Search

Schwartz-Jampel syndrome (SJS) type 1 is characterized by short stature, myotonia, and chondrodysplasia, and is caused by partial loss-of-function mutations in HSPG2 encoding perlecan. Six missense mutations have been reported in SJS to date and only one has been characterized using a recombinant protein. We report an 11-year-old Japanese boy with SJS, who shows "rigid" walking with less flexion of knees/ankles and protruded mouth. His intelligence is normal. We identified by whole genome resequencing a heterozygous missense p.Leu1088Pro in domain III-2 and a heterozygous nonsense p.Gln3061Ter in domain IV of perlecan. Expression studies revealed that p.Leu1088Pro markedly reduces the cellular expression of domain III-2 and almost nullifies its secretion into the culture medium. As five of the seven missense mutations in SJS affect domain III of perlecan, domain III is likely to be essential for secretion of perlecan into the extracellular space., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Tardive dyskinesia (TD) is characterized by repetitive, involuntary, and purposeless movements that develop in patients treated with long-term dopaminergic antagonists, usually antipsychotics. By a genome-wide association screening of TD in 50 Japanese schizophrenia patients with treatment-resistant TD and 50 Japanese schizophrenia patients without TD (non-TD group) and subsequent confirmation in independent samples of 36 treatment-resistant TD and 136 non-TD subjects, we identified association of a single nucleotide polymorphism, rs2445142, (allelic p=2 x 10(-5)) in the HSPG2 (heparan sulfate proteoglycan 2, perlecan) gene with TD. The risk allele was significantly associated with higher expression of HSPG2 in postmortem human prefrontal brain (p<0.01). Administration of daily injection of haloperidol (HDL) for 50 weeks significantly reduced Hspg2 expression in mouse brains (p<0.001). Vacuous chewing movements (VCMs) induced by 7-week injection of haloperidol-reserpine were significantly infrequent in adult Hspg2 hetero-knockout mice compared with wild-type littermates (p<0.001). Treatment by the acetylcholinesterase inhibitor, physostigmine, was significantly effective for reduction of VCMs in wild-type mice but not in Hspg2 hetero-knockout mice. These findings suggest that the HSPG2 gene is involved in neuroleptic-induced TD and higher expression of HSPG2, probably even after antipsychotic treatment, and may be associated with TD susceptibility.

Background: An association between versican (CSPG2), perlecan (HSPG2), fibrillin 2 (FBN2) and collagen 4A1 (COL4A1) gene variants and intracranial aneurysms (IA) has been reported in 2 studies analyzing Dutch IA patients. The aim of this study was to verify these associations in a Japanese IA population. In addition, a meta-analysis on the association of these genes and IA for the combined Dutch and Japanese populations was performed., Methods: The associated single nucleotide polymorphisms (SNPs) in these genes identified in the Dutch study were genotyped in 632 Japanese IA patients and 808 healthy control subjects using TaqMan SNP genotyping assays., Results: A similar association to that previously found in the Dutch population was found for the CSPG2 (rs251124) and HSPG2 (rs3767137) SNPs, although both associations were not statistically significant in the Japanese population (CSPG2 OR 1.18, 95% CI 0.98-1.41, p = 0.08; HSPG2 OR 1.09, 95% CI 0.90-1.32). Combining the Dutch and Japanese data for a meta-analysis showed an overall association between the CSPG2 SNP and IA (OR 1.29, 95% CI 1.12-1.48, p = 0.0005) and the HSPG2 SNP and IA (OR 1.22, 95% CI 1.08-1.39, p = 0.002). No differences in SNP frequency were observed for FBN2 and COL4A1 between Japanese patients and controls., Conclusions: By analyzing HSPG2, CSPG2, FBN2 and COL4A1, we were able to replicate the association of CSPG2 and show that there is a trend for HSPG2 towards association in the Japanese IA population by means of a meta-analysis combining the Dutch and Japanese results. The association of FBN2 and COL4A1 could not be replicated in the Japanese IA population., (2009 S. Karger AG, Basel.)