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Frequency of the deletion polymorphism of DNASE1L1 in 137 patients with acid maltase deficiency (Pompe disease)
Experimental and Molecular Pathology 80 (2006) 308 – 309 www.elsevier.com/locate/yexmp
Letter to the Editor Frequency of the deletion polymorphism of DNASE1L1 in 137 patients with acid maltase deficiency (Pompe disease) In 2001, Malferrari et al. (2001) reported on the frequency of a deletion polymorphism of the X-linked DNASE1L1 gene in patients with acid maltase deficiency (AMD, acid α-glucosidase deficiency, Pompe disease), an autosomal recessive disorder characterized by skeletal muscle weakness and cardiac involvement in severe cases. The disease is classified into early- and late-onset phenotypes (Hirschhorn and Reuser, 2001). Investigating the cause of clinical heterogeneity (Hirschhorn and Reuser, 2001; Wokke et al., 1995), the authors showed that a 196-bp deletion in the 3′ untranslated region (exon 9) of the DNASE1L1 gene was present more frequently on the Xchromosome of affected infants (50%, 5 patients tested) than in adults (6.25%, 28 patients tested) and healthy controls (4.7%, 16 controls tested). This observation, combined with the fact that DNASE1L1 is highly expressed in heart and muscle and over-expressed in the muscle of patients with a lysosomal pathology like Pompe disease (Malferrari et al., 1999), raised the question of whether the DNASE1L1 polymorphism had any value for assessing the risk and severity of AMD (Malferrari et al., 2001). Following from the observations of Malferrari et al. (2001), we tested 137 ethnically diverse patients and 84 healthy controls for the presence of the 196-bp deletion in the DNASE1L1 gene. The AMD diagnosis was confirmed by proven deficiency of acid α-glucosidase or by the presence of two pathogenic mutations in the gene (GAA). To amplify exon 9 of the DNASE1L1 gene, we used the primer pair described by Parrish et al. (1995). The product was visualized on a 2% agarose gel to distinguish the 791-bp band from the 595-bp band with the 196-bp deletion. Male carriers of the
Table 1 Allele frequencies of the DNASE1L1 deletion in 137 patients with early- and late-onset acid maltase deficiency and 84 healthy controls Phenotype
Number of males
Number of females
Deletion allele frequency (95% CI)
P value (2-sided) a
Early onset Late onset Controls
39 39 50
27 32 34
1.1% (0.0–5.8%) 6.8% (2.8–13.5%) 2.5% (5.3–7.2%)
0.63 0.19
a
P value for the differences between early- and late-onset AMD and controls. 0014-4800/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.yexmp.2006.02.003
deletion showed only the 595-bp band, while female carriers showed both fragments, demonstrating the X-linked nature of DNASE1L1. Table 1 shows the allele frequency of the deletion in 71 patients with late-onset AMD, in 66 severely affected infants, and in 84 healthy controls. P values (2-sided) were calculated using Fisher's Exact Test. In our cohort of patients with lateonset AMD, the frequency of the DNASE1L1 allele with the 196-bp deletion was nearly the same as previously published (6.8%, 103 X-chromosomes versus 6.25%, 42 X-chromosomes tested) (Malferrari et al., 2001). The frequency in healthy controls was 2.5% (118 X-chromosomes tested) and not significantly different from the frequencies of 4.7% and 5% (21 and 99 X-chromosomes tested, respectively) reported in two earlier studies (Malferrari et al., 2001; Parrish et al., 1995). However, the frequency in our group of 66 affected infants was far lower (1.1%, 93 X-chromosomes versus 50%, 6 X-chromosomes) than that reported by Malferrari et al. (2001). Thus, our data from a large number of ethnically diverse patients do not support the tentative conclusion of Malferrari et al. that a polymorphism of