Abstract
An autosomal recessive deficiency of acid alpha-glucosidase (GAA), type II glycogenosis, is genetically and clinically heterogeneous. The discovery of an enzyme-inactivating genomic deletion of exon 18 in three unrelated genetic compound patients--two infants and an adult--provided a rare opportunity to analyze the effect of the second mutation in patients who displayed dramatically different phenotypes. A deletion of Lys-903 in one patient and a substitution of Arg for Leu-299 in another resulted in the fatal infantile form. In the adult, a T-to-G base change at position -13 of intron 1 resulted in alternatively spliced transcripts with deletion of exon 2, the location of the start codon. The low level of active enzyme (12% of normal) generated from the leakage of normally spliced mRNA sustained the patient to adult life.
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Selected References
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- Aviv H., Leder P. Purification of biologically active globin messenger RNA by chromatography on oligothymidylic acid-cellulose. Proc Natl Acad Sci U S A. 1972 Jun;69(6):1408–1412. doi: 10.1073/pnas.69.6.1408. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Beratis N. G., LaBadie G. U., Hirschhorn K. Acid alpha-glucosidase: kinetic and immunologic properties of enzyme variants in health and disease. Isozymes Curr Top Biol Med Res. 1983;11:25–36. [PubMed] [Google Scholar]
- Blin N., Stafford D. W. A general method for isolation of high molecular weight DNA from eukaryotes. Nucleic Acids Res. 1976 Sep;3(9):2303–2308. doi: 10.1093/nar/3.9.2303. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brown B. I., Brown D. H., Jeffrey P. L. Simultaneous absence of alpha-1,4-glucosidase and alpha-1,6-glucosidase activities (pH 4) in tissues of children with type II glycogen storage disease. Biochemistry. 1970 Mar 17;9(6):1423–1428. doi: 10.1021/bi00808a017. [DOI] [PubMed] [Google Scholar]
- Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
- Courtecuissf V., Royer P., Habib R., Monnier C., Demos J. Glycogenose musculaire par deficit d'alpha-1-4-glucosidase simulant une dystrophie musculaire progressive. (Etude clinique et enzymatique. Microscopie optique electronique) Arch Fr Pediatr. 1965 Dec;22(10):1153–1164. [PubMed] [Google Scholar]
- DiMauro S., Stern L. Z., Mehler M., Nagle R. B., Payne C. Adult-onset acid maltase deficiency: a postmortem study. Muscle Nerve. 1978 Jan-Feb;1(1):27–36. doi: 10.1002/mus.880010105. [DOI] [PubMed] [Google Scholar]
- Engel A. G. Acid maltase deficiency in adults: studies in four cases of a syndrome which may mimic muscular dystrophy or other myopathies. Brain. 1970;93(3):599–616. doi: 10.1093/brain/93.3.599. [DOI] [PubMed] [Google Scholar]
- Engel A. G., Dale A. J. Autophagic glycogenosis of late onset with mitochondrial abnormalities: light and electron microscopic observations. Mayo Clin Proc. 1968 Apr;43(4):233–279. [PubMed] [Google Scholar]
- Engel A. G., Gomez M. R., Seybold M. E., Lambert E. H. The spectrum and diagnosis of acid maltase deficiency. Neurology. 1973 Jan;23(1):95–106. doi: 10.1212/wnl.23.1.95. [DOI] [PubMed] [Google Scholar]
- Engel A. G., Seybold M. E., Lambert E. H., Gomez M. R. Acid maltase deficiency: comparison of infantile, childhood, and adult types. Neurology. 1970 Apr;20(4):382–382. [PubMed] [Google Scholar]
- Galjaard H., Mekes M., Josselin de Jong JE D. E., Niermeijer M. F. A method for rapid prenatal diagnosis of glycogenosis II (Pompe's disease). Clin Chim Acta. 1973 Dec 27;49(3):361–375. doi: 10.1016/0009-8981(73)90234-9. [DOI] [PubMed] [Google Scholar]
