Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome

Krawitz, Peter; Schweiger, Michal R.; Rödelsperger, Christian; Marcelis, Carlo; Kölsch, Uwe; Meisel, Christian; Stephani, Friederike; Kinoshita, Taroh; Murakami, Yoshiko; Bauer, Sebastian; Isau, Melanie; Fischer, Axel; Dahl, Andreas; Kerick, Martin; Hecht, Jochen; Köhler, Sebastian; Jäger, Marten; Grünhagen, Johannes; Condor, Birgit Jonske de; Doelken, Sandra C.; Brunner, Han G.; Meinecke, Peter; Passarge, Eberhard; Thompson, Miles D.; Cole, David E. C.; Horn, Denise; Roscioli, Tony; Mundlos, Stefan; Robinson, Peter N.

doi:10.1038/ng.653

Cited by 285 publications

(240 citation statements)

References 33 publications

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“…This analysis pinpointed to MLL2 as the major cause of this syndrome. Krawitz et al 36 Johnson et al 54 Zuchner et al 55 Norton et al 38 Wang et al 51a Musunuru et al 52b…”

Section: Affecting Protein Sequencementioning

confidence: 99%

Disease gene identification strategies for exome sequencing

et al. 2012

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“…This analysis pinpointed to MLL2 as the major cause of this syndrome. Krawitz et al 36 Johnson et al 54 Zuchner et al 55 Norton et al 38 Wang et al 51a Musunuru et al 52b…”

Section: Affecting Protein Sequencementioning

confidence: 99%

Disease gene identification strategies for exome sequencing

et al. 2012

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“…Serait-il possible que cette pathologie se caractérise au niveau moléculaire par une CIN constitutionnelle ? Dans ce contexte, il est curieux de noter que des mutations de deux autres gènes codant des enzymes intervenant dans la synthèse du GPI sont aussi responsables du syndrome HPMR [10,11]. Ces deux gènes, PIGV et PIGO, sont localisés respectivement sur les chromosomes 1p36 et 9p13, dans des régions où les pertes d'hétérozygotie sont fréquentes dans les cancers.…”

Section: Identification Des Bases Génétiques De La Cinunclassified

Instabilité chromosomique et cancer, enfin des CIN révélateurs

2013

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aneusomies segmentaires et pourraient donc être à la base de la majorité des cas de CIN. Reste que la distinction, parmi les mécanismes moléculaires responsables de la CIN, entre défauts prémitotiques ou mitotiques, méritait d'être abordée de manière systé-matique ; c'est ce qui a été entrepris par le groupe britannique dont les résultats ont été récemment publiés dans la revue Nature [3]. Stress réplicatif, une condition « CINe qua non » pour l'instabilité chromosomiqueAfin de discriminer si la CIN est due à une défaillance de mécanismes prémitotiques ou mitotiques, l'équipe britannique a réalisé une analyse d'images d'anaphases à haute résolution sur une série de cellules de lignées de cancers colorectaux (CRC) avec CIN (CIN+) ou sans CIN (CIN-). Une quantification des aberrations chromosomiques observées a montré que la majorité de celles-ci consistaient en des chromosomes acentriques ou des ponts anaphasiques. De plus, aucun défaut notable de la fonction du point de contrôle de mitose ou de la cohésion des chromatides soeurs, ni aucune augmentation significative du nombre de fuseaux mitotiques multipolaires n'ont été observés dans les lignées CIN+. Ainsi, la première conclusion surprenante de ce travail était que les défauts chromosomiques spécifiques à la CIN évo-quaient un dérèglement de type prémitotique.

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“…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

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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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Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome

Cited by 285 publications

References 33 publications

Disease gene identification strategies for exome sequencing

Disease gene identification strategies for exome sequencing

Instabilité chromosomique et cancer, enfin des CIN révélateurs

Cerebral visual impairment and intellectual disability caused by PGAP1 variants

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