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  Mutations in PGAP3 impair GPI-anchor maturation, causing a subtype of hyperphosphatasia with mental retardation

Howard, M. F., Murakami, Y., Pagnamenta, A. T., Daumer-Haas, C., Fischer, B., Hecht, J., et al. (2014). Mutations in PGAP3 impair GPI-anchor maturation, causing a subtype of hyperphosphatasia with mental retardation. The American Journal of Human Genetics, 94(2), 278-287. doi:10.1016/j.ajhg.2013.12.012.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-786D-C Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-786E-A
Genre: Journal Article

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 Creators:
Howard, M. F., Author
Murakami, Y., Author
Pagnamenta, A. T., Author
Daumer-Haas, C., Author
Fischer, B.1, Author
Hecht, J.2, Author              
Keays, D. A., Author
Knight, S. J., Author
Kolsch, U., Author
Kruger, U., Author
Leiz, S., Author
Maeda, Y., Author
Mitchell, D., Author
Mundlos, S.2, Author              
Phillips, J. A., 3rd, Author
Robinson, P. N.2, Author              
Kini, U., Author
Taylor, J. C., Author
Horn, D., Author
Kinoshita, T., Author
Krawitz, P. M.1, Author more..
Affiliations:
1Max Planck Society, ou_persistent13              
2Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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Free keywords: Abnormalities, Multiple/*genetics/pathology Alkaline Phosphatase/blood Amino Acid Sequence Animals Asian Continental Ancestry Group/genetics CHO Cells Child Child, Preschool Chromosome Mapping Consanguinity Cricetinae Cricetulus European Continental Ancestry Group/genetics Exome Female Homozygote Humans Intellectual Disability/*genetics/pathology Molecular Sequence Data *Mutation, Missense Pakistan Pedigree Phosphorus Metabolism Disorders/*genetics/pathology Phylogeny Polymorphism, Single Nucleotide Receptors, Cell Surface/*genetics/metabolism Saudi Arabia United States
 Abstract: Glycosylphophatidylinositol (GPI)-anchored proteins play important roles in many biological processes, and mutations affecting proteins involved in the synthesis of the GPI anchor are reported to cause a wide spectrum of intellectual disabilities (IDs) with characteristic additional phenotypic features. Here, we describe a total of five individuals (from three unrelated families) in whom we identified mutations in PGAP3, encoding a protein that is involved in GPI-anchor maturation. Three siblings in a consanguineous Pakistani family presented with profound developmental delay, severe ID, no speech, psychomotor delay, and postnatal microcephaly. A combination of autozygosity mapping and exome sequencing identified a 13.8 Mb region harboring a homozygous c.275G>A (p.Gly92Asp) variant in PGAP3 region 17q11.2-q21.32. Subsequent testing showed elevated serum alkaline phosphatase (ALP), a GPI-anchored enzyme, in all three affected children. In two unrelated individuals in a cohort with developmental delay, ID, and elevated ALP, we identified compound-heterozygous variants c.439dupC (p.Leu147Profs( *)16) and c.914A>G (p.Asp305Gly) and homozygous variant c.314C>G (p.Pro105Arg). The 1 bp duplication causes a frameshift and nonsense-mediated decay. Further evidence supporting pathogenicity of the missense mutations c.275G>A, c.314C>G, and c.914A>G was provided by the absence of the variants from ethnically matched controls, phylogenetic conservation, and functional studies on Chinese hamster ovary cell lines. Taken together with recent data on PGAP2, these results confirm the importance of the later GPI-anchor remodelling steps for normal neuronal development. Impairment of PGAP3 causes a subtype of hyperphosphatasia with ID, a congenital disorder of glycosylation that is also referred to as Mabry syndrome.

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Language(s): eng - English
 Dates: 2014-01-162014-02-06
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.ajhg.2013.12.012
ISSN: 1537-6605 (Electronic)0002-9297 (Print)
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Title: The American Journal of Human Genetics
  Other : Am. J. Hum. Genet.
Source Genre: Journal
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Affiliations:
Publ. Info: American Society of Human Genetics
Pages: - Volume / Issue: 94 (2) Sequence Number: - Start / End Page: 278 - 287 Identifier: ISSN: 0002-9297
CoNE: https://pure.mpg.de/cone/journals/resource/954925377893_1