Spectrum of HSPG2 (Perlecan) mutations in patients with Schwartz-Jampel syndrome.
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.
Stum
Morgane
M
Inserm, U546, Paris, France.
Davoine
Claire-Sophie
CS
Vicart
Savine
S
Guillot-Noël
Léna
L
Topaloglu
Haluk
H
Carod-Artal
Francisco Javier
FJ
Kayserili
Hülya
H
Hentati
Fayçal
F
Merlini
Luciano
L
Urtizberea
Jon Andoni
JA
Hammouda
El-Hadi
el-H
Quan
Phuc Canh
PC
Fontaine
Bertrand
B
Nicole
Sophie
S
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
D019812:Heparan Sulfate Proteoglycans; D050505:Mutant Proteins; C071927:perlecan