Mutations in the Glycosylphosphatidylinositol Gene PIGL Cause CHIME Syndrome

Ng, Bobby G.; Hackmann, Karl; Jones, Melanie A.; Eroshkin, Alexey; He, Ping; Wiliams, Roy; Bhide, Shruti; Cantagrel, Vincent; Gleeson, Joseph G.; Paller, Amy S.; Schnur, Rhonda E.; Tinschert, Sigrid; Zunich, Janice; Hegde, Madhuri; Freeze, Hudson H.

doi:10.1016/j.ajhg.2012.02.010

Cited by 117 publications

(92 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In cells defective in early steps in the GPI biosynthetic pathway, GPI transamidase action to preproproteins is less effi cient and preproproteins are degraded by ER-associated degradation. Indeed, hyperphosphatasia does not occur, or occurs only mildly, in PIGA -, PIGQ -, and PIGL -defi ciencies (119)(120)(121). Balance between degradation and secretion due to cleavage by GPI transamidase seems to be affected by other unknown factors, such as genetic backgrounds, because highly elevated hyperphosphatasia associated with PIGL -defi ciency was recently reported ( 122 ).…”

Section: Defi Ciency In Pgap1mentioning

confidence: 99%

Thematic Review Series: Glycosylphosphatidylinositol (GPI) Anchors: Biochemistry and Cell Biology Biosynthesis of GPI-anchored proteins: special emphasis on GPI lipid remodeling

Kinoshita

Fujita

2016

Journal of Lipid Research

232

165

View full text Add to dashboard Cite

Section: Defi Ciency In Pgap1mentioning

confidence: 99%

Thematic Review Series: Glycosylphosphatidylinositol (GPI) Anchors: Biochemistry and Cell Biology Biosynthesis of GPI-anchored proteins: special emphasis on GPI lipid remodeling

Kinoshita

Fujita

2016

Journal of Lipid Research

232

165

View full text Add to dashboard Cite

“…Therefore, it is obvious that perturbations resulting in altered GPIanchored protein traffi cking, as well as plasma membrane organization, can lead to several diseases. Recent studies have shown that the genes involved in the biosynthesis of GPI-anchored proteins are linked with various diseases because the fully processed GPI anchor is essential for the proper functioning, as well as targeting, of the protein ( 9,(103)(104)(105)(106). Mutations in GPI remodeling enzymes, like PGAP3, are known to generate intellectual disorders, like hyperphosphatasia ( 9 ), and deletion of this gene results in impaired T cell receptor signaling ( 107 ).…”

Section: Physiological Relevance Of Gpi-anchored Protein Structure Anmentioning

confidence: 99%

GPI-anchored protein organization and dynamics at the cell surface

Saha

Anilkumar

Mayor

2016

Journal of Lipid Research

View full text Add to dashboard Cite

of the protein called glycosylphosphatidylinositol (GPI)-anchored proteins. The basic structure of a GPI-anchored protein consists of phosphatidylinositol (PI) linked to an unusual non-N -acetyl glucosamine, which, in turn, is linked to three mannose residues followed by an ethanolamine covalently linked to the protein via an amide linkage (EtNP-6Man ␣ 1-2Man ␣ 1-6Man ␣ 1-4GlcN ␣ 1-6 myo inositolphospholipid, Fig. 1A ). Depending on the species and functional context, there may exist variations in the side chain associated with the glycan core. These have been summarized in ( 1 ). The lipid moiety is necessary for the incorporation of GPI-anchored proteins into so-called lipid rafts/microdomains ( 2, 3 ), which can serve as a sorting station for a number of cell signaling molecules, thereby functioning as a reaction center. GPI-anchored proteins can exist in different forms depending on the context and the tissue in which they are expressed. Alternate splicing can cause the same protein to exhibit TM, soluble, or GPI-anchored forms; for example, neural cell adhesion molecule (NCAM) can exist in its GPI-anchored and soluble form when expressed in muscles; whereas, it takes up a TM form instead of the soluble form in brain. GPI anchoring of proteins occurs at the luminal face of The plasma membrane of the cell is comprised of a diverse set of proteins, many of which are transmembrane (TM) proteins spanning the entire bilayer, but a significant proportion of proteins are also lipid tethered, containing a complex glycan core attached to the C terminus

show abstract

“…15 Several genes known to be involved in the GPI anchor biosynthesis (PIGA, PIGL, PIGN, PIGT, PIGV, PIGO, PIGW and PIGQ) and modeling (PGAP2 and PGAP3) are implicated in X-linked and autosomal recessive intellectual disability disorders. [16][17][18][19][20][21][22][23][24][25][26] Additional features such as seizures, congenital abnormalities and facial dysmorphisms are commonly present. Moreover, CVI has been reported in individuals with PIGA, PIGN and PIGT variants, suggesting that the GPI anchor biosynthesis is important in the development of the visual areas of the brain.…”

