Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency.
Abnormalities, Multiple
/ genetics
Adolescent
Alternative Splicing
/ genetics
Carrier Proteins
/ genetics
Child, Preschool
Developmental Disabilities
/ genetics
Epilepsy
/ genetics
Female
Fibroblasts
/ metabolism
GPI-Linked Proteins
/ metabolism
Glycosylphosphatidylinositols
/ biosynthesis
Homozygote
Humans
Infant
Infant, Newborn
Intellectual Disability
/ genetics
Male
Membrane Proteins
/ genetics
Mutation
Neutrophils
/ metabolism
Pedigree
Exome Sequencing
Early infantile epileptic encephalopathy 38
Endoplasmic reticulum
GPI-anchor synthesis
Rare disease
Journal
Molecular genetics and metabolism
ISSN: 1096-7206
Titre abrégé: Mol Genet Metab
Pays: United States
ID NLM: 9805456
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
21
10
2019
revised:
15
01
2020
accepted:
07
02
2020
pubmed:
14
3
2020
medline:
9
2
2021
entrez:
14
3
2020
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 32165008
pii: S1096-7192(20)30055-X
doi: 10.1016/j.ymgme.2020.02.005
pmc: PMC7303973
mid: NIHMS1574779
pii:
doi:
Substances chimiques
ARV1 protein, human
0
Carrier Proteins
0
GPI-Linked Proteins
0
Glycosylphosphatidylinositols
0
Membrane Proteins
0
Types de publication
Case Reports
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
49-57Subventions
Organisme : Intramural NIH HHS
ID : Z01 HG000100
Pays : United States
Organisme : Intramural NIH HHS
ID : Z01 HG000215
Pays : United States
Informations de copyright
Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.
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