Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy.
There are over 150 known human proteins which are tethered to the cell surface via glycosylphosphatidylinositol (GPI) anchors. These proteins play a variety of important roles in development, and particularly in neurogenesis. Not surprisingly, mutations in the GPI anchor biosynthesis and remodeling pathway cause a number of developmental disorders. This group of conditions has been termed inherited GPI deficiencies (IGDs), a subgroup of congenital disorders of glycosylation; they present with variable phenotypes, often including seizures, hypotonia and intellectual disability. Here, we report two siblings with compound heterozygous variants in the gene phosphatidylinositol glycan anchor biosynthesis, class P (PIGP) (NM_153681.2: c.74T > C;p.Met25Thr and c.456delA;p.Glu153AsnFs*34). PIGP encodes a subunit of the enzyme that catalyzes the first step of GPI anchor biosynthesis. Both children presented with early-onset refractory seizures, hypotonia, and profound global developmental delay, reminiscent of other IGD phenotypes. Functional studies with patient cells showed reduced PIGP mRNA levels, and an associated reduction of GPI-anchored cell surface proteins, which was rescued by exogenous expression of wild-type PIGP. This work associates mutations in the PIGP gene with a novel autosomal recessive IGD, and expands our knowledge of the role of PIG genes in human development.
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario K1H8L1, Canada.
Devon L
DL
Johnstone
Research Center, CHU Sainte-Justine, University of Montreal, Montreal, Quebec H3T1C5, Canada.
Thi-Tuyet-Mai
TT
Nguyen
WPI Immunology Frontier Research Center and Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
Yoshiko
Y
Murakami
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario K1H8L1, Canada.
Kristin D
KD
Kernohan
Department of Human Genetics, McGill University, Montreal, Quebec H3A1B1, Canada.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec H3A0G1, Canada.
Martine
M
Tétreault
Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H8L1, Canada.
Claire
C
Goldsmith
Division of Neurology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H8L1, Canada.
Asif
A
Doja
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario K1H8L1, Canada.
Justin D
JD
Wagner
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario K1H8L1, Canada.
Lijia
L
Huang
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario K1H8L1, Canada.
Taila
T
Hartley
Research Center, CHU Sainte-Justine, University of Montreal, Montreal, Quebec H3T1C5, Canada.
Anik
A
St-Denis
Research Center, CHU Sainte-Justine, University of Montreal, Montreal, Quebec H3T1C5, Canada.
Françoise
F
le Deist
Department of Human Genetics, McGill University, Montreal, Quebec H3A1B1, Canada.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec H3A0G1, Canada.
Jacek
J
Majewski
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario K1H8L1, Canada.
Dennis E
DE
Bulman
WPI Immunology Frontier Research Center and Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
Taroh
T
Kinoshita
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario K1H8L1, Canada.|Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H8L1, Canada.
David A
DA
Dyment
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario K1H8L1, Canada.|Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H8L1, Canada.
Kym M
KM
Boycott
Research Center, CHU Sainte-Justine, University of Montreal, Montreal, Quebec H3T1C5, Canada.|Department of Pediatrics, Sainte-Justine Hospital, University of Montreal, Montreal, Quebec H3T1C5, Canada.
Philippe M
PM
Campeau
D000015:Abnormalities, Multiple / Q000235:genetics; D000328:Adult; D002460:Cell Line; D002648:Child; D002658:Developmental Disabilities / Q000235:genetics; D017261:Glycosylphosphatidylinositols / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics; D006602:Hexosyltransferases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009123:Muscle Hypotonia / Q000235:genetics; D009154:Mutation; D010375:Pedigree; D012640:Seizures / Q000235:genetics; D013036:Spasms, Infantile / Q000235:genetics* / Q000378:metabolism
D017261:Glycosylphosphatidylinositols; D008565:Membrane Proteins; D006602:Hexosyltransferases; C414441:PIGP protein, human