Mutations in the Liver Glycogen Phosphorylase Gene (PYGL) Underlying Glycogenosis Type VI (Hers Disease) Barbara Burwinkel, Henk D. Bakker, Eliezer Herschkovitz,

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Mutations in the Liver Glycogen Phosphorylase Gene (PYGL) Underlying Glycogenosis Type VI (Hers Disease) Barbara Burwinkel, Henk D. Bakker, Eliezer Herschkovitz, Shimon W. Moses, Yoon S. Shin, Manfred W. Kilimann The American Journal of Human Genetics Volume 62, Issue 4, Pages 785-791 (April 1998) DOI: 10.1086/301790 Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 1 RT-PCR products indicating aberrant mRNA processing due to splice-site mutations in patients 1 and 2. Sequence intervals B and D were amplified from RNAs of patients 1–3, and the products were resolved by agarose gel electrophoresis and were stained with ethidium bromide. The central lane carries a 100-nt molecular-size ladder (top band; 1,000 nt). The American Journal of Human Genetics 1998 62, 785-791DOI: (10.1086/301790) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 2 Identification of PYGL mutations in patients 1–3. The left column shows the sequencing electropherograms documenting the mutations. Triangles denote insertions or deletions; asterisks (*) denote nucleotide replacements; and arrowheads indicate where sequences have to be read in complementary fashion from right to left. On the right, normal and mutant sequences are shown in comparison, with mutant sequence positions highlighted in boldface type and shaded. Patients 1 and 3 are homozygous for their respective mutations. The two mutant alleles of patient 2 give homogeneous sequences if determined from RT-PCR products, because both lie in interval B, so that the RT-PCR products derived from the two alleles have different lengths and are separated by electrophoresis before being sequenced (fig. 1). Amplified from genomic DNA, the splice-site mutation (mut 1) of patient 2 is seen together with the normal nucleotide of the second allele in this position. Numbering of exons and introns is tentative, by analogy with the numbering of corresponding exons in PYGM. The GT dinucleotide in exon 14 (underlined) in patient 1 serves as an illegitimate 5′ splice site. The third aberrant-splicing product of patient 1, employing a GT in intron 14 (see fig. 3), is not illustrated. For the missense mutations of patients 2 and 3, high phylogenetic conservation of the mutated amino acids is illustrated by alignment of corresponding partial sequences from the three human glycogen phosphorylase isoforms, from yeast glycogen phosphorylase, and from both E. coli glycogen phosphorylase and maltodextrin phosphorylase. The sequences are taken from the work of Hudson et al. (1993), where an alignment with additional phosphorylase sequences from slime mold and potato (N338 and N376 being conserved also in these species) and an assignment of sequence positions to crystal structural features can also be found. The American Journal of Human Genetics 1998 62, 785-791DOI: (10.1086/301790) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 3 Partial structure of the human PYGL. Exons are denoted by uppercase letters, and introns are denoted by lowercase letters. Primers LP15, LPi1, LP13, LP14, LP12, LP7, and LP11 (from top to bottom), which were employed for amplification and sequencing, are underlined. The g residues that are mutated at the end of intron 4 and at the beginning of intron 14, in patients 2 and 1, respectively, are highlighted in boldface type. The GT dinucleotides in exon 14 and intron 14 that function as illegitimate 5′ splice sites in patient 1 are doubly underlined. Nucleotide numbering and amino acid numbering refer to the cDNA sequence. The sequences have been submitted to the database (accession numbers Y15229–Y15232). The American Journal of Human Genetics 1998 62, 785-791DOI: (10.1086/301790) Copyright © 1998 The American Society of Human Genetics Terms and Conditions