PGAP2 – Hyperphosphatasia-Intellectual Disability Syndrome

PGAP2 deficiency causes autosomal recessive hyperphosphatasia-intellectual disability syndrome 3 (PGAP2; hyperphosphatasia-intellectual disability syndrome). Affected individuals present with global developmental delay, precocious puberty, hypotonia, seizures, and persistent hyperphosphatasia.

Compound heterozygous PGAP2 variants were identified in a 5-year-old female with global developmental delay and precocious puberty: c.103del (p.Leu35SerfsTer90) and c.134A>G (p.His45Arg) (PMID:36636587). Additional homozygous missense variants have been reported: c.46C>T (p.Arg16Trp) in two unrelated individuals (PMID:23561847), c.554G>A (p.Arg185Gln) in a consanguineous Bedouin kindred (PMID:29119105), and c.881C>T (p.Thr294Met) in index cases (PMID:31805394).

Segregation analyses demonstrated cosegregation of recessive PGAP2 alleles with disease in two families (PMID:23561847; PMID:29119105).

Functional assays in PGAP2-null cells revealed that p.Arg16Trp and p.Thr294Met impair GPI-anchor fatty-acid remodeling, resulting in reduced surface expression of CD55 and CD59 (PMID:23561847; PMID:31805394). Rescue experiments in CHO cells confirmed the hypomorphic effect of p.Thr294Met (PMID:31805394).

The pathogenic mechanism is loss of PGAP2-mediated GPI-anchor remodeling, destabilizing GPI-anchored proteins at the cell membrane and leading to neurological and endocrine dysfunction.

Early genetic diagnosis of PGAP2-related HPMRS3 enables management of biochemical abnormalities; pyridoxine and folinic acid supplementation normalized CSF metabolites and improved developmental outcomes in one case (PMID:36636587).

These data provide strong evidence for autosomal recessive PGAP2 mutations in HPMRS3, supporting clinical genetic testing and targeted therapeutic interventions.

References

• JIMD reports • 2023 • Hyperphosphatasia with mental retardation syndrome 3: Cerebrospinal fluid abnormalities and correction with pyridoxine and Folinic acid. PMID:36636587
• American journal of human genetics • 2013 • PGAP2 mutations, affecting the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation syndrome. PMID:23561847
• BioMed research international • 2017 • A Rare Variant in PGAP2 Causes Autosomal Recessive Hyperphosphatasia with Mental Retardation Syndrome, with a Mild Phenotype in Heterozygous Carriers. PMID:29119105
• European journal of medical genetics • 2020 • A post glycosylphosphatidylinositol (GPI) attachment to proteins, type 2 (PGAP2) variant identified in Mabry syndrome index cases: Molecular genetics of the prototypical inherited GPI disorder. PMID:31805394

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