A novel A97P amino acid substitution in alpha-galactosidase A leads to a classical Fabry disease with cardiac manifestations

Kimura, Kouichi; Sato‐Matsumura, Kazuko C.; Nakamura, Hideki; Onodera, Yuya; Morita, Ken; Enami, Norihiro; Shougase, T.; Ohsaki, Tomohiro; Kato, Masaaki; Takahashi, Tohru; Yamaguchi, Yube; Shimizu, Hiroshi

doi:10.1046/j.1365-2133.2002.04902.x

Cited by 9 publications

(3 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As a case in point, Fabry patients with varying levels of residual enzyme activity have been reported to develop either no clinical signs of the disease or late-onset, mild forms with restricted organ involvement. Even classical hemizygotes may have residual ␣-Gal A activity (13,31,32). In our study, the enzyme enhancement effected by the DGJ treatment was sufficient to clear the lysosomal storage of Gb3 in such Fabry fibroblasts.…”

Section: Discussionmentioning

confidence: 45%

A synthetic chaperone corrects the trafficking defect and disease phenotype in a protein misfolding disorder

2005

View full text Add to dashboard Cite

Mutations in proteins that induce misfolding and proteasomal degradation are common causes of inherited diseases. Fabry disease is a lysosomal storage disorder caused by a deficiency of alpha-galactosidase A activity in lysosomes resulting in an accumulation of glycosphingolipid globotriosylceramide (Gb3). Some classical Fabry hemizygotes and all cardiac variants have residual alpha-galactosidase A activity, but the mutant enzymes are unstable. Such mutant enzymes appear to be misfolded, recognized by the ER protein quality control, and degraded before sorting into lysosomes. Hence, correction of the trafficking defect of mutant but catalytically active enzyme into lysosomes would be beneficial for treatment of the disease. Here we show that a nontoxic competitive inhibitor (1-deoxygalactonojirimycin) of alpha-galactosidase A functions as a chemical chaperone by releasing ER-retained mutant enzyme from BiP. The treatment with subinhibitory doses resulted in efficient, long-term lysosomal trafficking of the ER-retained mutant alpha-galactosidase A. Successful clearance of lysosomal Gb3 storage and a near-normal lysosomal phenotype was achieved in human Fabry fibroblasts harboring different types of mutations. Small molecule chemical chaperones will be therapeutically useful for various lysosomal storage disorders as well as for other genetic metabolic disorders caused by mutant but nonetheless catalytically active enzymes.

show abstract

Section: Discussionmentioning

confidence: 45%

A synthetic chaperone corrects the trafficking defect and disease phenotype in a protein misfolding disorder

2005

View full text Add to dashboard Cite

show abstract

“…In contrast to atherosclerosis where lipid-loaded EC are restricted to the atherosclerotic plaque, in Fabry's disease they are located in all vasculature. In addition to the classical clinical manifestations (angiokeratomas of the skin, pain in the extremities, corneal and lenticular opacities) [6] the progressive Gb3 accumulation with age leads to systemic vasculopathy, cardiac disorders, kidney failure [4,7,8,9]. Although the mechanisms of the formation of lipid loaded-EC in Fabry's disease and atherogenesis may be different, the EC dysfunction is a common feature.…”

Section: Introductionmentioning

confidence: 99%

Relationship of eNOS gene variants to diseases that have in common an endothelial cell dysfunction

et al. 2005

View full text Add to dashboard Cite

The endothelial cell (EC) dysfunction is a common characteristic of various pathologies that include atherosclerosis, hypertension, and Fabry's disease. Aware of the role of eNO and ACE in EC dysfunction, we questioned whether polymorphism of eNOS and/or ACE gene may be a common denominator in these pathologies. Patients with CHD (108), HT (109), Fabry's disease (37) and healthy subjects (control, 141) were genotyped for the eNOSG894T by RFLP‐PCR technique and for eNOS4b/a, and ACEI/D polymorphisms by PCR amplification. The results of these studies were statistically evaluated. Compared to controls, the frequency of the eNOSG894T (T allele) was higher in CHD (P=0.03) and Fabry (P=0.01), while the eNOS4b/a (a allele) in CHD (P=0.01) and HT patients (P=0.01). The proportion of the ACEI/D was similar in all subjects. In CHD patients at “low risk” of atherogenic factors, the frequency of the T and a alleles of eNOS gene was high (P=0.03 and 0.02, respectively). Carriers of the T allele of eNOSG894T were over‐represented (P=0.04) in Fabry subgroup with renal failure. Compared to women, the eNOS894T alleles were more frequent (P=0.03) in men with CHD and HT, whereas ACE I/D in men (P=0.03) with HT. These findings suggest: (i) the frequency of eNOSG894T and/or eNOS4b/a is significantly associated with coronary dysfunction; (ii) eNOS4b/a confers a relatively high risk of hypertension in subjects with atherogenic risk factors; (iii) the frequency of eNOSG894T is high in Fabry hemizygotes with renal complications. Therefore, eNOS gene polymorphism represent a frequent risk factor for vascular abnormalities in CHD, HT and Fabry's disease, afflictions which have in common, the endothelial dysfunction.

show abstract

“…Genomic DNA was first extracted from peripheral blood mononuclear cells obtained from patients in addition to 100 unrelated healthy volunteers as controls, which was followed by PCR amplification and subsequent direct sequencing. Oligonucleotide primers to amplify all exons Nagasaki A et al 6 6 including GLA exon-intron borders, and PCR conditions were based on a previous report [9]. As summarized in Table 1, we found 3 missense mutations comprising of single base nucleotide substitutions (cases 1-3) and 1 nonsense mutation due to a single base nucleotide deletion (case 4), all of which could not be detected in any of the control samples and were therefore unlikely to be polymorphisms (Table 1 and Fig.…”

mentioning

confidence: 99%

Clinical and genetic analysis of Fabry disease: Report of six cases including three heterozygous females

Nagasaki

Nishie²,

Satô³

et al. 2008

Journal of Dermatological Science

View full text Add to dashboard Cite

A novel A97P amino acid substitution in alpha-galactosidase A leads to a classical Fabry disease with cardiac manifestations

Abstract: These results indicate that the A97P amino acid substitution in GLA might tend to induce classical Fabry disease.

Cited by 9 publications

References 5 publications

A synthetic chaperone corrects the trafficking defect and disease phenotype in a protein misfolding disorder

A synthetic chaperone corrects the trafficking defect and disease phenotype in a protein misfolding disorder

Relationship of eNOS gene variants to diseases that have in common an endothelial cell dysfunction

Clinical and genetic analysis of Fabry disease: Report of six cases including three heterozygous females

Contact Info

Product

Resources

About