Mutations in PIGU Impair the Function of the GPI Transamidase Complex, Causing Severe Intellectual Disability, Epilepsy, and Brain Anomalies

• Published in: American journal of human genetics Vol. 105; no. 2; pp. 395 - 402
• Main Authors: Knaus, Alexej, Kortüm, Fanny, Kleefstra, Tjitske, Stray-Pedersen, Asbjørg, Đukić, Dejan, Murakami, Yoshiko, Gerstner, Thorsten, van Bokhoven, Hans, Iqbal, Zafar, Horn, Denise, Kinoshita, Taroh, Hempel, Maja, Krawitz, Peter M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2019; Elsevier
• Subjects: Acyltransferases - genetics; Adolescent; Adult; Amino Acid Sequence; automated facial analysis; Brain Diseases - etiology; Brain Diseases - pathology; Child; Child, Preschool; deep phenotyping; epilepsy; Epilepsy - etiology; Epilepsy - pathology; Female; glycosylphosphatidylinositol; Glycosylphosphatidylinositols - biosynthesis; Glycosylphosphatidylinositols - deficiency; Glycosylphosphatidylinositols - genetics; GPIBD; Humans; Infant; Infant, Newborn; inherited GPI deficiency; Intellectual Disability - etiology; Intellectual Disability - pathology; Male; multicolor flow cytometry; Mutation; Pedigree; PIGU; Seizures - genetics; Seizures - pathology; Sequence Homology; Young Adult; epilepsy; PIGU; inherited GPI deficiency; automated facial analysis; multicolor flow cytometry; glycosylphosphatidylinositol; deep phenotyping; GPIBD
• DOI: 10.1016/j.ajhg.2019.06.009
• ISSN: 0002-9297; 1537-6605

The glycosylphosphatidylinositol (GPI) anchor links over 150 proteins to the cell surface and is present on every cell type. Many of these proteins play crucial roles in neuronal development and function. Mutations in 18 of the 29 genes implicated in the biosynthesis of the GPI anchor have been identified as the cause of GPI biosynthesis deficiencies (GPIBDs) in humans. GPIBDs are associated with intellectual disability and seizures as their cardinal features. An essential component of the GPI transamidase complex is PIGU, along with PIGK, PIGS, PIGT, and GPAA1, all of which link GPI-anchored proteins (GPI-APs) onto the GPI anchor in the endoplasmic reticulum (ER). Here, we report two homozygous missense mutations (c.209T>A [p.Ile70Lys] and c.1149C>A [p.Asn383Lys]) in five individuals from three unrelated families. All individuals presented with global developmental delay, severe-to-profound intellectual disability, muscular hypotonia, seizures, brain anomalies, scoliosis, and mild facial dysmorphism. Using multicolor flow cytometry, we determined a characteristic profile for GPI transamidase deficiency. On granulocytes this profile consisted of reduced cell-surface expression of fluorescein-labeled proaerolysin (FLAER), CD16, and CD24, but not of CD55 and CD59; additionally, B cells showed an increased expression of free GPI anchors determined by T5 antibody. Moreover, computer-assisted facial analysis of different GPIBDs revealed a characteristic facial gestalt shared among individuals with mutations in PIGU and GPAA1. Our findings improve our understanding of the role of the GPI transamidase complex in the development of nervous and skeletal systems and expand the clinical spectrum of disorders belonging to the group of inherited GPI-anchor deficiencies.