PGAP3 Associated with Hyperphosphatasia with Mental Retardation Plays a Novel Role in Brain Morphogenesis and Neuronal Wiring at Early Development

Cells. 2020 Jul 27;9(8):1782. doi: 10.3390/cells9081782.


Recessive mutations in Post-GPI attachment to proteins 3 (PGAP3) cause the rare neurological disorder hyperphosphatasia with mental retardation syndrome 4 type (HPMRS4). Here, we report a novel homozygous nonsense mutation in PGAP3 (c.265C>T-p.Gln89*), in a 3-year-old boy with unique novel clinical features. These include decreased intrauterine fetal movements, dysgenesis of the corpus callosum, olfactory bulb agenesis, dysmorphic features, cleft palate, left ear constriction, global developmental delay, and hypotonia. The zebrafish functional modeling of PGAP3 loss resulted in HPMRS4-like features, including structural brain abnormalities, dysmorphic cranial and facial features, hypotonia, and seizure-like behavior. Remarkably, morphants displayed defective neural tube formation during the early stages of nervous system development, affecting brain morphogenesis. The significant aberrant midbrain and hindbrain formation demonstrated by separation of the left and right tectal ventricles, defects in the cerebellar corpus, and caudal hindbrain formation disrupted oligodendrocytes expression leading to shorter motor neurons axons. Assessment of zebrafish neuromuscular responses revealed epileptic-like movements at early development, followed by seizure-like behavior, loss of touch response, and hypotonia, mimicking the clinical phenotype human patients. Altogether, we report a novel pathogenic PGAP3 variant associated with unique phenotypic hallmarks, which may be related to the gene's novel role in brain morphogenesis and neuronal wiring.

Keywords: human disease model; hyperphosphatasia mental retardation syndrome 4 (HPMRS4); neural tube defect; neurological disorder; post-GPI attachment to proteins 3 (PGAP3); whole genome sequencing; zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / metabolism
  • Animals
  • Brain / pathology*
  • Carboxylic Ester Hydrolases / adverse effects*
  • Disease Models, Animal
  • Humans
  • Intellectual Disability / genetics*
  • Intellectual Disability / metabolism
  • Morphogenesis
  • Phosphorus Metabolism Disorders / genetics*
  • Phosphorus Metabolism Disorders / metabolism
  • Receptors, Cell Surface
  • Zebrafish


  • Receptors, Cell Surface
  • Carboxylic Ester Hydrolases
  • PGAP3 protein, human

Supplementary concepts

  • Hyperphosphatasia with Mental Retardation