title: Spectrum of HSPG2 (Perlecan) mutations in patients with Schwartz-Jampel syndrome.
abstract: Schwartz-Jampel syndrome (SJS) is a rare autosomal recessive condition defined by the association of myotonia with chondrodysplasia. SJS results from mutations in the HSPG2 gene, which encodes perlecan, a major component of basement membranes. Only eight HSPG2 mutations have been reported in six SJS families. Here, we describe the molecular findings in 23 families (35 patients) with SJS, being one-third of the SJS cases reported in the medical literature. We identified 22 new HSPG2 mutations and unreported polymorphisms. Mutations included nine deletion or insertion (41%), six splice site (27%), five missense (23%), and two nonsense mutations (9%). All but four mutations were private, and we found no evidence for a founder effect. Analyses of HSPG2 messenger RNA (mRNA) and perlecan immunostaining on patients' cells revealed a hypomorphic effect of the studied mutations. They also demonstrated distinct consequences of truncating and missense mutations on perlecan expression as truncating mutations resulted in instability of HSPG2 mRNA through nonsense mRNA-mediated decay, whereas missense mutations involving cysteine residues led to intracellular retention of perlecan, probably due to quality control pathways. Our analyses strengthen the idea that SJS results from hypomorphic mutations of the HSPG2 gene. They also propose tools for its molecular diagnosis and provide new clues for the understanding of its pathophysiology.
authors.affiliation: Inserm, U546, Paris, France.
authors.forename: Morgane
authors.initials: M
authors.lastname: Stum
authors.forename: Claire-Sophie
authors.initials: CS
authors.lastname: Davoine
authors.forename: Savine
authors.initials: S
authors.lastname: Vicart
authors.forename: Léna
authors.initials: L
authors.lastname: Guillot-Noël
authors.forename: Haluk
authors.initials: H
authors.lastname: Topaloglu
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Carod-Artal
authors.forename: Hülya
authors.initials: H
authors.lastname: Kayserili
authors.forename: Fayçal
authors.initials: F
authors.lastname: Hentati
authors.forename: Luciano
authors.initials: L
authors.lastname: Merlini
authors.forename: Jon Andoni
authors.initials: JA
authors.lastname: Urtizberea
authors.forename: El-Hadi
authors.initials: el-H
authors.lastname: Hammouda
authors.forename: Phuc Canh
authors.initials: PC
authors.lastname: Quan
authors.forename: Bertrand
authors.initials: B
authors.lastname: Fontaine
authors.forename: Sophie
authors.initials: S
authors.lastname: Nicole
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D001483:Base Sequence; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006239:Haplotypes; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008957:Models, Genetic; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics*; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: D019812:Heparan Sulfate Proteoglycans; D050505:Mutant Proteins; C071927:perlecan