Hypomorphic promoter mutation in PIGM causes inherited glycosylphosphatidylinositol deficiency

Abstract

Attachment to the plasma membrane by linkage to a glycosylphosphatidylinositol (GPI) anchor is a mode of protein expression highly conserved from protozoa to mammals. As a clinical entity, deficiency of GPI has been recognized as paroxysmal nocturnal hemoglobinuria, an acquired clonal disorder associated with somatic mutations of the X-linked PIGA gene in hematopoietic cells. We have identified a novel disease characterized by a propensity to venous thrombosis and seizures in which deficiency of GPI is inherited in an autosomal recessive manner. In two unrelated kindreds, a point mutation (c --> g) at position -270 from the start codon of PIGM, a mannosyltransferase-encoding gene, disrupts binding of the transcription factor Sp1 to its cognate promoter motif. This mutation substantially reduces transcription of PIGM and blocks mannosylation of GPI, leading to partial but severe deficiency of GPI. These findings indicate that biosynthesis of GPI is essential to maintain homeostasis of blood coagulation and neurological function.

Screening Using Serum Percentage of Carbohydrate-Deficient Transferrin for Congenital Disorders of Glycosylation in Children with Suspected Metabolic Disease

“…To date, 30 CDG hypoglycosylation defects have been identified, including 17 N-glycosylation defects (13 CDG-I or N-glycan assembly defects and 4 CDG-II or N-glycan processing defects), 6 O-glycosylation defects, 5 combined N-and Oglycosylation defects, and 2 lipid glycosylation defects (2)(3)(4)(5)(6)(7)(8)(9).…”

Diseases of glycosylation beyond classical congenital disorders of glycosylation

“…6). To date, three cases of PIGM deficiency originating from two families have been described [87]. The patients showed increased thrombosis but no signs of hemolysis, although the levels of several GPI anchored proteins were reduced on hematopoietic cells.…”

Potential Roles of GPI-Anchor Remodeling in Protein Trafficking and Raft Association in Mammalian Cells

“…In recent years, however, complete genome and exome analyses using next generation sequencing have revealed that partial defects in GPI biosynthetic genes may cause disease. To date, congenital GPI deficiencies caused by mutations in PIG-A, PIG-L, PIG-M, PIG-V, PIG-N, and PIG-O have been reported (13)(14)(15)(16)(17)(18). Although the symptoms are different for each gene deficit, epileptic seizure and mental retardation are common symptoms of many congenital GPI deficiencies, and they also present with symptoms such as abnormal facial configuration, cardiac disease, a short phalange, hearing loss, and hyperphosphatasia depending on the mutations in the GPI biosynthetic genes (19).…”