A novel iPSC model reveals selective vulnerability of neurons in multiple sulfatase deficiency.

Multiple sulfatase deficiency (MSD) is an ultra-rare, inherited lysosomal storage disease caused by mutations in the gene sulfatase modifying factor 1 (SUMF1). MSD is characterized by the functional deficiency of all sulfatase enzymes, leading to the storage of sulfated substrates including glycosaminoglycans (GAGs), sulfolipids, and steroid sulfates. Patients with MSD experience severe neurological impairment, hearing loss, organomegaly, corneal clouding, cardiac valve disease, dysostosis multiplex, contractures, and ichthyosis. Here, we generated a novel human model of MSD by reprogramming patient peripheral blood mononuclear cells to establish an MSD induced pluripotent stem cell (iPSC) line (SUMF1 p.A279V). We also generated an isogenic control iPSC line by correcting the pathogenic variant with CRISPR/Cas9 gene editing. We successfully differentiated these iPSC lines into neural progenitor cells (NPCs) and NGN2-induced neurons (NGN2-iN) to model the neuropathology of MSD. Mature neuronal cells exhibited decreased SUMF1 gene expression, increased lysosomal stress, impaired neurite outgrowth and maturation, reduced sulfatase activities, and GAG accumulation. Interestingly, MSD iPSCs and NPCs did not exhibit as severe of phenotypes, suggesting that as neurons differentiate and mature, they become more vulnerable to loss of SUMF1. In summary, we demonstrate that this human iPSC-derived neuronal model recapitulates the cellular and biochemical features of MSD. These cell models can be used as tools to further elucidate the mechanisms of MSD pathology and for the development of therapeutics.

The Dasya baillouviana and D. cryptica complexes (Delesseriaceae, Rhodophyta) in Bermuda with three additional new species from the archipelago.

Continuing molecular studies of the red algal genus Dasya collected off the coast of Bermuda have revealed two new species in the developing D. cryptica species complex-one from each the euphotic and mesophotic zones, D. orae sp. nov. and D. bathypelagica sp. nov., respectively. Furthermore, what was known as D. baillouviana in Bermuda is shown to represent D. hibernae sp. nov., a sibling of D. pedicellata from New England and New York, USA. Despite morphological similarities to the recently described shallow subtidal species from the islands, D. cryptica, molecular sequencing and morphological comparisons demonstrated that a new set of inshore specimens represented D. orae. The larger, new deep-water species, D. bathypelagica, was genetically compared with recent Bermuda collections of D. baillouviana and others worldwide morphologically falling under this epithet and represented a new species also grouping in the D. cryptica complex. The specimens of D. hibernae from Bermuda were shown to be genetically distinct from specimens of D. pedicellata from southern New England and New York. Molecular analyses necessitated the resurrection of D. pedicellata and uncovered undescribed species in the D. baillouviana complex in the western Atlantic. Based upon genetic evidence provided here, the generitype of Rhodoptilum nested among species in the D. baillouviana complex including the generitype. This finding required the synonymy of the genus Rhodoptilum with Dasya and allowed for the reinstatement of D. plumosa. Furthermore, Dasya collinsiana resolved in the lineage including a closely related species to the generitype of Dasysiphonia, necessitating the transfer of this Bermudian species and others worldwide from the genus Dasya to Dasysiphonia.