- HERS H. G. alpha-Glucosidase deficiency in generalized glycogenstorage disease (Pompe's disease). Biochem J. 1963 Jan;86:11–16. doi: 10.1042/bj0860011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Haverstick D. M., Jeziorski M., Bannon M. J. Developmental profile of striatal preprotachykinin gene expression. J Neurochem. 1990 Sep;55(3):764–768. doi: 10.1111/j.1471-4159.1990.tb04557.x. [DOI] [PubMed] [Google Scholar]
- Hermans M. M., Kroos M. A., de Graaff E., Oostra B. A., Reuser A. J. Two mutations affecting the transport and maturation of lysosomal alpha-glucosidase in an adult case of glycogen storage disease type II. Hum Mutat. 1993;2(4):268–273. doi: 10.1002/humu.1380020406. [DOI] [PubMed] [Google Scholar]
- Hermans M. M., Kroos M. A., van Beeumen J., Oostra B. A., Reuser A. J. Human lysosomal alpha-glucosidase. Characterization of the catalytic site. J Biol Chem. 1991 Jul 25;266(21):13507–13512. [PubMed] [Google Scholar]
- Hermans M. M., Wisselaar H. A., Kroos M. A., Oostra B. A., Reuser A. J. Human lysosomal alpha-glucosidase: functional characterization of the glycosylation sites. Biochem J. 1993 Feb 1;289(Pt 3):681–686. doi: 10.1042/bj2890681. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hermans M. M., de Graaff E., Kroos M. A., Wisselaar H. A., Oostra B. A., Reuser A. J. Identification of a point mutation in the human lysosomal alpha-glucosidase gene causing infantile glycogenosis type II. Biochem Biophys Res Commun. 1991 Sep 16;179(2):919–926. doi: 10.1016/0006-291x(91)91906-s. [DOI] [PubMed] [Google Scholar]
- Hermans M. M., de Graaff E., Kroos M. A., Wisselaar H. A., Willemsen R., Oostra B. A., Reuser A. J. The conservative substitution Asp-645-->Glu in lysosomal alpha-glucosidase affects transport and phosphorylation of the enzyme in an adult patient with glycogen-storage disease type II. Biochem J. 1993 Feb 1;289(Pt 3):687–693. doi: 10.1042/bj2890687. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hoefsloot L. H., Hoogeveen-Westerveld M., Kroos M. A., van Beeumen J., Reuser A. J., Oostra B. A. Primary structure and processing of lysosomal alpha-glucosidase; homology with the intestinal sucrase-isomaltase complex. EMBO J. 1988 Jun;7(6):1697–1704. doi: 10.1002/j.1460-2075.1988.tb02998.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hoefsloot L. H., Hoogeveen-Westerveld M., Reuser A. J., Oostra B. A. Characterization of the human lysosomal alpha-glucosidase gene. Biochem J. 1990 Dec 1;272(2):493–497. doi: 10.1042/bj2720493. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hoefsloot L. H., Willemsen R., Kroos M. A., Hoogeveen-Westerveld M., Hermans M. M., Van der Ploeg A. T., Oostra B. A., Reuser A. J. Expression and routeing of human lysosomal alpha-glucosidase in transiently transfected mammalian cells. Biochem J. 1990 Dec 1;272(2):485–492. doi: 10.1042/bj2720485. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hudgson P., Gardner-Medwin D., Worsfold M., Pennington R. J., Walton J. N. Adult myopathy from glycogen storage disease due to acid maltase deficiency. Brain. 1968 Sep;91(3):435–462. doi: 10.1093/brain/91.3.435. [DOI] [PubMed] [Google Scholar]
- Huie M. L., Chen A. S., Brooks S. S., Grix A., Hirschhorn R. A de novo 13 nt deletion, a newly identified C647W missense mutation and a deletion of exon 18 in infantile onset glycogen storage disease type II (GSDII). Hum Mol Genet. 1994 Jul;3(7):1081–1087. doi: 10.1093/hmg/3.7.1081. [DOI] [PubMed] [Google Scholar]
- Huie M. L., Chen A. S., Tsujino S., Shanske S., DiMauro S., Engel A. G., Hirschhorn R. Aberrant splicing in adult onset glycogen storage disease type II (GSDII): molecular identification of an IVS1 (-13T-->G) mutation in a majority of patients and a novel IVS10 (+1GT-->CT) mutation. Hum Mol Genet. 1994 Dec;3(12):2231–2236. doi: 10.1093/hmg/3.12.2231. [DOI] [PubMed] [Google Scholar]