Section: Introductionmentioning

confidence: 99%

Cerebral visual impairment and intellectual disability caused by PGAP1 variants

et al. 2015

View full text Add to dashboard Cite

Homozygous variants in PGAP1 (post-GPI attachment to proteins 1) have recently been identified in two families with developmental delay, seizures and/or spasticity. PGAP1 is a member of the glycosylphosphatidylinositol anchor biosynthesis and remodeling pathway and defects in this pathway are a subclass of congenital disorders of glycosylation. Here we performed whole-exome sequencing in an individual with cerebral visual impairment (CVI), intellectual disability (ID), and factor XII deficiency and revealed compound heterozygous variants in PGAP1, c.274_276del (p.(Pro92del)) and c.921_925del (p.(Lys308Asnfs*25)). Subsequently, PGAP1-deficient Chinese hamster ovary (CHO)-cell lines were transfected with either mutant or wild-type constructs and their sensitivity to phosphatidylinositol-specific phospholipase C (PI-PLC) treatment was measured. The mutant constructs could not rescue the PGAP1-deficient CHO cell lines resistance to PI-PLC treatment. In addition, lymphoblastoid cell lines (LCLs) of the affected individual showed no sensitivity to PI-PLC treatment, whereas the LCLs of the heterozygous carrier parents were partially resistant. In conclusion, we report novel PGAP1 variants in a boy with CVI and ID and a proven functional loss of PGAP1 and show, to our knowledge, for the first time this genetic association with CVI. INTRODUCTIONCerebral visual impairment (CVI) accounts for 27% of the visual impairment in children, and is due to a disorder in projection and/or interpretation of the visual input in the brain. 1-3 Acquired damages, for example, due to preterm birth, are well known causes of CVI, whereas genetic factors are largely unidentified. 4 Several chromosomal aberrations have been associated with CVI, such as Phelan-McDermid syndrome (22q13.3 deletion) and 1p36 microdeletion syndrome. 5 Moreover, single-gene disorders can be implicated in CVI, and, recently, we identified de novo variants in NR2F1 as a cause of CVI. 6 In addition, in several congenital disorders of glycosylation (CDG type 1a, type 1q and type 1v) CVI has been reported. 4,[7][8][9] Glycosylation disorders are caused by a defect in the glycosylation of glycoproteins and glycolipids, and one subclass is the defect in glycosylphosphatidylinositol (GPI) anchor glycosylation. 10 GPI anchor many cell-surface proteins with various functions, so called GPI-anchored proteins (GPI-APs), to the membrane of eukaryotic cells. 11-13 GPI is synthesized in the endoplasmic reticulum, transferred to the proteins, and remodeled. During the biosynthesis of GPI anchors, an acyl chain is linked to the inositol. This acyl chain is a transient structure and is necessary for efficient completion of later steps in GPI biosynthesis. After the attachment of GPI to the protein, this acyl chain is removed by PGAP1 (post-GPI attachment to proteins 1), the first step of the remodeling phase. 14 Subsequently, the GPI anchor is transported from the endoplasmic reticulum to the plasma membrane through the Golgi apparatus and further remodeled. When the inositol-linked...

show abstract

Mutations in the Glycosylphosphatidylinositol Gene PIGL Cause CHIME Syndrome

Cited by 117 publications

References 14 publications

Thematic Review Series: Glycosylphosphatidylinositol (GPI) Anchors: Biochemistry and Cell Biology Biosynthesis of GPI-anchored proteins: special emphasis on GPI lipid remodeling

Thematic Review Series: Glycosylphosphatidylinositol (GPI) Anchors: Biochemistry and Cell Biology Biosynthesis of GPI-anchored proteins: special emphasis on GPI lipid remodeling

GPI-anchored protein organization and dynamics at the cell surface

Cerebral visual impairment and intellectual disability caused by PGAP1 variants

Contact Info

Product

Resources

About