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Cerebral visual impairment and intellectual disability caused by PGAP1 variants

Daniëlle G M Bosch1,2,3,4, F Nienke Boonstra2,4, Taroh Kinoshita5

  • 1Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

European Journal of Human Genetics : EJHG
|March 26, 2015
PubMed

Insights

Novel variants in the PGAP1 gene were identified in a boy with intellectual disability and cerebral visual impairment. These findings confirm a functional loss of PGAP1, linking it to these neurological conditions.

Area of Science:

  • Genetics
  • Neuroscience
  • Biochemistry

Background:

  • Post-translational modification of proteins is crucial for cellular function.
  • Defects in the glycosylphosphatidylinositol (GPI) anchor biosynthesis pathway lead to congenital disorders of glycosylation.
  • The PGAP1 gene plays a role in the remodeling of GPI anchors.

Observation:

  • Whole-exome sequencing identified compound heterozygous variants in PGAP1 in an individual with cerebral visual impairment (CVI), intellectual disability (ID), and factor XII deficiency.
  • Functional studies using PGAP1-deficient Chinese hamster ovary (CHO) cells and lymphoblastoid cell lines (LCLs) demonstrated a loss of PGAP1 function.
  • Mutant PGAP1 constructs failed to rescue PI-PLC resistance in deficient CHO cells, and the patient's LCLs showed no PI-PLC sensitivity.

Findings:

  • Novel compound heterozygous variants, c.274_276del (p.(Pro92del)) and c.921_925del (p.(Lys308Asnfs*25)), in the PGAP1 gene were identified.
  • Functional assays confirmed a complete loss of PGAP1 function in the affected individual.
  • The study establishes a genetic link between PGAP1 variants and CVI, alongside ID and seizures/spasticity.

Implications:

  • This research expands the known phenotypic spectrum associated with PGAP1 mutations.
  • It highlights the critical role of PGAP1 in neurological development, particularly visual pathways.
  • The findings provide a basis for genetic counseling and potential therapeutic strategies for individuals with PGAP1-related disorders.

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