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

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Title: Rare Noncoding Mutations Extend the Mutational Spectrum in the PGAP3 Subtype of Hyperphosphatasia with Mental Retardation Syndrome
Authors: Knaus, A
Awaya, T
Helbig, I
Afawi, Z
Pendziwiat, M
Abu-Rachma, J
Thompson, MD
Cole, DE
Skinner, S
Annese, F
Canham, N
Schweiger, MR
Robinson, PN
Mundlos, S
Kinoshita, T
Munnich, A
Murakami, Y
Horn, D
Krawitz, PM
Item Type: Journal Article
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.
Issue Date: 19-May-2016
Date of Acceptance: 3-Apr-2016
URI: http://hdl.handle.net/10044/1/39918
DOI: http://dx.doi.org/10.1002/humu.23006
ISSN: 1098-1004
Publisher: Wiley
Start Page: 737
End Page: 744
Journal / Book Title: Human Mutation
Volume: 37
Issue: 8
Copyright Statement: © 2016 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Mabry syndrome
Hyperphosphatasia with Mental Retardation
Intellectual Disability
Noncoding Mutations
Genetics & Heredity
Clinical Sciences
Publication Status: Published
Appears in Collections:School of Public Health