- Jeffrey P. L., Brown D. H., Brown B. I. Studies of lysosomal alpha-glucosidase. II. Kinetics of action of the rat liver enzyme. Biochemistry. 1970 Mar 17;9(6):1416–1422. doi: 10.1021/bi00808a016. [DOI] [PubMed] [Google Scholar]
- Jézéquel A. M., Arakawa K., Steiner J. W. The fine structure of the normal, neonatal mouse liver. Lab Invest. 1965 Nov;14(11):1894–1930. [PubMed] [Google Scholar]
- Martiniuk F., Bodkin M., Tzall S., Hirschhorn R. Identification of the base-pair substitution responsible for a human acid alpha glucosidase allele with lower "affinity" for glycogen (GAA 2) and transient gene expression in deficient cells. Am J Hum Genet. 1990 Sep;47(3):440–445. [PMC free article] [PubMed] [Google Scholar]
- Martiniuk F., Mehler M., Bodkin M., Tzall S., Hirschhorn K., Zhong N., Hirschhorn R. Identification of a missense mutation in an adult-onset patient with glycogenosis type II expressing only one allele. DNA Cell Biol. 1991 Nov;10(9):681–687. doi: 10.1089/dna.1991.10.681. [DOI] [PubMed] [Google Scholar]
- Martiniuk F., Mehler M., Pellicer A., Tzall S., La Badie G., Hobart C., Ellenbogen A., Hirschhorn R. Isolation of a cDNA for human acid alpha-glucosidase and detection of genetic heterogeneity for mRNA in three alpha-glucosidase-deficient patients. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9641–9644. doi: 10.1073/pnas.83.24.9641. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Martiniuk F., Mehler M., Tzall S., Meredith G., Hirschhorn R. Extensive genetic heterogeneity in patients with acid alpha glucosidase deficiency as detected by abnormalities of DNA and mRNA. Am J Hum Genet. 1990 Jul;47(1):73–78. [PMC free article] [PubMed] [Google Scholar]
- Mehler M., DiMauro S. Residual acid maltase activity in late-onset acid maltase deficiency. Neurology. 1977 Feb;27(2):178–184. doi: 10.1212/wnl.27.2.178. [DOI] [PubMed] [Google Scholar]
- Miranda A. F., Shanske S., Hays A. P., DiMauro S. Immunocytochemical analysis of normal and acid maltase-deficient muscle cultures. Arch Neurol. 1985 Apr;42(4):371–373. doi: 10.1001/archneur.1985.04060040081017. [DOI] [PubMed] [Google Scholar]
- Myers R. M., Fischer S. G., Lerman L. S., Maniatis T. Nearly all single base substitutions in DNA fragments joined to a GC-clamp can be detected by denaturing gradient gel electrophoresis. Nucleic Acids Res. 1985 May 10;13(9):3131–3145. doi: 10.1093/nar/13.9.3131. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nichols R. C., Raben N. Hints for direct sequencing of PCR-generated single-stranded DNA. Biotechniques. 1994 Sep;17(3):412–414. [PubMed] [Google Scholar]
- Ninomiya N., Matsuda I., Matsuoka T., Iwamasa T., Nonaka I. Demonstration of acid alpha-glucosidase in different types of Pompe disease by use of an immunochemical method. J Neurol Sci. 1984 Nov-Dec;66(2-3):129–139. doi: 10.1016/0022-510x(84)90001-7. [DOI] [PubMed] [Google Scholar]
- Reuser A. J., Koster J. F., Hoogeveen A., Galjaard H. Biochemical, immunological, and cell genetic studies in glycogenosis type II. Am J Hum Genet. 1978 Mar;30(2):132–143. [PMC free article] [PubMed] [Google Scholar]
- Reuser A. J., Kroos M., Oude Elferink R. P., Tager J. M. Defects in synthesis, phosphorylation, and maturation of acid alpha-glucosidase in glycogenosis type II. J Biol Chem. 1985 Jul 15;260(14):8336–8341. [PubMed] [Google Scholar]
- Reuser A. J., Kroos M., Willemsen R., Swallow D., Tager J. M., Galjaard H. Clinical diversity in glycogenosis type II. Biosynthesis and in situ localization of acid alpha-glucosidase in mutant fibroblasts. J Clin Invest. 1987 Jun;79(6):1689–1699. doi: 10.1172/JCI113008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rosenow E. C., 3rd, Engel A. G. Acid maltase deficiency in adults presenting as respiratory failure. Am J Med. 1978 Mar;64(3):485–491. doi: 10.1016/0002-9343(78)90235-8. [DOI] [PubMed] [Google Scholar]
