Schwartz-Jampel syndrome (SJS1) is a rare autosomal recessive disorder characterized by permanent myotonia (prolonged failure of muscle relaxation) and skeletal dysplasia, resulting in reduced stature, kyphoscoliosis, bowing of the diaphyses and irregular epiphyses1. Electromyographic investigations reveal repetitive muscle discharges, which may originate from both neurogenic and myogenic alterations2,3. We previously localized the SJS1 locus to chromosome 1p34–p36.1 and found no evidence of genetic heterogeneity4,5. Here we describe mutations, including missense and splicing mutations, of the gene encoding perlecan (HSPG2) in three SJS1 families. In so doing, we have identified the first human mutations in HSPG2, which underscore the importance of perlecan not only in maintaining cartilage integrity but also in regulating muscle excitability.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Viljoen, D. & Beighton, P. Schwartz-Jampel syndrome (chondrodystrophic myotonia). J. Med. Genet. 29, 58–62 (1992).
Christova, L.G., Alexandrov, A.S. & Ishpekova, B.A. Single motor unit activity pattern in patients with Schwartz-Jampel syndrome. J. Neurol. Neurosurg. Psychiatry 66, 252–253 (1999).
Cadilhac, J., Baldet, P., Greze, J. & Duday, H. E.M.G. studies of two family cases of the Schwartz and Jampel syndrome (osteo-chondro-muscular dystrophy with myotonia). Electromyogr. Clin. Neurophysiol. 15, 5–12 (1975).
Nicole, S. et al. Localization of the Schwartz-Jampel syndrome (SJS) locus to chromosome 1p34-p36.1 by homozygosity mapping. Hum. Mol. Genet. 4, 1633–1636 (1995).
Fontaine, B. et al. Recessive Schwartz-Jampel syndrome (SJS): confirmation of linkage to chromosome 1p, evidence of genetic homogeneity and reduction of the SJS locus to a 3-cM interval. Hum. Genet. 98, 380–385 (1996).
Iozzo, R.V. Matrix proteoglycans: from molecular design to cellular function. Annu. Rev. Biochem. 67, 609–652 (1998).
Hassell, J.R. et al. Isolation of a heparan sulfate-containing proteoglycan from basement membrane. Proc. Natl Acad. Sci. USA 77, 4494–4498 (1980).
SundarRaj, N., Fite, D., Ledbetter, S., Chakravarti, S. & Hassell, J.R. Perlecan is a component of cartilage matrix and promotes chondrocyte attachment. J. Cell. Sci. 108, 2663–2672 (1995).
Arikawa-Hirasawa, E., Watanabe, H., Takami, H., Hassell, J.R. & Yamada, Y. Perlecan is essential for cartilage and cephalic development. Nature Genet. 23, 354–358 (1999).
Costell, M. et al. Perlecan maintains the integrity of cartilage and some basement membranes. J. Cell. Biol. 147, 1109–1122 (1999).
Murdoch, A.D., Dodge, G.R., Cohen, I., Tuan, R.S. & Iozzo, R.V. Primary structure of the human heparan sulfate proteoglycan from basement membrane (HSPG2/perlecan). A chimeric molecule with multiple domains homologous to the low density lipoprotein receptor, laminin, neural cell adhesion molecules, and epidermal growth factor. J. Biol. Chem. 267, 8544–8557 (1992).
Cohen, I.R., Grassel, S., Murdoch, A.D. & Iozzo, R.V. Structural characterization of the complete human perlecan gene and its promoter. Proc. Natl Acad. Sci. USA 90, 10404–10408 (1993).
Shapiro, M.B. & Senapathy, P. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res. 15, 7155–7174 (1987).
Noonan, D.M. & Hassell, J.R. Perlecan, the large low-density proteoglycan of basement membranes: structure and variant forms. Kidney Int. 43, 53–60 (1993).
