PIGV – Hyperphosphatasia with Intellectual Disability Syndrome 1

PIGV is associated with Hyperphosphatasia with Intellectual Disability Syndrome 1, an autosomal recessive congenital disorder of glycosylphosphatidylinositol biosynthesis (GPIBD) characterized by elevated serum alkaline phosphatase (ALP), seizures, developmental delay, and dysmorphic features.

Biallelic PIGV variants were first implicated in a sibship of four affected children described by Mabry et al in 1970 (PMID:38790248). Subsequent exome and genome sequencing identified 26 unrelated probands and an observational study of 6 Polish patients—all homozygous for c.1022C>A (p.Ala341Glu)—yielding 32 total cases (PMID:37372388).

Segregation analysis in these families, including the original four siblings, confirms autosomal recessive inheritance of PIGV mutations with full penetrance in homozygotes (PMID:38790248).

The variant spectrum is dominated by hypomorphic missense changes. Notably, c.1022C>A (p.Ala341Glu) recurs in European populations as a founder allele, with additional substitutions such as c.766C>A (p.Gln256Lys), p.Ala341Val, and p.His385Pro documented in affected individuals.

Functional assays in CHO cells demonstrated that p.Ala341Glu, p.Ala341Val, and p.Gln256Lys drastically reduce PIGV expression and cause secretion of ALP due to incomplete GPI anchor attachment (PMID:22228761). A hypomorphic pigv-1(qm34) allele in C. elegans leads to 75% loss of GPI-anchored proteins at the cell surface and embryonic epithelial ruptures, modeling tissue integrity defects seen in patients (PMID:25807459).

A CRISPR–Cas9 mouse bearing the Pigv:p.Ala341Glu variant mirrors human pathology, exhibiting motor coordination deficits, cognitive impairment, increased seizure susceptibility, reduced hippocampal synaptic transmission, and altered gene expression in microglia and neurons (PMID:33402532).

Together, genetic, cellular, and animal model data provide strong, concordant evidence that biallelic PIGV mutations underlie HPMRS1 through GPI-anchor biosynthesis deficiency. PIGV sequencing should be integrated into diagnostic panels for congenital disorders of glycosylation. Key take-home: PIGV variants define a clinically recognizable and functionally validated hyperphosphatasia syndrome amenable to molecular diagnosis.

References

• Genes • 2024 • Rare Genetic Developmental Disabilities: Mabry Syndrome (MIM 239300) Index Cases and Glycophosphatidylinositol (GPI) Disorders. PMID:38790248
• Genes • 2023 • Characteristics of Neuroimaging and Behavioural Phenotype in Polish Patients with PIGV-CDG-An Observational Study and Literature Review. PMID:37372388
• The 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 USA • 2021 • A CRISPR-Cas9-engineered mouse model for GPI-anchor deficiency mirrors human phenotypes and exhibits hippocampal synaptic dysfunctions. PMID:33402532
• PLoS Genetics • 2015 • Glycosyl phosphatidylinositol anchor biosynthesis is essential for maintaining epithelial integrity during Caenorhabditis elegans embryogenesis. PMID:25807459

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