Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability

Lars Hansen; Hasan Tawamie; Yoshiko Murakami; Yuan Mang; Shoaib ur Rehman; Rebecca Buchert; Stefanie Schaffer; Safia Muhammad; Mads Bak; Markus M Nöthen; Eric P Bennett; Yusuke Maeda; Michael Aigner; André Reis; Taroh Kinoshita; Niels Tommerup; Shahid Mahmood Baig; Rami Abou Jamra

doi:10.1016/j.ajhg.2013.03.008

Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability

Lars Hansen, Hasan Tawamie, Yoshiko Murakami, Yuan Mang, Shoaib ur Rehman, Rebecca Buchert, Stefanie Schaffer, Safia Muhammad, Mads Bak, Markus M Nöthen, Eric P Bennett, Yusuke Maeda, Michael Aigner, André Reis, Taroh Kinoshita, Niels Tommerup, Shahid Mahmood Baig, Rami Abou Jamra

73 Citations (Scopus)

Abstract

PGAP2 encodes a protein involved in remodeling the glycosylphosphatidylinositol (GPI) anchor in the Golgi apparatus. After synthesis in the endoplasmic reticulum (ER), GPI anchors are transferred to the proteins and are remodeled while transported through the Golgi to the cell membrane. Germline mutations in six genes (PIGA, PIGL, PIGM, PIGV, PIGN, and PIGO) in the ER-located part of the GPI-anchor-biosynthesis pathway have been reported, and all are associated with phenotypes extending from malformation and lethality to severe intellectual disability, epilepsy, minor dysmorphisms, and elevated alkaline phosphatase (ALP). We performed autozygosity mapping and ultra-deep sequencing followed by stringent filtering and identified two homozygous PGAP2 alterations, p.Tyr99Cys and p.Arg177Pro, in seven offspring with nonspecific autosomal-recessive intellectual disability from two consanguineous families. Rescue experiments with the altered proteins in PGAP2-deficient Chinese hamster ovary cell lines showed less expression of cell-surface GPI-anchored proteins DAF and CD59 than of the wild-type protein, substantiating the pathogenicity of the identified alterations. Furthermore, we observed a full rescue when we used strong promoters before the mutant cDNAs, suggesting a hypomorphic effect of the mutations. We report on alterations in the Golgi-located part of the GPI-anchor-biosynthesis pathway and extend the phenotypic spectrum of the GPI-anchor deficiencies to isolated intellectual disability with elevated ALP. GPI-anchor deficiencies can be interpreted within the concept of a disease family, and we propose that the severity of the phenotype is dependent on the location of the altered protein in the biosynthesis chain.

Original language	English
Journal	American Journal of Human Genetics
Volume	92
Issue number	4
Pages (from-to)	575-83
Number of pages	9
ISSN	0002-9297
DOIs	https://doi.org/10.1016/j.ajhg.2013.03.008
Publication status	Published - 4 Apr 2013

Keywords

Alkaline Phosphatase
Amino Acid Sequence
Animals
Biological Transport
CHO Cells
Child
Child, Preschool
Cricetinae
Cricetulus
Endoplasmic Reticulum
Female
Genes, Recessive
Glycosylphosphatidylinositols
Golgi Apparatus
Humans
Intellectual Disability
Lymphocytes
Male
Molecular Sequence Data
Mutation
Nuclear Proteins
Pedigree
Sequence Homology, Amino Acid

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Hansen, L., Tawamie, H., Murakami, Y., Mang, Y., ur Rehman, S., Buchert, R., Schaffer, S., Muhammad, S., Bak, M., Nöthen, M. M., Bennett, E. P., Maeda, Y., Aigner, M., Reis, A., Kinoshita, T., Tommerup, N., Baig, S. M., & Abou Jamra, R. (2013). Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability. American Journal of Human Genetics, 92(4), 575-83. https://doi.org/10.1016/j.ajhg.2013.03.008

