Evaluation of Human-Induced Pluripotent Stem Cells Derived from a Patient with Schwartz–Jampel Syndrome Revealed Distinct Hyperexcitability in the Skeletal Muscles

Abstract

Schwartz–Jampel syndrome (SJS) is an autosomal recessive disorder caused by loss-of-function mutations in heparan sulfate proteoglycan 2 (HSPG2), which encodes the core basement membrane protein perlecan. Myotonia is a major criterion for the diagnosis of SJS; however, its evaluation is based solely on physical examination and can be challenging in neonates and young children. Furthermore, the pathomechanism underlying SJS-related myotonia is not fully understood, and effective treatments for SJS are limited. Here, we established a cellular model of SJS using patient-derived human-induced pluripotent stem cells. This model exhibited hyper-responsiveness to acetylcholine as a result of abnormalities in the perlecan molecule, which were confirmed via comparison of their calcium imaging with calcium imaging of satellite cells derived from Hspg2−/−-Tg mice, which exhibit myotonic symptoms similar to SJS symptoms. Therefore, our results confirm the utility of creating cellular models for investigating SJS and their application in evaluating myotonia in clinical cases, while also providing a useful tool for the future screening of SJS therapies.

Novel HSPG2 Gene Mutation Causing Schwartz–Jampel Syndrome in a Moroccan Family: A Literature Review

“…Domain I contains attachment sites for heperan sulfate chains and interacts with laminin, collagen and fibronectin; domain II is arranged into four cysteine-rich modules and binds low-density lipoprotein (LDL) receptor; domain III consists of an altering arrangement of three cysteine-free globular modules within a laminin epidermal growth factor-like motif; domain IV is made up of a tandem array of twenty-one immunoglobulin-like repeats; domain V is composed of a tandem arrangement of three laminin-type G and four EGF-like modules [ 3 , 8 , 9 , 10 , 11 ]. This ubiquitous protein binds to a wide range of molecules including growth factors and other multivalent extracellular matrix components, and has multiple functions, including growth factor signalling, cell adhesion, angiogenesis, basement membrane and cartilage maintenance and acetylcholinesterase anchoring at the neuromuscular junction, and plays an important role in maintaining cartilaginous tissue integrity and regulating muscle excitability [ 12 , 13 ].…”

Le syndrome de Schwartz-Jampel

“…Une équipe de chercheurs du Texas dédiée à l'étude de la matrice extra-cellulaire continue toutefois à s'intéresser au perlécan et à ses fonctions. Des chercheurs chinois ont mis au point des cellules souches pluripotentes issues de patients atteints de SJS avec lesquelles ils ont pu récemment montrer que l'hyperexcitabilité se situait plus au niveau du muscle que des terminaisons nerveuses[46].…”