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Abstract
Glycogen storage disease type 1 (GSD-1) is a group of genetic disorders caused by a deficiency in the activity of the enzyme glucose-6-phosphatase. (G6Pase). GSD-1a and GSD-1b, the two major subgroups, have been confirmed at the molecular genetic level. The gene responsible for GSD-1b maps to human chromosome 11q23 and a candidate human GSD-1b cDNA that encodes a microsomal transmembrane protein has been identified. In this study, we show that this cDNA maps to chromosome 11q23; thus it is a strong candidate for GSD-1b. Furthermore, we isolated and characterized candidate murine and rat GSD-1b cDNAs. Both encode transmembrane proteins sharing 93-95% sequence homology to the human GSD-1b protein. The expression profiles of murine GSD-1b and G6Pase differ both in the liver and in the kidney; the GSD-1b transcript appears before the G6Pase mRNA during development. In addition to G6Pase deficiency, GSD-1b patients suffer neutropenia, neutrophil dysfunction, and recurrent bacterial infections. Interestingly, although the G6Pase mRNA is expressed primarily in the liver, kidney, and intestine, the GSD-1b mRNA is expressed in numerous tissues, including human neutrophils/monocytes.
Highlights
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF080468 and AF080469
Cloning of Human, Murine, and Rat GSD-1b cDNAs—The coding regions of human, murine, and rat cDNA clones were isolated by reverse transcriptase-polymerase chain reaction (PCR) amplification of the respective human, murine, or rat liver poly(A)ϩ RNA using two oligonucleotide primers derived from nucleotides 166 to 192 and 1439 to 1459 of the human GSD-1b cDNA [15]
Gerin et al [15] have identified a candidate human GSD-1b cDNA that encodes a transmembrane protein by sequence homology to bacterial phosphate ester transporters
Summary
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF080468 (rat) and AF080469 (mouse). Treatment of GSD-1b patients consists of a combination of dietary therapy [1, 2] to correct the symptoms of G6Pase deficiency and a human granulocyte-macrophage colony stimulating factor therapy [12, 13] to restore neutrophil/monocyte functions and to reduce the frequency of infection. We have mapped the GSD-1b locus to human chromosome 11q23 [14]. The encoded GSD-1b protein is predicted to contain an endoplasmic reticulum (ER) transmembrane protein retention motif at its carboxyl terminus, consistent with its proposed relationship to the G6Pase enzyme. We report the cloning and characterization of cDNAs encoding the putative GSD-1b proteins in the mouse and rat. We demonstrate that the human cDNA maps to chromosome 11q23, the site for the GSD-1b locus. Our results provide strong evidence that this protein is the putative GSD-1b gene product
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