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  Rare Noncoding Mutations Extend the Mutational Spectrum in the PGAP3 Subtype of Hyperphosphatasia with Mental Retardation Syndrome

Knaus, A., Awaya, T., Helbig, I., Afawi, Z., Pendziwiat, M., Abu-Rachma, J., et al. (2016). Rare Noncoding Mutations Extend the Mutational Spectrum in the PGAP3 Subtype of Hyperphosphatasia with Mental Retardation Syndrome. Human Mutations, 37(8), 737-744. doi:10.1002/humu.23006.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002E-1D45-2 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002E-1D46-F
Genre: Journal Article

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 Creators:
Knaus, A.1, Author
Awaya, T., Author
Helbig, I., Author
Afawi, Z., Author
Pendziwiat, M., Author
Abu-Rachma, J., Author
Thompson, M. D., Author
Cole, D. E., Author
Skinner, S., Author
Annese, F., Author
Canham, N., Author
Schweiger, M. R., Author
Robinson, P. N.1, Author              
Mundlos, S.1, Author              
Kinoshita, T., Author
Munnich, A., Author
Murakami, Y., Author
Horn, D., Author
Krawitz, P. M.1, Author
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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Free keywords: Mabry syndrome Pgap3 hyperphosphatasia with mental retardation intellectual disability noncoding mutations
 Abstract: HPMRS or Mabry syndrome is a heterogeneous glycosylphosphatidylinositol (GPI) anchor deficiency that is caused by an impairment of synthesis or maturation of the GPI-anchor. The expressivity of the clinical features in HPMRS varies from severe syndromic forms with multiple organ malformations to mild nonsyndromic intellectual disability. In about half of the patients with the clinical diagnosis of HPMRS, pathogenic mutations can be identified in the coding region in one of the six genes, one among them is PGAP3. In this work, we describe a screening approach with sequence specific baits for transcripts of genes of the GPI pathway that allows the detection of functionally relevant mutations also including introns and the 5' and 3' UTR. By this means, we also identified pathogenic noncoding mutations, which increases the diagnostic yield for HPMRS on the basis of intellectual disability and elevated serum alkaline phosphatase. In eight affected individuals from different ethnicities, we found seven novel pathogenic mutations in PGAP3. Besides five missense mutations, we identified an intronic mutation, c.558-10G>A, that causes an aberrant splice product and a mutation in the 3'UTR, c.*559C>T, that is associated with substantially lower mRNA levels. We show that our novel screening approach is a useful rapid detection tool for alterations in genes coding for key components of the GPI pathway.

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Language(s): eng - English
 Dates: 2016-05-192016-08
 Publication Status: Published in print
 Pages: 8
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1002/humu.23006
ISSN: 1098-1004 (Electronic)1059-7794 (Print)
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Title: Human Mutations
  Other : Hum Mut
Source Genre: Journal
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Publ. Info: New York, N.Y. : Wiley-Liss
Pages: - Volume / Issue: 37 (8) Sequence Number: - Start / End Page: 737 - 744 Identifier: ISSN: 1059-7794
CoNE: /journals/resource/954925597586