Summary
Fabry disease is an X-chromosomal storage disorder due to loss-of-function mutations of the GLA gene encoding the lysosomal enzyme α-galactosidase A. Accumulating glycosphingolipid deposits disturb the function of various cells, in particular that of myocytes, arterial smooth-muscle cells, and vascular endothelium. Hypertrophic cardiomyopathy, for example measured by left posterior wall thickness (LPWT) of the heart, represents a major component of Fabry disease morbidity in adult patients. Endothelium-derived nitric oxide (eNO), produced by eNO synthase (eNOS), is a key regulator of vessel wall function and cardiovascular homeostasis. We analysed the effect of the polymorphisms c.894G > T (p.Glu298Asp) in exon 7 and the 27 bp tandem repeat (VNTR; allele a: 4 and allele b: 5 repeats) in intron 4 of the NOS3 gene, encoding eNOS, on LPWT of 102 patients with Fabry disease. For the association analysis, the distance of each patient’s LPWT value from the cohort-specific, age-dependent regression line point (expected values) was used. In the cohort of 46 male patients, LPWT mean value of the group with GG genotype at position c.894 was smaller by 1 mm than that of (GT + TT) (p = 0.058). LPWT of patients with bb was thicker by 1.4 mm than that of (ab + aa) (p = 0.022). In patients with haplotype Ga, a thinner LPWT was seen than in those with Tb (p = 0.006). While no correlation was found between the GLA genotype and LPWT, the difference of 2.44 mm between the relative LPWT mean values of the two extreme NOS3 groups corresponds to the absolute LPWT increase that an average male patient with Fabry disease experiences during about 12 years. These are the first data showing a significant association of non-GLA-derived sequence variants with the cardiac phenotype in Fabry disease that may in part explain the great phenotypic variability of the disease.
Abbreviations
- adPKD:
-
autosomal dominant polycystic kidney disease
- eNO:
-
endothelium-derived nitric oxide
- eNOS:
-
endothelial nitric oxide synthase
- FD:
-
Fabry disease
- Gb3 :
-
globotriaosylceramide
- GLA :
-
gene for α-galactosidase A
- LPWT:
-
left posterior wall thickness
- NO:
-
nitric oxide
- NOS3 :
-
gene for eNOS
- VNTR:
-
variable number of tandem repeat
References
Altarescu G, Moore DF, Pursely R, et al (2001) Enhanced endothelium-dependent vasodilation in Fabry disease. Stroke 32: 1559–1562.
Casas JP, Cavalleri GL, Bautista LE, Smeeth L, Humphries SE, Hingnorani AD (2006) Endothelial nitric oxide synthase gene polymorphisms and cardiovascular disease: a HuGe review. Am J Epidemiol 164: 921–935. doi:10.1093/aje/kwj302.
Charles IG, Scorer CA, Moro MA (1996) Expression of human nitric oxide synthase isoforms. Methods Enzymol 268: 449–460. doi:10.1016/S0076-6879(96)68047-1.
Chimenti C, Hamdani N, Boontje NM, et al (2008) Myofilament degradation and dysfunction of human cardiomyocytes in Fabry disease. Am J Pathol 172: 1482–1490. doi:10.2353/ajpath.2008.070576.
Desnick R, Ioannou Y, Eng CM (2001). Alpha-galactosidase a deficiency: Fabry disease. In: Valle D, ed. The Metabolic and Molecular Bases of Inherited Storage Diseases, 8th ed. New York: McGraw-Hill, 3733–3774.
Elleder M, Bradova V, Smid V, et al (1990) Cardiocyte storage and hypertrophy as a sole manifestation of Fabry’s disease: report on a case simulating hypertrophic non-obstructive cardiomyopathy. Virchows Arch A Pathol Anat Histopathol 417: 449–455. doi:10.1007/BF01606034.
Forte P, Kneale BJ, Ritter JM (1998) Evidence for a difference in nitric oxide biosynthesis between healthy women and men. Hypertension 32: 730–734.
Heltianu C, Costache G, Azibi K, Poenaru L, Simionescu M (2002) Endothelial nitric oxide synthase gene polymorphisms in Fabry’s disease. Clin Genet 61: 423–429. doi:10.1034/j.1399-0004.2002.610605.x.
MacDermot KD, Holmes A, Miners AH (2001) Natural history of Fabry disease in affected males and obligate carriers. JInherit Metab Dis 24(Supplement 2): 13–14. doi:10.1023/A:1012447102358.
Marroni AS, Metzger IF, Souza-Costa DC, et al (2005) Consistent interethnic differences in the distribution of clinically relevant endothelial nitric oxide synthase genetic polymorphisms. Nitric Oxide 12: 177–182. doi:10.1016/j.niox.2005.02.002.
Persu A, Stoenoiu M, Messiaen T (2002) Modifier effect of eNOS in autosomal dominant polycystic kidney disease. Hum Mol Genet 11: 229–241. doi:10.1093/hmg/11.3.229.
Senthil D, Raveendran M, Shen YH, et al (2005). Genotype-dependant expression of endothelial nitric oxide synthase (eNOS) and its regulatory proteins in cultured endothelial cells. DNA Cell Biol 24: 218–224. doi:10.1089/dna.2005.24.218.
Tanus-Santos JE, Desai M, Flockhart DA (2001) Effects of ethnicity on the distribution of clinically relevant endothelial nitric oxide variants. Pharmacogenetics 11: 719–725. doi:10.1097/00008571-200111000-00011.
Veldman BA, Spiering W, Doevendans PA, et al (2002) The Glu298Asp polymorphism of the NOS3 gene as a determinant of the baseline production of nitric oxide. J Hypertens 20: 2023–2027. doi:10.1097/00004872-200210000-00022.
Wang J, Dudley D, Wang XL (2002) Haplotype-specific effects on endothelial NO synthase promoter efficiency: modifiable by cigarette smoking. Arterioscler Thromb Vasc Biol 22: e1–4. doi:10.1161/01.ATV.0000016248.51577.1F.
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Communicating editor: Guy Besley
Competing interests: None declared
References to electronic databases: Fabry disease: OMIM #301500. GLA gene: OMIM #300644. α-Galactosidase A: EC 3.2.1.22. NOS3 gene: OMIM #163729). Autosomal dominant polycystic kidney disease: OMIM #173900.
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Rohard, I., Schaefer, E., Kampmann, C. et al. Association between polymorphisms of endothelial nitric oxide synthase gene (NOS3) and left posterior wall thickness (LPWT) of the heart in Fabry disease. J Inherit Metab Dis 31 (Suppl 2), 349–356 (2008). https://doi.org/10.1007/s10545-008-0920-z
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DOI: https://doi.org/10.1007/s10545-008-0920-z