TY - JOUR
T1 - Bi-allelic Variants in the GPI Transamidase Subunit PIGK Cause a Neurodevelopmental Syndrome with Hypotonia, Cerebellar Atrophy, and Epilepsy
AU - Nguyen, Thi Tuyet Mai
AU - Murakami, Yoshiko
AU - Mobilio, Sabrina
AU - Niceta, Marcello
AU - Zampino, Giuseppe
AU - Philippe, Christophe
AU - Moutton, Sébastien
AU - Zaki, Maha S.
AU - James, Kiely N.
AU - Musaev, Damir
AU - Mu, Weiyi
AU - Baranano, Kristin
AU - Nance, Jessica R.
AU - Rosenfeld, Jill A.
AU - Braverman, Nancy
AU - Ciolfi, Andrea
AU - Millan, Francisca
AU - Person, Richard E.
AU - Bruel, Ange-Line
AU - Thauvin-Robinet, Christel
AU - Ververi, Athina
AU - Devile, Catherine
AU - Male, Alison
AU - Efthymiou, Stephanie
AU - Maroofian, Reza
AU - Houlden, Henry
AU - Maqbool, Shazia
AU - Rahman, Fatima
AU - Baratang, Nissan V.
AU - Rousseau, Justine
AU - St-Denis, Anik
AU - Elrick, Matthew J.
AU - Anselm, Irina
AU - Rodan, Lance H.
AU - Tartaglia, Marco
AU - Gleeson, Joseph
AU - Kinoshita, Taroh
AU - Campeau, Philippe M.
PY - 2020
Y1 - 2020
N2 - Glycosylphosphatidylinositol (GPI)-anchored proteins are critical for embryogenesis, neurogenesis, and cell signaling. Variants in several genes participating in GPI biosynthesis and processing lead to decreased cell surface presence of GPI-anchored proteins (GPI-APs) and cause inherited GPI deficiency disorders (IGDs). In this report, we describe 12 individuals from nine unrelated families with 10 different bi-allelic PIGK variants. PIGK encodes a component of the GPI transamidase complex, which attaches the GPI anchor to proteins. Clinical features found in most individuals include global developmental delay and/or intellectual disability, hypotonia, cerebellar ataxia, cerebellar atrophy, and facial dysmorphisms. The majority of the individuals have epilepsy. Two individuals have slightly decreased levels of serum alkaline phosphatase, while eight do not. Flow cytometric analysis of blood and fibroblasts from affected individuals showed decreased cell surface presence of GPI-APs. The overexpression of wild-type (WT) PIGK in fibroblasts rescued the levels of cell surface GPI-APs. In a knockout cell line, transfection with WT PIGK also rescued the GPI-AP levels, but transfection with the two tested mutant variants did not. Our study not only expands the clinical and known genetic spectrum of IGDs, but it also expands the genetic differential diagnosis for cerebellar atrophy. Given the fact that cerebellar atrophy is seen in other IGDs, flow cytometry for GPI-APs should be considered in the work-ups of individuals presenting this feature.
AB - Glycosylphosphatidylinositol (GPI)-anchored proteins are critical for embryogenesis, neurogenesis, and cell signaling. Variants in several genes participating in GPI biosynthesis and processing lead to decreased cell surface presence of GPI-anchored proteins (GPI-APs) and cause inherited GPI deficiency disorders (IGDs). In this report, we describe 12 individuals from nine unrelated families with 10 different bi-allelic PIGK variants. PIGK encodes a component of the GPI transamidase complex, which attaches the GPI anchor to proteins. Clinical features found in most individuals include global developmental delay and/or intellectual disability, hypotonia, cerebellar ataxia, cerebellar atrophy, and facial dysmorphisms. The majority of the individuals have epilepsy. Two individuals have slightly decreased levels of serum alkaline phosphatase, while eight do not. Flow cytometric analysis of blood and fibroblasts from affected individuals showed decreased cell surface presence of GPI-APs. The overexpression of wild-type (WT) PIGK in fibroblasts rescued the levels of cell surface GPI-APs. In a knockout cell line, transfection with WT PIGK also rescued the GPI-AP levels, but transfection with the two tested mutant variants did not. Our study not only expands the clinical and known genetic spectrum of IGDs, but it also expands the genetic differential diagnosis for cerebellar atrophy. Given the fact that cerebellar atrophy is seen in other IGDs, flow cytometry for GPI-APs should be considered in the work-ups of individuals presenting this feature.
KW - Abnormalities, Multiple
KW - Acyltransferases
KW - Alleles
KW - Cell Adhesion Molecules
KW - Cerebellar Diseases
KW - Epilepsy
KW - Female
KW - GPI8
KW - Genetic Variation
KW - Humans
KW - Intellectual Disability
KW - Male
KW - Muscle Hypotonia
KW - Nervous System Malformations
KW - Neurodevelopmental Disorders
KW - PIGK
KW - Pedigree
KW - Syndrome
KW - glycosylphosphatidylinositol (GPI)
KW - inherited GPI deficiency disorders (IGDs)
KW - transamidase
KW - Abnormalities, Multiple
KW - Acyltransferases
KW - Alleles
KW - Cell Adhesion Molecules
KW - Cerebellar Diseases
KW - Epilepsy
KW - Female
KW - GPI8
KW - Genetic Variation
KW - Humans
KW - Intellectual Disability
KW - Male
KW - Muscle Hypotonia
KW - Nervous System Malformations
KW - Neurodevelopmental Disorders
KW - PIGK
KW - Pedigree
KW - Syndrome
KW - glycosylphosphatidylinositol (GPI)
KW - inherited GPI deficiency disorders (IGDs)
KW - transamidase
UR - http://hdl.handle.net/10807/166628
U2 - 10.1016/j.ajhg.2020.03.001
DO - 10.1016/j.ajhg.2020.03.001
M3 - Article
SN - 0002-9297
VL - 106
SP - 484
EP - 495
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
ER -