ABSTRACT
In genetic disease, an accurate expression landscape of disease genes and faithful animal models will enable precise genetic diagnoses and therapeutic discoveries, respectively. We previously discovered that variants in NOS1AP , encoding nitric oxide synthase 1 (NOS1) adaptor protein, cause monogenic nephrotic syndrome (NS). Here, we determined that an intergenic splice product of N OS1AP / Nos1ap and neighboring C1orf226/Gm7694 , which precludes NOS1 binding, is the predominant isoform in mammalian kidney transcriptional and proteomic data. Gm7694 -/- mice, whose allele exclusively disrupts the intergenic product, developed NS phenotypes. In two human NS subjects, we identified causative NOS1AP splice variants, including one predicted to abrogate intergenic splicing but initially misclassified as benign based on the canonical transcript. Finally, by modifying genetic background, we generated a faithful mouse model of NOS1AP -associated NS, which responded to anti-proteinuric treatment. This study highlights the importance of intergenic splicing and a potential treatment avenue in a mendelian disorder.
ABSTRACT
Epidermal nevus syndromes encompass a highly heterogeneous group of systemic disorders, characterized by epidermal nevi, and a spectrum of neuromuscular, ocular, and bone abnormalities. Cutaneous-skeletal hypophosphatemia syndrome (CSHS) constitutes a specific sub-entity in which elevated levels of fibroblast growth factor-23 cause hypophosphatemic rickets that are, to date, not amenable to causal therapy. Here, we report the first long-term follow-up of causal treatment with burosumab in a 3-year-old female patient with CSHS. 4 weeks after initiation of burosumab treatment, serum phosphate normalized to age-appropriate levels. Furthermore, long-term follow-up of 42 months revealed significant improvement of linear growth and gross physical functions, including respiratory insufficiency. Radiographic rickets severity as well as subjective bone pain were strongly reduced, and no side effects were observed over the course of treatment. In summary, we, here, report about a successful treatment of hypophosphatemic rickets in CSHS with burosumab over the time course of 42 months. In our patient, burosumab showed convincing efficacy and safety profile, without any loss of effect or increase of dose.
