HSPG2 – Schwartz-Jampel syndrome type 1

Schwartz-Jampel syndrome type 1 (SJS1) is an autosomal recessive musculoskeletal disorder characterized by chondrodysplasia, short stature, myotonia and facial stiffness. It arises from partial loss-of-function mutations in HSPG2, which encodes the basement membrane proteoglycan perlecan essential for extracellular matrix integrity and neuromuscular junction function. Clinical hallmarks include rigid gait, joint contractures, pectus carinatum and kyphoscoliosis.

Genetic evidence for HSPG2 in SJS1 includes at least 35 probands across 23 unrelated families harboring biallelic variants ([PMID:16927315]). Reported variant classes comprise missense, nonsense, splice-site and frameshift mutations distributed throughout perlecan’s multiple domains. No founder alleles have been identified, and all but a few mutations are private. Compound heterozygous and homozygous configurations have been confirmed by segregation in parents, who are unaffected carriers.

Inheritance is autosomal recessive, with complete penetrance of biallelic deleterious alleles and no known dominant presentations. Segregation analyses across multiple families show that parents heterozygous for truncating or missense variants do not display SJS1 features. Overall, at least 35 affected individuals demonstrate consistent AR inheritance and co-segregation of disease alleles.

The variant spectrum is broad: nine insertions/deletions (41%), six splice-site changes (27%), five missense substitutions (23%) and two nonsense variants (9%) were catalogued in 35 patients ([PMID:16927315]). A representative missense allele is c.8788G>A (p.Glu2930Lys) observed in a Chinese SJS1 proband ([PMID:29901129]). Splice-site mutations such as c.4740+5G>A cause exon skipping in domain III, leading to loss of essential secretion motifs ([PMID:27521129]).

Functional assays provide strong concordant evidence: the p.Leu1088Pro substitution markedly reduces perlecan secretion in vitro ([PMID:26031903]), a Cys1532Tyr knock-in mouse model exhibits neuromyotonia with endplate acetylcholinesterase deficiency ([PMID:18647752]), and zebrafish hspg2 knockdown impairs neural crest-derived mandibular joint formation ([PMID:33678174]). These data support a hypomorphic loss-of-function mechanism for SJS1.

Integration of genetic and experimental findings establishes a definitive association between biallelic HSPG2 variants and SJS1. Diagnostic molecular testing for HSPG2 mutations combined with perlecan immunostaining enables early and accurate confirmation. Key Take-home: Biallelic loss-of-function HSPG2 mutations are conclusively linked to Schwartz-Jampel syndrome type 1, supporting robust molecular diagnosis and informing potential therapeutic targeting of extracellular matrix dysfunction.

References

• Neuromuscular disorders : NMD • 2015 • A missense mutation in domain III in HSPG2 in Schwartz-Jampel syndrome compromises secretion of perlecan into the extracellular space. PMID:26031903
• Neuromuscular disorders : NMD • 2016 • Identification of a novel splice site HSPG2 mutation and prenatal diagnosis in Schwartz Jampel Syndrome type 1 using whole exome sequencing. PMID:27521129
• Molecular medicine reports • 2018 • Novel HSPG2 mutations causing Schwartz–Jampel syndrome type 1 in a Chinese family: A case report PMID:29901129
• Genes • 2023 • Novel HSPG2 Gene Mutation Causing Schwartz-Jampel Syndrome in a Moroccan Family: A Literature Review. PMID:37761893
• 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
• BMC developmental biology • 2021 • Knockdown of hspg2 is associated with abnormal mandibular joint formation and neural crest cell dysfunction in zebrafish. PMID:33678174

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