the DNASE1L1 gene modifies the clinical course of AMD. The increased activity of DNASE1L1 in AMD may relate to the over-expression of lysosomal enzymes in general when lysosomal storage occurs, as for instance with the increased activity of acid phosphatase in AMD. References Hirschhorn, R., Reuser, A.J.J., 2001. Glycogen storage disease type II: acid α-glucosidase (acid maltase) deficiency. In: Scriver, C.R, Beaudet, A.L., Sly, W.S, Valle, D. (Eds.), The Metabolic and Molecular Bases of Inherited Disease. Medical Publishing Division, McGrawHill, pp. 3389–3418. Malferrari, G., Mazza, U., Tresoldi, C., Rovida, E., Nissim, M., Mirabella, M., Servidei, S., Biunno, I., 1999. Molecular characterization of a novel endonuclease (Xib) and possible involvement in lysosomal glycogen storage disorders. Exp. Mol. Pathol. 66, 123–130. Malferrari, G., Mirabella, M., D'Alessandra, Y., Servidei, S., Biunno, I., 2001. Deletion polymorphism of DNASE1L1, an X-linked Dnase I-like gene, in acid maltase deficiency disorders. Exp. Mol. Pathol. 70, 173–174. Parrish, J.E., Ciccodicola, A., Wehnert, M., Cox, G.F., Chen, E., Nelson, L., 1995. A muscle-specific Dnase I-like gene in human Xq28. Hum. Mol. Genet. 4, 1557–1564. Wokke, J.H.J., Ausems, M.G.E.M., van den Boogaard, M.J.H., Ippel, E.F., van Diggelen, O., Kroos, M.A., Boer, M., Jennekens, F.G.I., Reuser, A.J.J., Ploos van Amstel, H.K., 1995. Genotype–phenotype correlation in adultonset acid maltase deficiency. Ann. Neurol. 38, 450–454.
Letter to the Editor
Klaske D. Lichtenbelt Richard J. Sinke Margreet G.E.M. Ausems* Department of Medical Genetics, University Medical Centre Utrecht, Wilhelmina Children’s Hospital, KC.04.084.2, University Medical Center, P.O. Box 85090, 3508 AB Utrecht, The Netherlands E-mail address: [email protected]. ⁎ Corresponding author. Fax: +31 30 2503801.
309
Marian A. Kroos Arnold J.J. Reuser Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands John J.H. Wokke Department of Neurology, University Medical Centre Utrecht, The Netherlands
Letter to the Editor Frequency of the deletion polymorphism of DNASE1L1 in 137 patients with acid maltase deficiency (Pompe disease) In 2001, Malferrari et al. (2001) reported on the frequency of a deletion polymorphism of the X-linked DNASE1L1 gene in patients with acid maltase deficiency (AMD, acid α-glucosidase deficiency, Pompe disease), an autosomal recessive disorder characterized by skeletal muscle weakness and cardiac involvement in severe cases. The disease is classified into early- and late-onset phenotypes (Hirschhorn and Reuser, 2001). Investigating the cause of clinical heterogeneity (Hirschhorn and Reuser, 2001; Wokke et al., 1995), the authors showed that a 196-bp deletion in the 3′ untranslated region (exon 9) of the DNASE1L1 gene was present more frequently on the Xchromosome of affected infants (50%, 5 patients tested) than in adults (6.25%, 28 patients tested) and healthy controls (4.7%, 16 controls tested). This observation, combined with the fact that DNASE1L1 is highly expressed in heart and muscle and over-expressed in the muscle of patients with a lysosomal pathology like Pompe disease (Malferrari et al., 1999), raised the question of whether the DNASE1L1 polymorphism had any value for assessing the risk and severity of AMD (Malferrari et al., 2001). Following from the observations of Malferrari et al. (2001), we tested 137 ethnically diverse patients and 84 healthy controls for the presence of the 196-bp deletion in the DNASE1L1 gene. The AMD diagnosis was confirmed by proven deficiency of acid α-glucosidase or by the presence of two pathogenic mutations in the gene (GAA). To amplify exon 9 of the DNASE1L1 gene, we used the primer pair described by Parrish et al. (1995). The product was visualized on a 2% agarose gel to distinguish the 791-bp band from the 595-bp band with the 196-bp deletion. Male carriers of the
