Diminished GALNS activity in induced pluripotent stem cells of mucopolysaccharidosis IVA caused by compound p.S162Y and p.C165F mutation.

BACKGROUND

Mucopolysaccharidosis (MPS) IVA is a lysosomal storage disorder caused by mutations in the gene encoding the galactosamine (N-acetyl)-6-sulfatase (GALNS) enzyme. Children with MPS IVA usually develop pectus carinatum, genu valgum and multiple skeletal abnormalities.

AIM

To establish a patient-derived induced pluripotent stem cell (iPSC) disease model to investigate the effects of two GALNS missense mutations.

METHODS

The medical history and clinical manifestations of a patient with MPS IVA were first inspected. The effects of the identified GALNS mutations were predicted through bioinformatic analysis. iPSCs were then generated by using Sendai virus to introduce Yamanaka reprogramming factors to urinary cells isolated from the patient. The pluripotency, karyotypic integrity, genetic mutations and differentiation ability of the iPSCs were tested. The effects of the GALNS mutations were further experimentally characterized using patient-derived cells.

RESULTS

The patient exhibited a typical MPS IVA phenotype. Enzyme replacement therapy could not correct her skeletal abnormalities. GALNS c.485C>A (p.S162Y) and c.494G>T (p.C165F) mutations, inherited from her father and mother, respectively, were identified in the patient. These two mutations were predicted to disturb the hydrophobic core of the GALNS catalytic domain. Patient-derived iPSCs were successfully generated, and further characterization indicated that the two missense mutations significantly diminished GALNS activity without affecting its amount at both the RNA and protein levels.

CONCLUSIONS

We established a novel clinically relevant MPS IVA disease model that will be useful not only for investigating the pathogenic mechanisms of MPS IVA variants but also for drug screening and preclinical evaluation of novel therapies.