Mucolipidosis II: novel variants, clinical variation and assessment of HAP1 cells as a disease model.

Mucolipidosis type II is an autosomal recessive lysosomal storage disease resulting from biallelic variants in the GNPTAB gene encoding the N-acetylglucosamine phosphotransferase α/β subunits. Deficiency of this enzyme disrupts the mannose-6-phosphate (M6P) trafficking pathway, resulting in mistargeting of lysosomal acid hydrolases. Subsequently, lysosomal accumulation of undegraded macromolecules gives rise to a clinical phenotype with developmental/intellectual disability, skeletal deformities, coarse features, and cardiopulmonary dysfunction. Here, we report a cohort of eight patients (7 Egyptians and 1 Yemeni) from seven families with three reported homozygous pathogenic variants and three unreported variants (p.(Asn750Ilefs*4), p.(Val795Glyfs*7), and c.3602 + 2 T > C). In addition, the GNPTAB gene was ablated in the H. sapiens haploid HAP1 cells by CRISPR-Cas9 editing, to investigate the potential of this cell line for the assessment of variant pathogenicity. This included introduction of the recurrent c.3503_3504delTC variant. A phenotype of impaired autophagic flux was recapitulated, suggesting that HAP1 cells are a suitable model for this disorder.