Table 1 Allele frequencies of the DNASE1L1 deletion in 137 patients with early- and late-onset acid maltase deficiency and 84 healthy controls Phenotype
Number of males
Number of females
Deletion allele frequency (95% CI)
P value (2-sided) a
Early onset Late onset Controls
39 39 50
27 32 34
1.1% (0.0–5.8%) 6.8% (2.8–13.5%) 2.5% (5.3–7.2%)
0.63 0.19
a
P value for the differences between early- and late-onset AMD and controls. 0014-4800/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.yexmp.2006.02.003
deletion showed only the 595-bp band, while female carriers showed both fragments, demonstrating the X-linked nature of DNASE1L1. Table 1 shows the allele frequency of the deletion in 71 patients with late-onset AMD, in 66 severely affected infants, and in 84 healthy controls. P values (2-sided) were calculated using Fisher's Exact Test. In our cohort of patients with lateonset AMD, the frequency of the DNASE1L1 allele with the 196-bp deletion was nearly the same as previously published (6.8%, 103 X-chromosomes versus 6.25%, 42 X-chromosomes tested) (Malferrari et al., 2001). The frequency in healthy controls was 2.5% (118 X-chromosomes tested) and not significantly different from the frequencies of 4.7% and 5% (21 and 99 X-chromosomes tested, respectively) reported in two earlier studies (Malferrari et al., 2001; Parrish et al., 1995). However, the frequency in our group of 66 affected infants was far lower (1.1%, 93 X-chromosomes versus 50%, 6 X-chromosomes) than that reported by Malferrari et al. (2001). Thus, our data from a large number of ethnically diverse patients do not support the tentative conclusion of Malferrari et al. that a polymorphism of the DNASE1L1 gene modifies the clinical course of AMD. The increased activity of DNASE1L1 in AMD may relate to the over-expression of lysosomal enzymes in general when lysosomal storage occurs, as for instance with the increased activity of acid phosphatase in AMD. References Hirschhorn, R., Reuser, A.J.J., 2001. Glycogen storage disease type II: acid α-glucosidase (acid maltase) deficiency. In: Scriver, C.R, Beaudet, A.L., Sly, W.S, Valle, D. (Eds.), The Metabolic and Molecular Bases of Inherited Disease. Medical Publishing Division, McGrawHill, pp. 3389–3418. Malferrari, G., Mazza, U., Tresoldi, C., Rovida, E., Nissim, M., Mirabella, M., Servidei, S., Biunno, I., 1999. Molecular characterization of a novel endonuclease (Xib) and possible involvement in lysosomal glycogen storage disorders. Exp. Mol. Pathol. 66, 123–130. Malferrari, G., Mirabella, M., D'Alessandra, Y., Servidei, S., Biunno, I., 2001. Deletion polymorphism of DNASE1L1, an X-linked Dnase I-like gene, in acid maltase deficiency disorders. Exp. Mol. Pathol. 70, 173–174. Parrish, J.E., Ciccodicola, A., Wehnert, M., Cox, G.F., Chen, E., Nelson, L., 1995. A muscle-specific Dnase I-like gene in human Xq28. Hum. Mol. Genet. 4, 1557–1564. Wokke, J.H.J., Ausems, M.G.E.M., van den Boogaard, M.J.H., Ippel, E.F., van Diggelen, O., Kroos, M.A., Boer, M., Jennekens, F.G.I., Reuser, A.J.J., Ploos van Amstel, H.K., 1995. Genotype–phenotype correlation in adultonset acid maltase deficiency. Ann. Neurol. 38, 450–454.
Letter to the Editor
Klaske D. Lichtenbelt Richard J. Sinke Margreet G.E.M. Ausems* Department of Medical Genetics, University Medical Centre Utrecht, Wilhelmina Children’s Hospital, KC.04.084.2, University Medical Center, P.O. Box 85090, 3508 AB Utrecht, The Netherlands E-mail address: [email protected]. ⁎ Corresponding author. Fax: +31 30 2503801.
309
Marian A. Kroos Arnold J.J. Reuser Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands John J.H. Wokke Department of Neurology, University Medical Centre Utrecht, The Netherlands