PIGH deficiency can be associated with severe neurodevelopmental and skeletal manifestations

Abstract

Phosphatidylinositol Glycan Anchor Biosynthesis class H (PIGH) is an essential player in the glycosylphosphatidylinositol (GPI) synthesis, an anchor for numerous cell membrane‐bound proteins. PIGH deficiency is a newly described and rare disorder associated with developmental delay, seizures and behavioral difficulties. Herein, we report three new unrelated families with two different bi‐allelic PIGH variants, including one new variant p.(Arg163Trp) which seems associated with a more severe phenotype. The common clinical features in all affected individuals are developmental delay/intellectual disability and hypotonia. Variable clinical features include seizures, autism spectrum disorder, apraxia, severe language delay, dysarthria, feeding difficulties, facial dysmorphisms, microcephaly, strabismus, and musculoskeletal anomalies. The two siblings homozygous for the p.(Arg163Trp) variant have severe symptoms including profound psychomotor retardation, intractable seizures, multiple bone fractures, scoliosis, loss of independent ambulation, and delayed myelination on brain MRI. Serum iron levels were significantly elevated in one individual. All tested individuals with PIGH deficiency had normal alkaline phosphatase and CD16, a GPI‐anchored protein (GPI‐AP), was found to be decreased by 60% on granulocytes from one individual. This study expands the PIGH deficiency phenotype range toward the severe end of the spectrum with the identification of a novel pathogenic variant.

Constitutional PIGA mutations cause a novel subtype of hemochromatosis in patients with neurologic dysfunction

“…1g) and the less severe clinical phenotype of the affected patients indicate that the missense mutations of our patients retain a higher residual function thus likely explaining the milder neurologic phenotype allowing for sufficiently long survival to develop the iron overload phenotype. Moreover, our findings suggest that germline hypomorphic mutations in additional critical genes for the biosynthesis of GPI-anchors may also cause iron overload over time, as has been recently demonstrated by Tremblay-Laganière et al 13 . Interestingly, PIGA KO clones not only lack HJV but also show reduced levels of ceruloplasmin (CP), a ferroxidase required for efficient cellular iron export.…”

EROS is a selective chaperone regulating the phagocyte NADPH oxidase and purinergic signalling

“…This ER-associated transmembrane protein is part of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyses the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first step of GPI biosynthesis. GPI is an anchor for many membrane proteins, including key immune proteins such as the receptors CD16 and CD14 ( Wegner et al, 2021 ), as well as the complement regulatory proteins CD55 and CD59 ( Tremblay-Laganière et al, 2021 ). Therefore, we asked whether EROS might regulate the abundance of other proteins in different immune cell types.…”

EROS is a selective chaperone regulating the phagocyte NADPH oxidase and purinergic signalling

“…This ER-associated transmembrane protein is part of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyses the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first step of GPI biosynthesis. GPI is an anchor for many membrane proteins, including key immune proteins such as the receptors CD16 and CD14 (Wegner et al, 2021) as well as the complement regulatory proteins CD55 and CD59 (Tremblay-Laganiere et al, 2021). Therefore, we asked whether EROS might regulate the abundance of other proteins in different immune cell types.…”