SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling.

Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder. Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies. In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling. We show that SCUBE3 acts as a BMP2/BMP4 co-receptor, recruits the BMP receptor complexes into raft microdomains, and positively modulates signaling possibly by augmenting the specific interactions between BMPs and BMP type I receptors. Scube3-/- mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder. Our findings identify a human disease caused by defective function of a member of the SCUBE family, and link SCUBE3 to processes controlling growth, morphogenesis, and bone and teeth development through modulation of BMP signaling.

Schwartz Jampel syndrome responding positively to carbamazepine therapy: a case report and a novel mutation.

Gürbüz G, Mutlu Albayrak H. Schwartz Jampel syndrome responding positively to carbamazepine therapy: a case report and a novel mutation. Turk J Pediatr 2019; 61: 967-970. Schwartz Jampel syndrome was first described in 1962. It is an autosomal recessive disease with generalized myotonic myopathy and skeletal dysplasia. A mutation in the HSPG2 gene occurs. Approximately 150 cases have been reported in literature. A 4-year-old girl presented to the pediatric neurology clinic due to difficulty in walking. The patient had difficulty opening her mouth and swallowing. She was unable to eat solid foods and was bottle fed. She was able to stand leaning forward, with her legs open and with one hand supported. Bilateral blepharospasm, posterior cleft palate, microstomia, pursed lips, kyphoscoliosis, contracture in the elbows, long thin fingers and campodactyly in the bilateral 5th fingers were present. Myotonic contraction with thenar percussion was observed. Previously undescribed mutation was determined in HSPG2 gene in the genetic study. Oral carbamazepine therapy was initiated and 1.5 months later the patient`s muscle rigidity had decreased and her motor skills had improved. This report contributes to the literature by defining a new mutation in HSPG2 gene and showing the importance of early diagnosis of the disease.