Mutations in PGAP3 Impair GPI-Anchor Maturation, Causing a Subtype of Hyperphosphatasia with Mental Retardation

Howard, Malcolm F.; Murakami, Yoshiko; Pagnamenta, Alistair T.; Daumer‐Haas, Cornelia; Fischer, Björn; Hecht, Jochen; Keays, David A.; Knight, Samantha J. L.; Kölsch, Uwe; Krüger, Ulrike; Leiz, Steffen; Maeda, Yusuke; Mitchell, Daphne B.; Mundlos, Stefan; Phillips, John A.; Robinson, Peter N.; Kini, Usha; Taylor, Jenny C.; Horn, Denise; Kinoshita, Taroh; Krawitz, Peter

doi:10.1016/j.ajhg.2013.12.012

Cited by 98 publications

(124 citation statements)

References 26 publications

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“…57 Furthermore, humans with PGAP3 loss-of-function mutations present with neurological and renal phenotypes. 56,58 These experimental observations support our computational results. Figure 3.…”

Section: Kidney Eqtl Highlights the Genetics Of Disease Traitssupporting

confidence: 88%

“…The modification is crucial for linking GPIanchored proteins to lipid rafts, which plays an important role in protein sorting and trafficking. 56 One of the major phenotypes of Pgap3 knockout mice is progressive enlarged renal glomeruli with deposition of immune complexes and matrix expansion upon aging. 57 Furthermore, humans with PGAP3 loss-of-function mutations present with neurological and renal phenotypes.…”

Section: Kidney Eqtl Highlights the Genetics Of Disease Traitsmentioning

confidence: 99%

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Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease

Qiu

et al. 2017

The American Journal of Human Genetics

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Chronic kidney disease (CKD) is a complex gene-environmental disease affecting close to 10% of the US population. Genome-wide association studies (GWASs) have identified sequence variants, localized to non-coding genomic regions, associated with kidney function. Despite these robust observations, the mechanism by which variants lead to CKD remains a critical unanswered question. Expression quantitative trait loci (eQTL) analysis is a method to identify genetic variation associated with gene expression changes in specific tissue types. We hypothesized that an integrative analysis combining CKD GWAS and kidney eQTL results can identify candidate genes for CKD. We performed eQTL analysis by correlating genotype with RNA-seq-based gene expression levels in 96 human kidney samples. Applying stringent statistical criteria, we detected 1,886 genes whose expression differs with the sequence variants. Using direct overlap and Bayesian methods, we identified new potential target genes for CKD. With respect to one of the target genes, lysosomal beta A mannosidase (MANBA), we observed that genetic variants associated with MANBA expression in the kidney showed statistically significant colocalization with variants identified in CKD GWASs, indicating that MANBA is a potential target gene for CKD. The expression of MANBA was significantly lower in kidneys of subjects with risk alleles. Suppressing manba expression in zebrafish resulted in renal tubule defects and pericardial edema, phenotypes typically induced by kidney dysfunction. Our analysis shows that gene-expression changes driven by genetic variation in the kidney can highlight potential new target genes for CKD development.

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Section: Kidney Eqtl Highlights the Genetics Of Disease Traitssupporting

confidence: 88%

Section: Kidney Eqtl Highlights the Genetics Of Disease Traitsmentioning

confidence: 99%

Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease

Qiu

et al. 2017

The American Journal of Human Genetics

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“…This increase is due to diminished GPIAPs on the cell surface, resulting in less binding of ALP to the cell membrane and more ALP in the plasma. [22][23][24]40,41 ALP was not measured in the PGAP1-affected individuals, but in PGAP1-deficient cells, no diminished cell-surface expression of GPI-APs was measured, making elevated ALP levels less likely. 15 In addition, the typical facial dysmorphisms of Mabry syndrome, consisting of apparent hypertelorism, long palpebral fissures, short nose with broad nasal bridge and tip and tented upper lip vermillion, were not present in the here presented individual.…”

Section: Pi-plc Treatment and Facs Analysismentioning

confidence: 99%

“…[22][23][24] These individuals showed, in addition to ID, seizures, typical facial dysmorphisms and an increased alkaline phosphatase (ALP). This increase is due to diminished GPIAPs on the cell surface, resulting in less binding of ALP to the cell membrane and more ALP in the plasma.…”

Section: Pi-plc Treatment and Facs Analysismentioning

confidence: 99%

“…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%

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Cerebral visual impairment and intellectual disability caused by PGAP1 variants

et al. 2015

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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...

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Mutations in PIGL in a patient with Mabry syndrome

Fujiwara

Murakami

Niihori

et al. 2015

American J of Med Genetics Pt A

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Mabry syndrome, hyperphosphatasia mental retardation syndrome (HPMRS), is an autosomal recessive disease characterized by increased serum levels of alkaline phosphatase (ALP), severe developmental delay, intellectual disability, and seizures. Recent studies have revealed mutations in PIGV, PIGW, PIGO, PGAP2, and PGAP3 (genes that encode molecules of the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway) in patients with HPMRS. We performed whole-exome sequencing of a patient with severe intellectual disability, distinctive facial appearance, fragile nails, and persistent increased serum levels of ALP. The result revealed a compound heterozygote with a 13-bp deletion in exon 1 (c.36_48del) and a two-base deletion in exon 2 (c.254_255del) in phosphatidylinositol glycan anchor, class L (PIGL) that caused frameshifts resulting in premature terminations. The 13-bp deletion was inherited from the father, and the two-base deletion was inherited from the mother. Expressing c.36_48del or c.254_255del cDNA with an HA-tag at the C- or N-terminus in PIGL-deficient CHO cells only partially restored the surface expression of GPI-anchored proteins (GPI-APs). Nonsynonymous changes or frameshift mutations in PIGL have been identified in patients with CHIME syndrome, a rare autosomal recessive disorder characterized by colobomas, congenital heart defects, early onset migratory ichthyosiform dermatosis, intellectual disability, and ear abnormalities. Our patient did not have colobomas, congenital heart defects, or early onset migratory ichthyosiform dermatosis and hence was diagnosed with HPMRS, and not CHIME syndrome. These results suggest that frameshift mutations that result in premature termination in PIGL cause a phenotype that is consistent with HPMRS.

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Mutations in PGAP3 Impair GPI-Anchor Maturation, Causing a Subtype of Hyperphosphatasia with Mental Retardation

Cited by 98 publications

References 26 publications

Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease

Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease

Cerebral visual impairment and intellectual disability caused by PGAP1 variants

Mutations in PIGL in a patient with Mabry syndrome

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