an Institutional Development Award to the Center of Applied Genomics from The Children's Hospital of Philadelphia .

Funding Information:
The authors would like to thank all patients and their families for their participation in this research. We also thank Yan Huang for establishing primary fibroblast cultures and for sample preparations. This research was in part supported by the Intramural Research Program of the National Human Genome Research Institute and the NIH Office of the Director's Common Fund. The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government‘s Operational Infrastructure Support Program. Whole Exome Sequencing of two case samples (Family II) and Sanger validation of eight samples, including relevant bioinformatics data analysis was supported by an Institutional Development Award to the Center of Applied Genomics from The Children's Hospital of Philadelphia.

Publisher Copyright:
© 2020

Keywords

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

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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

Davids, M, Menezes, M, Guo, Y, McLean, SD, Hakonarson, H, Collins, F, Worgan, L, Billington, CJ, Maric, I, Littlejohn, RO, Onyekweli, T, Members of the UDN, OTUDN, Adams, DR, Tifft, CJ, Gahl, WA, Wolfe, LA, Christodoulou, J & Malicdan, MCV 2020, 'Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency', Molecular Genetics and Metabolism, vol. 130, no. 1, pp. 49-57. https://doi.org/10.1016/j.ymgme.2020.02.005

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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",

author = "Mariska Davids and Minal Menezes and Yiran Guo and McLean, {Scott D.} and Hakon Hakonarson and Felicity Collins and Lisa Worgan and Billington, {Charles J.} and Irina Maric and Littlejohn, {Rebecca Okashah} and Tito Onyekweli and {Members of the UDN}, {of the UDN} and Adams, {David R.} and Tifft, {Cynthia J.} and Gahl, {William A.} and Wolfe, {Lynne A.} and John Christodoulou and Malicdan, {May Christine V.}",

note = "Funding Information: The authors would like to thank all patients and their families for their participation in this research. We also thank Yan Huang for establishing primary fibroblast cultures and for sample preparations. This research was in part supported by the Intramural Research Program of the National Human Genome Research Institute and the NIH Office of the Director's Common Fund . The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government{\textquoteleft}s Operational Infrastructure Support Program . Whole Exome Sequencing of two case samples (Family II) and Sanger validation of eight samples, including relevant bioinformatics data analysis was supported by an Institutional Development Award to the Center of Applied Genomics from The Children's Hospital of Philadelphia . Funding Information: The authors would like to thank all patients and their families for their participation in this research. We also thank Yan Huang for establishing primary fibroblast cultures and for sample preparations. This research was in part supported by the Intramural Research Program of the National Human Genome Research Institute and the NIH Office of the Director's Common Fund. The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government{\textquoteleft}s Operational Infrastructure Support Program. Whole Exome Sequencing of two case samples (Family II) and Sanger validation of eight samples, including relevant bioinformatics data analysis was supported by an Institutional Development Award to the Center of Applied Genomics from The Children's Hospital of Philadelphia. Publisher Copyright: {\textcopyright} 2020",

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AU - Hakonarson, Hakon

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N2 - 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.

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

Abstract

Bibliographical note

Keywords

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