A Rare Variant in PGAP2 Causes Autosomal Recessive Hyperphosphatasia with Mental Retardation Syndrome, with a Mild Phenotype in Heterozygous Carriers

Mutations in genes involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor cause autosomal recessive glycosylation defects, with a wide phenotypic spectrum of intellectual disability, seizures, minor facial dysmorphism, hypotonia, and elevated serum alkaline phosphatase. We now...

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Main Authors:	Yonatan Perez, Ohad Wormser, Yair Sadaka, Ruth Birk, Ginat Narkis, Ohad S. Birk
Format:	Article
Language:	English
Published:	Hindawi Limited 2017-01-01
Series:	BioMed Research International
Online Access:	http://dx.doi.org/10.1155/2017/3470234

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spelling	doaj-64951dca37cc4511bb3198c5a8c8c41b2020-11-24T21:30:00ZengHindawi LimitedBioMed Research International2314-61332314-61412017-01-01201710.1155/2017/34702343470234A Rare Variant in PGAP2 Causes Autosomal Recessive Hyperphosphatasia with Mental Retardation Syndrome, with a Mild Phenotype in Heterozygous CarriersYonatan Perez0Ohad Wormser1Yair Sadaka2Ruth Birk3Ginat Narkis4Ohad S. Birk5The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Faculty of Health Sciences, Ben Gurion University of the Negev, 84105 Beer Sheva, IsraelThe Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Faculty of Health Sciences, Ben Gurion University of the Negev, 84105 Beer Sheva, IsraelPediatric Neurology Unit, Division of Pediatrics, Soroka University Medical Center, Faculty of Health Sciences, Ben Gurion University of the Negev, 84101 Beer Sheva, IsraelFaculty of Health Sciences, Ariel University, Ariel, IsraelGenetics Institute, Soroka University Medical Center, Ben Gurion University of the Negev, 84101 Beer Sheva, IsraelThe Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Faculty of Health Sciences, Ben Gurion University of the Negev, 84105 Beer Sheva, IsraelMutations in genes involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor cause autosomal recessive glycosylation defects, with a wide phenotypic spectrum of intellectual disability, seizures, minor facial dysmorphism, hypotonia, and elevated serum alkaline phosphatase. We now describe consanguineous Bedouin kindred presenting with an autosomal recessive syndrome of intellectual disability and elevated serum alkaline phosphatase. Genome-wide linkage analysis identified 6 possible disease-associated loci. Whole-exome sequencing followed by Sanger sequencing validation identified a single variant in PGAP2 as the disease-causing mutation (C.554G>A; p.185(R>Q)), segregating as expected within the kindred and not found in 150 Bedouin controls. The mutation replaces a highly conserved arginine residue with glutamine within the Frag1 (FGF receptor activating) domain of PGAP2. Interestingly, this mutation is a known dbSNP variant (rs745521288, build 147) with a very low allele frequency (0.00000824 in dbSNP, no homozygotes reported), highlighting the fact that dbSNP variants should not be automatically ruled out as disease-causing mutations. We further showed that PGAP2 is ubiquitously expressed, but in line with the disease phenotype, it is highly transcribed in human brain, skeletal muscle, and liver. Interestingly, a mild phenotype of slightly elevated serum levels of alkaline phosphatase and significant learning disabilities was observed in heterozygous carriers.http://dx.doi.org/10.1155/2017/3470234
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Yonatan Perez Ohad Wormser Yair Sadaka Ruth Birk Ginat Narkis Ohad S. Birk
spellingShingle	Yonatan Perez Ohad Wormser Yair Sadaka Ruth Birk Ginat Narkis Ohad S. Birk A Rare Variant in PGAP2 Causes Autosomal Recessive Hyperphosphatasia with Mental Retardation Syndrome, with a Mild Phenotype in Heterozygous Carriers BioMed Research International
author_facet	Yonatan Perez Ohad Wormser Yair Sadaka Ruth Birk Ginat Narkis Ohad S. Birk
author_sort	Yonatan Perez
title	A Rare Variant in PGAP2 Causes Autosomal Recessive Hyperphosphatasia with Mental Retardation Syndrome, with a Mild Phenotype in Heterozygous Carriers
title_short	A Rare Variant in PGAP2 Causes Autosomal Recessive Hyperphosphatasia with Mental Retardation Syndrome, with a Mild Phenotype in Heterozygous Carriers
title_full	A Rare Variant in PGAP2 Causes Autosomal Recessive Hyperphosphatasia with Mental Retardation Syndrome, with a Mild Phenotype in Heterozygous Carriers
title_fullStr	A Rare Variant in PGAP2 Causes Autosomal Recessive Hyperphosphatasia with Mental Retardation Syndrome, with a Mild Phenotype in Heterozygous Carriers
title_full_unstemmed	A Rare Variant in PGAP2 Causes Autosomal Recessive Hyperphosphatasia with Mental Retardation Syndrome, with a Mild Phenotype in Heterozygous Carriers
title_sort	rare variant in pgap2 causes autosomal recessive hyperphosphatasia with mental retardation syndrome, with a mild phenotype in heterozygous carriers
publisher	Hindawi Limited
series	BioMed Research International
issn	2314-6133 2314-6141
publishDate	2017-01-01
description	Mutations in genes involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor cause autosomal recessive glycosylation defects, with a wide phenotypic spectrum of intellectual disability, seizures, minor facial dysmorphism, hypotonia, and elevated serum alkaline phosphatase. We now describe consanguineous Bedouin kindred presenting with an autosomal recessive syndrome of intellectual disability and elevated serum alkaline phosphatase. Genome-wide linkage analysis identified 6 possible disease-associated loci. Whole-exome sequencing followed by Sanger sequencing validation identified a single variant in PGAP2 as the disease-causing mutation (C.554G>A; p.185(R>Q)), segregating as expected within the kindred and not found in 150 Bedouin controls. The mutation replaces a highly conserved arginine residue with glutamine within the Frag1 (FGF receptor activating) domain of PGAP2. Interestingly, this mutation is a known dbSNP variant (rs745521288, build 147) with a very low allele frequency (0.00000824 in dbSNP, no homozygotes reported), highlighting the fact that dbSNP variants should not be automatically ruled out as disease-causing mutations. We further showed that PGAP2 is ubiquitously expressed, but in line with the disease phenotype, it is highly transcribed in human brain, skeletal muscle, and liver. Interestingly, a mild phenotype of slightly elevated serum levels of alkaline phosphatase and significant learning disabilities was observed in heterozygous carriers.
url	http://dx.doi.org/10.1155/2017/3470234
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A Rare Variant in PGAP2 Causes Autosomal Recessive Hyperphosphatasia with Mental Retardation Syndrome, with a Mild Phenotype in Heterozygous Carriers

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