Hopf, M., Gohring, W., Kohfeldt, E., Yamada, Y. & Timpl, R. Recombinant domain IV of perlecan binds to nidogens, laminin-nidogen complex, fibronectin, fibulin-2 and heparin. Eur. J. Biochem. 259, 917–925 (1999).
Aberfeld, D.C., Hinterbuchner, L.P. & Schneider, M. Myotonia, dwarfism, diffuse bone disease and unusual ocular and facial abnormalities (a new syndrome). Brain 88, 313–322 (1965).
Ben Hamida, M., Miladi, N. & Ben Hamida, C. Schwartz-Jampel syndrome. Clinical and histopathological study of 4 cases. Rev. Neurol. (Paris) 147, 279–284 (1991).
Rogalski, T.M., Gilchrist, E.J., Mullen, G.P. & Moerman, D.G. Mutations in the unc-52 gene responsible for body wall muscle defects in adult Caenorhabditis elegans are located in alternatively spliced exons. Genetics 139, 159–169 (1995).
Couchman, J.R. & Ljubimov, A.V. Mammalian tissue distribution of a large heparan sulfate proteoglycan detected by monoclonal antibodies. Matrix 9, 311–321 (1989).
Fontaine, B., Plassart-Schiess, E. & Nicole, S. Diseases caused by voltage-gated ion channels. Mol. Aspects Med. 18, 415–463 (1997).
Srinivasan, J., Schachner, M. & Catterall, W.A. Interaction of voltage-gated sodium channels with the extracellular matrix molecules tenascin-C and tenascin-R. Proc. Natl Acad. Sci. USA 95, 15753–15757 (1998).
Xiao, Z.C. et al. Tenascin-R is a functional modulator of sodium channel β subunits. J. Biol. Chem. 274, 26511–26517 (1999).
Peng, H.B., Xie, H., Rossi, S.G. & Rotundo, R.L. Acetylcholinesterase clustering at the neuromuscular junction involves perlecan and dystroglycan. J. Cell. Biol. 145, 911–921 (1999).
van Dijk, J.G., Lammers, G.J., Wintzen, A.R. & Molenaar, P.C. Repetitive CMAPs: mechanisms of neural and synaptic genesis. Muscle Nerve 19, 1127–1133 (1996).
Hansen, P.M. et al. Genetic variation of the heparan sulfate proteoglycan gene (perlecan gene). Association with urinary albumin excretion in IDDM patients. Diabetes 46, 1658–1659 (1997).
Kallunki, P. & Tryggvason, K. Human basement membrane heparan sulfate proteoglycan core protein: a 467-kD protein containing multiple domains resembling elements of the low density lipoprotein receptor, laminin, neural cell adhesion molecules, and epidermal growth factor. J. Cell. Biol. 116, 559–571 (1992).
Schulze, B., Mann, K., Battistutta, R., Wiedemann, H. & Timpl, R. Structural properties of recombinant domain III-3 of perlecan containing a globular domain inserted into an epidermal-growth-factor-like motif. Eur. J. Biochem. 231, 551–556 (1995).
We thank the patients, their families and the physicians for participation; A. Munnich for human chrondrocyte RNA; the UK HGMP for PAC PCR pools of the RPCI-1 library and PAC clones; the Banque de Tissus pour la Recherche de l'Association Française contre les Myopathies (AFM-BTR) for skeletal muscle samples; the cell and DNA banks of the Institut National de la Santé et de la Recherche Médicale (INSERM) U289 and of the Groupe Hospitalier Cochin-Port Royal for lymphoblastoid cell lines and DNA samples; and N. Tabti for comments on the manuscript. S.N. was supported by grants from the Académie Nationale de Médecine and, subsequently, AFM. This work received financial support from AFM and INSERM (APEX).
About this article
Neuromuscular Disorders (2019)
The Journal of Pediatrics (2018)
Frontiers in Pharmacology (2018)
Protein-anchoring therapy to target extracellular matrix proteins to their physiological destinations
Matrix Biology (2018)