PGAP2 Mutations, Affecting the GPI-Anchor-Synthesis Pathway, Cause Hyperphosphatasia with Mental Retardation Syndrome

Krawitz, Peter; Murakami, Yoshiko; Rieß, Angelika; Hietala, Marja; Krüger, Ulrike; Zhu, Na; Kinoshita, Taroh; Mundlos, Stefan; Hecht, Jochen; Robinson, Peter N.; Horn, Denise

doi:10.1016/j.ajhg.2013.03.011

Cited by 101 publications

(94 citation statements)

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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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Section: Pi-plc Treatment and Facs Analysismentioning

confidence: 99%

Section: Pi-plc Treatment and Facs Analysismentioning

confidence: 99%

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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“…HPMRS was recently shown to be caused by homozygous and compound heterozygous mutations in PIGV (MIM 610274), PIGO (MIM 614730), and PGAP2 (MIM 615187), which are members of the glycosylphosphatidylinositol (GPI) anchor synthesis pathway. [1][2][3][4] The transcripts altered by PIGV and PIGO mutations are either aberrantly spliced, decrease the membrane stability of the protein, or impair enzyme function This leads to a defect in GPI anchor synthesis with a corresponding reduction in the level of GPI-anchored substrates such as AP localized at the cell surface. 3,4 The third gene, PGAP2, is involved in fatty acid remodeling of the GPI anchor, which is required for stable association of GPI-anchored proteins with the cell surface membrane rafts.…”

Section: Introductionmentioning

confidence: 99%

“…3,4 The third gene, PGAP2, is involved in fatty acid remodeling of the GPI anchor, which is required for stable association of GPI-anchored proteins with the cell surface membrane rafts. 2 PIGV mutations as one of the causes of HPMRS have been reported in eight affected families so far. 3,5,6 In two families with HPMRS, PIGO mutations have been identified; in two further families PGAP2 mutations have been found.…”

Section: Introductionmentioning

confidence: 99%

Delineation of PIGV mutation spectrum and associated phenotypes in hyperphosphatasia with mental retardation syndrome

et al. 2013

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Three different genes of the glycosylphosphatidylinositol anchor synthesis pathway, PIGV, PIGO, and PGAP2, have recently been implicated in hyperphosphatasia-mental retardation syndrome (HPMRS), also known as Mabry syndrome, a rare autosomal recessive form of intellectual disability. The aim of this study was to delineate the PIGV mutation spectrum as well as the associated phenotypic spectrum in a cohort of 16 individuals diagnosed with HPMRS on the basis of intellectual disability and elevated serum alkaline phosphate as minimal diagnostic criteria. All PIGV exons and intronic boundaries were sequenced in 16 individuals. Biallelic PIGV mutations were identified in 8 of 16 unrelated families with HPMRS. The most frequent mutation detected in about 80% of affected families including the cases reported here is the c.1022C4A PIGV mutation, which was found in both the homozygous as well as the heterozygous state. Four further mutations found in this study (c. 176T4G, c.53G4A, c.905T4C, and c.1405C4T) are novel. Our findings in the largest reported cohort to date significantly extend the range of reported manifestations associated with PIGV mutations and demonstrate that the severe end of the clinical spectrum presents as a multiple congenital malformation syndrome with a high frequency of Hirschsprung disease, vesicoureteral, and renal anomalies as well as anorectal malformations. PIGV mutations are the major cause of HPMRS, which displays a broad clinical variability regarding associated malformations and growth patterns. Severe developmental delays, particular facial anomalies, brachytelephalangy, and hyperphosphatasia are consistently found in PIGV-positive individuals.

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A novel germline PIGA mutation in Ferro‐Cerebro‐Cutaneous syndrome: A neurodegenerative X‐linked epileptic encephalopathy with systemic iron‐overload

Swoboda

Margraf

Carey

et al. 2013

American J of Med Genetics Pt A

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Three related males presented with a newly recognized x-linked syndrome associated with neurodegeneration, cutaneous abnormalities, and systemic iron overload. Linkage studies demonstrated that they shared a haplotype on Xp21.3– Xp22.2 and exome sequencing was used to identify candidate variants. Of the segregating variants, only a PIGA mutation segregated with disease in the family. The c.328_330delCCT PIGA variant predicts, p.Leu 110 del (or c.1030_1032delCTT, p. Leu344del depending on the reference sequence). The unaffected great-grandfather shared his X allele with the proband but he did not have the PIGA mutation, indicating that the mutation arose de novo in his daughter. A single family with a germline PIGA mutation has been reported; affected males had a phenotype characterized by multiple congenital anomalies and severe neurologic impairment resulting in infantile lethality. In contrast, affected boys in the family described here were born without anomalies and were neurologically normal prior to onset of seizures after 6 months of age, with two surviving to the second decade. PIGA encodes an enzyme in the GPI anchor biosynthesis pathway. An affected individual in the family studied here was deficient in GPI anchor proteins on granulocytes but not erythrocytes. In conclusion, the PIGA mutation in this family likely causes a reduction in GPI anchor protein cell surface expression in various cell types, resulting in the observed pleiotropic phenotype involving central nervous system, skin, and iron metabolism.

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PGAP2 Mutations, Affecting the GPI-Anchor-Synthesis Pathway, Cause Hyperphosphatasia with Mental Retardation Syndrome

Cited by 101 publications

References 22 publications

Cerebral visual impairment and intellectual disability caused by PGAP1 variants

Cerebral visual impairment and intellectual disability caused by PGAP1 variants

Delineation of PIGV mutation spectrum and associated phenotypes in hyperphosphatasia with mental retardation syndrome

A novel germline PIGA mutation in Ferro‐Cerebro‐Cutaneous syndrome: A neurodegenerative X‐linked epileptic encephalopathy with systemic iron‐overload

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