Glycosylphosphatidylinositol (GPI) anchor deficiency caused by mutations in<i>PIGW</i>is associated with West syndrome and hyperphosphatasia with mental retardation syndrome

Chiyonobu, Tomohiro; Inoue, Norimitsu; Morimoto, Masafumi; Kinoshita, Taroh; Murakami, Yoshiko

doi:10.1136/jmedgenet-2013-102156

Cited by 93 publications

(83 citation statements)

References 19 publications

(15 reference statements)

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“…Biallelic mutations in the PIGW gene were found in a Japanese boy with early-onset epilepsy initially diagnosed as West syndrome ( 111 ). He was born to nonconsanguineous healthy parents and showed profound developmental delay and constantly elevated serum ALP levels, as well as seizures.…”

Section: Deacylation Of Inositol From Nascent Gpi-apsmentioning

confidence: 99%

“…Functional activity of mutant PIG-Ws can be measured by determining their ability to restore cell surface expression of GPI-APs after transfection into PIGW -defective CHO cells ( 42 ). Both mutant PIG-Ws had greatly decreased activity in this assay ( 111 ). It was apparent that these loss-of-function PIGW mutations caused decreases in the cell surface levels of GPI-APs and affected proper functions of neuronal cells and other cells.…”

Section: Deacylation Of Inositol From Nascent Gpi-apsmentioning

confidence: 99%

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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

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225

165

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Section: Deacylation Of Inositol From Nascent Gpi-apsmentioning

confidence: 99%

Section: Deacylation Of Inositol From Nascent Gpi-apsmentioning

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

Self Cite

225

165

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“…1a) [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. Inherited congenital deficiencies in GPI anchor biosynthesis and attachment comprise a subset of congenital disorders of glycosylation (CDGs) and cause a spectrum of symptoms in humans, including seizures, intellectual disabilities, and congenital anomalies.…”

mentioning

confidence: 99%

Expanding the clinical and molecular characteristics of PIGT-CDG, a disorder of glycosylphosphatidylinositol anchors

Lam

Golas

Davids

et al. 2015

Molecular Genetics and Metabolism

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PIGT-CDG, an autosomal recessive syndromic intellectual disability disorder of glycosylphosphatidylinositol (GPI) anchors, was recently described in two independent kindreds [Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 3 (OMIM, #615398)]. PIGT encodes phosphatidylinositol-glycan biosynthesis class T, a subunit of the heteropentameric transamidase complex that facilitates the transfer of GPI to proteins. GPI facilitates attachment (anchoring) of proteins to cell membranes. We describe, at ages 7 and 6 years, two children of non-consanguineous parents; they had hypotonia, severe global developmental delay, and intractable seizures along with endocrine, ophthalmologic, skeletal, hearing, and cardiac anomalies. Exome sequencing revealed that both siblings had compound heterozygous variants in PIGT (NM_015937.5), i.e., c.918dupC, a novel duplication leading to a frameshift, and c.1342C> T encoding a previously described missense variant. Flow cytometry studies showed decreased surface expression of GPI-anchored proteins on granulocytes, consistent with findings in previous cases. These siblings further delineate the clinical spectrum of PIGT-CDG, reemphasize the neuro-ophthalmologic presentation, clarify the endocrine features, and add hypermobility, low CSF albumin quotient, and hearing loss to the phenotypic spectrum. Our results emphasize that GPI anchor-related congenital disorders of glycosylation (CDGs) should be considered in subjects with early onset severe seizure disorders and dysmorphic facial features, even in the presence of a normal carbohydrate-deficient transferrin pattern and N-glycan profiling. Currently available screening for CDGs will not reliably detect this family of disorders, and our case reaffirms that the use of flow cytometry and genetic testing is essential for diagnosis in this group of disorders.

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“…For inherited GPIanchor deficiencies, IGDs, for example hyperphosphatasia was expected to be a hallmark feature. However, exome sequencing of large cohorts with patients with intellectual disability and epilepsies have also identified several novel cases with GPI-anchor deficiencies, but normal levels of alkaline phosphatase [11]. On the other hand, there were many symptoms present in these patients that fit very well to an IGD, such as muscular hypotonia, certain organ malformations, and skeletal abnormalities, but their expressivity is highly variable in this disorder.…”

Section: Phenotypic Overlapmentioning

confidence: 99%

Challenges ahead for matchmaking

Krawitz

2016

It - Information Technology

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With every additional individual whose genome is sequenced thousands of novel variants enter the scene. It is these variants of unknown clinical significance, VUCS, that represent a great challenge to geneticists, who are dealing with high-throughput sequencing data sets. Especially in diagnostics of patients with unknown monogenic disease the joint effort of geneticists is required to find new disease gene associations. For this purpose, online platforms for matchmaking have been developed that allow clinician scientists to collaborate worldwide and to share medically relevant data. However, for a success of these tools, skills in deep phenotyping as well as new statistical approaches will be required.

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Glycosylphosphatidylinositol (GPI) anchor deficiency caused by mutations inPIGWis associated with West syndrome and hyperphosphatasia with mental retardation syndrome

Abstract: Here we describe the first patient with deficiency of PIGW, which is involved in the addition of the acyl-chain to inositol in an early step of GPI biosynthesis. Therefore, IGD should be considered in West syndrome and flow cytometric analysis of blood cells is effective in screening IGD.

Cited by 93 publications

References 19 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

Expanding the clinical and molecular characteristics of PIGT-CDG, a disorder of glycosylphosphatidylinositol anchors

Challenges ahead for matchmaking

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