PIGV – Hyperphosphatasia-intellectual disability syndrome

Hyperphosphatasia-intellectual disability syndrome (HPMRS) is an autosomal recessive glycosylphosphatidylinositol (GPI) biosynthesis disorder marked by elevated serum alkaline phosphatase, intellectual disability, seizures, and hypotonia. Biallelic pathogenic variants in PIGV, encoding a mannosyltransferase essential for GPI assembly, underlie this condition.

To date, five unrelated families with biallelic PIGV variants have been reported. A prenatal case carried compound heterozygous c.1253C>A (p.Ala418Asp) and c.1022C>A (p.Ala341Glu) presenting with diaphragmatic hernia, polyhydramnios, and hyperphosphatasia (PMID:28817240). Additional missense substitutions—including p.Gln256Lys, p.His385Pro, and p.Ala341Val—have been identified in four other families, with consistent segregation of variants with disease (PMID:22228761).

Functional assays in CHO cells demonstrated that PIGV missense variants drastically reduce protein expression, leading to accumulation of incomplete mannose-bearing GPI intermediates and secretion of alkaline phosphatase instead of membrane anchoring (PMID:22228761). Rescue of GPI-anchored markers was only partial in variant constructs, establishing a loss-of-function mechanism.

A CRISPR-Cas9 knock-in mouse carrying the orthologous p.Ala341Glu mutation recapitulates core HPMRS features, including elevated ALP, cognitive and motor impairments, altered sociability, and seizure susceptibility. Histological and electrophysiological analyses revealed hippocampal synaptic dysfunction, supporting the neurological phenotype (PMID:33402532).

No conflicting reports have emerged, and concordant clinical, cellular, and animal model data support a strong gene–disease relationship. Routine sequencing of PIGV should be considered in patients with unexplained hyperphosphatasia and neurodevelopmental impairment.

Key Take-home: Biallelic PIGV variants cause autosomal recessive HPMRS; molecular testing of PIGV informs diagnosis and genetic counseling.

References

• American journal of medical genetics. Part A • 2017 • Prenatal presentation of Mabry syndrome with congenital diaphragmatic hernia and phenotypic overlap with Fryns syndrome. PMID:28817240
• Journal of biological chemistry • 2012 • Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia mental retardation syndrome. PMID:22228761
• Proceedings of the National Academy of Sciences of the United States of America • 2021 • A CRISPR-Cas9-engineered mouse model for GPI-anchor deficiency mirrors human phenotypes and exhibits hippocampal synaptic dysfunctions. PMID:33402532

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