Hansen, L, Tawamie, H, Murakami, Y, Mang, Y, ur Rehman, S, Buchert, R, Schaffer, S, Muhammad, S, Bak, M, Nöthen, MM, Bennett, EP, Maeda, Y, Aigner, M, Reis, A, Kinoshita, T, Tommerup, N, Baig, SM & Abou Jamra, R 2013, 'Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability', American Journal of Human Genetics, vol. 92, no. 4, pp. 575-83. https://doi.org/10.1016/j.ajhg.2013.03.008

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title = "Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability",

abstract = "PGAP2 encodes a protein involved in remodeling the glycosylphosphatidylinositol (GPI) anchor in the Golgi apparatus. After synthesis in the endoplasmic reticulum (ER), GPI anchors are transferred to the proteins and are remodeled while transported through the Golgi to the cell membrane. Germline mutations in six genes (PIGA, PIGL, PIGM, PIGV, PIGN, and PIGO) in the ER-located part of the GPI-anchor-biosynthesis pathway have been reported, and all are associated with phenotypes extending from malformation and lethality to severe intellectual disability, epilepsy, minor dysmorphisms, and elevated alkaline phosphatase (ALP). We performed autozygosity mapping and ultra-deep sequencing followed by stringent filtering and identified two homozygous PGAP2 alterations, p.Tyr99Cys and p.Arg177Pro, in seven offspring with nonspecific autosomal-recessive intellectual disability from two consanguineous families. Rescue experiments with the altered proteins in PGAP2-deficient Chinese hamster ovary cell lines showed less expression of cell-surface GPI-anchored proteins DAF and CD59 than of the wild-type protein, substantiating the pathogenicity of the identified alterations. Furthermore, we observed a full rescue when we used strong promoters before the mutant cDNAs, suggesting a hypomorphic effect of the mutations. We report on alterations in the Golgi-located part of the GPI-anchor-biosynthesis pathway and extend the phenotypic spectrum of the GPI-anchor deficiencies to isolated intellectual disability with elevated ALP. GPI-anchor deficiencies can be interpreted within the concept of a disease family, and we propose that the severity of the phenotype is dependent on the location of the altered protein in the biosynthesis chain.",

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author = "Lars Hansen and Hasan Tawamie and Yoshiko Murakami and Yuan Mang and {ur Rehman}, Shoaib and Rebecca Buchert and Stefanie Schaffer and Safia Muhammad and Mads Bak and N{\"o}then, {Markus M} and Bennett, {Eric P} and Yusuke Maeda and Michael Aigner and Andr{\'e} Reis and Taroh Kinoshita and Niels Tommerup and Baig, {Shahid Mahmood} and {Abou Jamra}, Rami",

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doi = "10.1016/j.ajhg.2013.03.008",

language = "English",

volume = "92",

pages = "575--83",

journal = "American Journal of Human Genetics",

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T1 - Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability

