HSPG2 – Schwartz-Jampel Syndrome

Schwartz-Jampel syndrome (SJS; MONDO:0009717) is a rare autosomal recessive disorder characterized by congenital myotonia, skeletal dysplasia, short stature and facial dysmorphism, including micrognathia and pursed lips. The responsible gene, HSPG2, encodes perlecan, a heparan sulfate proteoglycan essential for basement membrane integrity and neuromuscular junction function.

Genetic evidence demonstrates biallelic loss-of-function and hypomorphic HSPG2 variants in over 35 probands from more than 23 unrelated families, with families showing recessive segregation of private and recurrent alleles (PMID:11101850; PMID:16927315). Representative pathogenic variants include c.4595G>A (p.Cys1532Tyr) (PMID:11101850), splice site mutations, nonsense and frameshift alleles. These mutations reduce perlecan secretion or stability, resulting in deficient extracellular matrix deposition and impaired acetylcholinesterase anchoring at neuromuscular junctions.

Inheritance is strictly autosomal recessive with compound heterozygous or homozygous genotypes. Segregation analysis across multiple consanguineous and non-consanguineous families identified at least 10 additional affected siblings with concordant genotypes and phenotypes.

Functional studies in patient fibroblasts and muscle biopsies reveal reduced perlecan expression, intracellular retention of mutant proteins, synaptic acetylcholinesterase deficiency, nerve terminal remodeling and complex repetitive discharges on electromyography (PMID:18647752; PMID:11101850). A knock-in mouse model harboring the p.Cys1532Tyr substitution recapitulates neuromyotonia, perlecan dosage-dependent severity and endplate acetylcholinesterase deficiency, confirming a dosage-sensitive haploinsufficiency mechanism (PMID:18647752).

No conflicting reports have been described. The consistent genotype-phenotype correlations, extensive allelic heterogeneity, and concordant in vitro and in vivo functional data over two decades support a definitive gene-disease relationship.

Key Take-home: Biallelic HSPG2 mutations cause autosomal recessive Schwartz-Jampel syndrome via perlecan deficiency leading to neuromuscular hyperexcitability and cartilage dysplasia, guiding molecular diagnosis and therapeutic monitoring.

References

• Nature Genetics • 2000 • Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz-Jampel syndrome (chondrodystrophic myotonia) PMID:11101850
• Human Mutation • 2006 • Spectrum of HSPG2 (Perlecan) mutations in patients with Schwartz-Jampel syndrome PMID:16927315
• Human Molecular Genetics • 2008 • Evidence of a dosage effect and a physiological endplate acetylcholinesterase deficiency in the first mouse models mimicking Schwartz-Jampel syndrome neuromyotonia PMID:18647752

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