- Selden R. F., Howie K. B., Rowe M. E., Goodman H. M., Moore D. D. Human growth hormone as a reporter gene in regulation studies employing transient gene expression. Mol Cell Biol. 1986 Sep;6(9):3173–3179. doi: 10.1128/mcb.6.9.3173. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shanske S., Bresolin N., DiMauro S. Multiple neutral maltase activities in normal and acid maltase-deficient human muscle. Exp Neurol. 1984 Jun;84(3):565–578. doi: 10.1016/0014-4886(84)90204-8. [DOI] [PubMed] [Google Scholar]
- Sheffield V. C., Cox D. R., Lerman L. S., Myers R. M. Attachment of a 40-base-pair G + C-rich sequence (GC-clamp) to genomic DNA fragments by the polymerase chain reaction results in improved detection of single-base changes. Proc Natl Acad Sci U S A. 1989 Jan;86(1):232–236. doi: 10.1073/pnas.86.1.232. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shin-Buehring Y. S., Drefers M., Kroenner H., Osang M., Schaub J. Separation of acid and neutral alpha-glucosidase isoenzymes from fetal and adult tissues, cultivated fibroblasts and amniotic fluid cells by DEAE-cellulose and sephadex G-100 column chromatography. Clin Chim Acta. 1978 Nov 1;89(3):393–404. doi: 10.1016/0009-8981(78)90401-1. [DOI] [PubMed] [Google Scholar]
- Soyama K., Ono E., Shimada N., Tanaka K., Oya N. Properties of the alpha-glucosidase from various human tissues in relation to glycogenosis type II (Pompe's disease). Clin Chim Acta. 1977 Aug 1;78(3):473–478. doi: 10.1016/0009-8981(77)90080-8. [DOI] [PubMed] [Google Scholar]
- Steckel F., Gieselmann V., Waheed A., Hasilik A., von Figura K., Oude Elferink R., Kalsbeek R., Tager J. M. Biosynthesis of acid alpha-glucosidase in late-onset forms of glycogenosis type II (Pompe's disease). FEBS Lett. 1982 Dec 13;150(1):69–76. doi: 10.1016/0014-5793(82)81306-9. [DOI] [PubMed] [Google Scholar]
- Tanaka S., Liu L., Kimura J., Shiojiri S., Takahashi Y., Kitaguchi N., Nakamura S., Ueda K. Age-related changes in the proportion of amyloid precursor protein mRNAs in Alzheimer's disease and other neurological disorders. Brain Res Mol Brain Res. 1992 Oct;15(3-4):303–310. doi: 10.1016/0169-328x(92)90122-r. [DOI] [PubMed] [Google Scholar]
- Tanaka S., Nakamura S., Kimura J., Ueda K. Age-related change in the proportion of amyloid precursor protein mRNAs in the gray matter of cerebral cortex. Neurosci Lett. 1993 Nov 26;163(1):19–21. doi: 10.1016/0304-3940(93)90219-b. [DOI] [PubMed] [Google Scholar]
- Van der Kraan M., Kroos M. A., Joosse M., Bijvoet A. G., Verbeet M. P., Kleijer W. J., Reuser A. J. Deletion of exon 18 is a frequent mutation in glycogen storage disease type II. Biochem Biophys Res Commun. 1994 Sep 30;203(3):1535–1541. doi: 10.1006/bbrc.1994.2360. [DOI] [PubMed] [Google Scholar]
- Wisselaar H. A., Kroos M. A., Hermans M. M., van Beeumen J., Reuser A. J. Structural and functional changes of lysosomal acid alpha-glucosidase during intracellular transport and maturation. J Biol Chem. 1993 Jan 25;268(3):2223–2231. [PubMed] [Google Scholar]
- Zhong N., Martiniuk F., Tzall S., Hirschhorn R. Identification of a missense mutation in one allele of a patient with Pompe disease, and use of endonuclease digestion of PCR-amplified RNA to demonstrate lack of mRNA expression from the second allele. Am J Hum Genet. 1991 Sep;49(3):635–645. [PMC free article] [PubMed] [Google Scholar]
- de Barsy T., Jacquemin P., Devos P., Hers H. G. Rodent and human acid -glucosidase. Purification, properties and inhibition by antibodies. Investigation in type II glycogenosis. Eur J Biochem. 1972 Nov 21;31(1):156–165. doi: 10.1111/j.1432-1033.1972.tb02514.x. [DOI] [PubMed] [Google Scholar]