AU - Hansen, Lars

AU - Tawamie, Hasan

AU - Murakami, Yoshiko

AU - Mang, Yuan

AU - ur Rehman, Shoaib

AU - Buchert, Rebecca

AU - Schaffer, Stefanie

AU - Muhammad, Safia

AU - Bak, Mads

AU - Nöthen, Markus M

AU - Bennett, Eric P

AU - Maeda, Yusuke

AU - Aigner, Michael

AU - Reis, André

AU - Kinoshita, Taroh

AU - Tommerup, Niels

AU - Baig, Shahid Mahmood

AU - Abou Jamra, Rami

PY - 2013/4/4

Y1 - 2013/4/4

N2 - PGAP2 encodes a protein involved in remodeling the glycosylphosphatidylinositol (GPI) anchor in the Golgi apparatus. After synthesis in the endoplasmic reticulum (ER), GPI anchors are transferred to the proteins and are remodeled while transported through the Golgi to the cell membrane. Germline mutations in six genes (PIGA, PIGL, PIGM, PIGV, PIGN, and PIGO) in the ER-located part of the GPI-anchor-biosynthesis pathway have been reported, and all are associated with phenotypes extending from malformation and lethality to severe intellectual disability, epilepsy, minor dysmorphisms, and elevated alkaline phosphatase (ALP). We performed autozygosity mapping and ultra-deep sequencing followed by stringent filtering and identified two homozygous PGAP2 alterations, p.Tyr99Cys and p.Arg177Pro, in seven offspring with nonspecific autosomal-recessive intellectual disability from two consanguineous families. Rescue experiments with the altered proteins in PGAP2-deficient Chinese hamster ovary cell lines showed less expression of cell-surface GPI-anchored proteins DAF and CD59 than of the wild-type protein, substantiating the pathogenicity of the identified alterations. Furthermore, we observed a full rescue when we used strong promoters before the mutant cDNAs, suggesting a hypomorphic effect of the mutations. We report on alterations in the Golgi-located part of the GPI-anchor-biosynthesis pathway and extend the phenotypic spectrum of the GPI-anchor deficiencies to isolated intellectual disability with elevated ALP. GPI-anchor deficiencies can be interpreted within the concept of a disease family, and we propose that the severity of the phenotype is dependent on the location of the altered protein in the biosynthesis chain.

AB - PGAP2 encodes a protein involved in remodeling the glycosylphosphatidylinositol (GPI) anchor in the Golgi apparatus. After synthesis in the endoplasmic reticulum (ER), GPI anchors are transferred to the proteins and are remodeled while transported through the Golgi to the cell membrane. Germline mutations in six genes (PIGA, PIGL, PIGM, PIGV, PIGN, and PIGO) in the ER-located part of the GPI-anchor-biosynthesis pathway have been reported, and all are associated with phenotypes extending from malformation and lethality to severe intellectual disability, epilepsy, minor dysmorphisms, and elevated alkaline phosphatase (ALP). We performed autozygosity mapping and ultra-deep sequencing followed by stringent filtering and identified two homozygous PGAP2 alterations, p.Tyr99Cys and p.Arg177Pro, in seven offspring with nonspecific autosomal-recessive intellectual disability from two consanguineous families. Rescue experiments with the altered proteins in PGAP2-deficient Chinese hamster ovary cell lines showed less expression of cell-surface GPI-anchored proteins DAF and CD59 than of the wild-type protein, substantiating the pathogenicity of the identified alterations. Furthermore, we observed a full rescue when we used strong promoters before the mutant cDNAs, suggesting a hypomorphic effect of the mutations. We report on alterations in the Golgi-located part of the GPI-anchor-biosynthesis pathway and extend the phenotypic spectrum of the GPI-anchor deficiencies to isolated intellectual disability with elevated ALP. GPI-anchor deficiencies can be interpreted within the concept of a disease family, and we propose that the severity of the phenotype is dependent on the location of the altered protein in the biosynthesis chain.

KW - Alkaline Phosphatase

KW - Amino Acid Sequence

KW - Animals

KW - Biological Transport

KW - CHO Cells

KW - Child

KW - Child, Preschool

KW - Cricetinae

KW - Cricetulus

KW - Endoplasmic Reticulum

KW - Female

KW - Genes, Recessive

KW - Glycosylphosphatidylinositols

KW - Golgi Apparatus

KW - Humans

KW - Intellectual Disability

KW - Lymphocytes

KW - Male

KW - Molecular Sequence Data

KW - Mutation

KW - Nuclear Proteins

KW - Pedigree

KW - Sequence Homology, Amino Acid

U2 - 10.1016/j.ajhg.2013.03.008

DO - 10.1016/j.ajhg.2013.03.008

M3 - Journal article

C2 - 23561846

SN - 0002-9297

VL - 92

SP - 575

EP - 583

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 4

ER -

Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability

Abstract

Keywords

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