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Letters to the Editor Dutch Patients with Glycogen Storage Disease Type J Med Genet 2001;38:527–567 527 Letters to the Editor J Med Genet: first published as 10.1136/jmg.38.8.551 on 1 August 2001. Downloaded from Dutch patients with glycogen storage disease type II show common ancestry for the 525delT and del exon 18 mutations MargreetGEMAusems, Klara ten Berg, Lodewijk A Sandkuijl, Marian A Kroos, Alfons F J Bardoel, Katerina N Roumelioti, Arnold J J Reuser, Richard Sinke, Cisca Wijmenga EDITOR—Glycogen storage disease type II Analysis of the deletion junction showed a (GSD II) is an autosomal recessive lysosomal direct eight nucleotide repeat sequence flank- storage disorder caused by deficiency of acid ing the deletion, with one direct repeat á-glucosidase. The enzyme deficiency results included in the deletion and the second direct in intralysosomal accumulation of glycogen in repeat at the deletion junction.14 15 This repeat skeletal muscle and in other tissues. There are sequence could be instrumental in the muta- early and late onset phenotypes which diVer tion event. So far, the mutation has not been with respect to age at onset, extent of organ reported in patients of non-white origin. The involvement, and clinical course of the disease.1 525delT mutation has also not been reported The genotype frequency of GSD II was in non-white patients, and is relatively rare in recently shown to be 1 in 40 000 by mutation “non-Dutch” patients.16 screening in the general population, which is In order to determine whether the 525delT higher than previously estimated.23 and del exon 18 mutations represent founder Over 40 diVerent mutations in the acid events or independent, de novo mutations, we á-glucosidase (GAA) gene have been re- constructed haplotypes using four single nucle- ported.4 Most mutations are rare and have otide polymorphisms (SNPs) in the GAA gene. been found in only a few patients. However, We used a set of 28 unrelated GSD II patients J Med Genet some mutations have been reported in several to determine the extent of haplotype sharing 2001;38:527–529 between the individual patients carrying identi- unrelated patients with defined ethnic origins. http://jmg.bmj.com/ The C1935A transversion, frequently found in cal mutations. The patient population included Department of Chinese patients with infantile GSD II, 26 white Dutch patients and their parents from Medical Genetics, 5 26 families with infantile GSD II, and three University Medical appears to originate from a common founder. Centre Utrecht, PO Other frequent mutations include the R854X white Dutch patients and their parents from Box 85090, 3508 AB mutation in Afro-Americans,6 the two families with adult GSD II. All patients Utrecht, The 2741AG→CAGG insertion in Turkish pa- carried at least one frequent mutation Netherlands tients,7 and the G925A mutation in European (525delT or del exon 18) and had deficient MGEMAusems patients.8 It remains to be determined whether GAA activity, measured in fibroblasts and leu- on September 23, 2021 by guest. Protected copyright. K ten Berg cocytes. Genomic DNA was extracted from L A Sandkuijl these frequent mutations represent common cultured skin fibroblasts and from peripheral F J Bardoel descent or result from independent recurrence. 17 K N Roumelioti The IVS1(−13T→G) mutation is the most fre- blood cells using standard procedures. Muta- R Sinke quent mutation in late onset GSD II patients tion analysis was performed as described previ- C Wijmenga 11 from diVerent ethnic origins.9–11 ously. We analysed four intragenic single In The Netherlands, most late onset GSD II nucleotide polymorphisms (SNPs) by PCR Department of Clinical amplification, followed by digestion of the PCR patients carry the IVS1(−13T→G) mutation in Genetics, Erasmus product with the appropriate restriction en- University, Academic combination with either the 525delT or the del zyme (table 1). To amplify exons 3, 8, 11, and Hospital Rotterdam, exon 18 mutation, whereas infantile GSD II 17, information was obtained from Martiniuk The Netherlands patients often show homozygosity or com- L A Sandkuijl et al.18 Fragments were electrophoresed on a M A Kroos pound heterozygosity for the 525delT and the 10 2% agarose gel. Genotyping parents of GSD II A J J Reuser del exon 18 mutations. The latter mutations patients assigned the phase of the alleles. The are fully deleterious and are associated with order of SNPs and mutations was as follows: Correspondence to: complete loss of enzyme activity.12 13 The dele- Dr Ausems, 525delT - exon 3 SNP - exon 8 SNP - exon 11 M.G.E.M.Ausems@dmg. tion of exon 18 extends from IVS17 to IVS18 SNP - exon 17 SNP - del exon 18. azu.nl and includes the coding sequence of exon 18. We estimated allele frequencies by direct Table 1 Analysis of SNPs within the GAA gene counting of chromosomes. It has been shown in several studies19 that inclusion of genotypes Exon 3 SNP Exon 8 SNP Exon 11 SNP Exon 17 SNP from incomplete families, or the inclusion of Polymorphism C642T A1203G A1581G A2338G reconstructed genotypes, may introduce seri- Restriction enzyme DdeI BsrI BanII BsrI ous bias into the estimation of allele and haplo- Major allele 389 bp 186, 175, 45, 24 bp 442 bp 317 bp type frequencies. Therefore, in the analysis of Minor allele 310, 79 bp 361, 45, 24 bp 123, 319 bp 246, 71 bp linkage disequilibrium and the estimation of www.jmedgenet.com 528 Letters Table 2 Allele frequencies in wild type and mutant chromosomes Table 4 Distribution of extended 525delT and del exon 18 haplotypes among Dutch GSD II patients J Med Genet: first published as 10.1136/jmg.38.8.551 on 1 August 2001. Downloaded from Exon 3 SNPˆ Exon 8 SNPˆ Exon 11 SNPˆ Exon 17 SNPˆ Exon 3 Exon 8 Exon 11 Exon 17 No A N 525 d18 N 525 d18 N 525 d18 N 525 d18 525delT 1 0.24 0.81 1.0 1.0 0.74 0.82 0.22 0.08 Minor Major Minor Minor 16 2 0.76 1.0 1.0 0.19 0.26 1.0 0.18 0.78 1.0 0.92 Minor Major NI Minor 5 No 51 24 12 52 23 13 41 17 11 50 22 13 Minor Major NI ND 1 Minor Major NI NI 1 A denotes the diVerent alleles; allele 1 represents the major allele and allele 2 the minor allele (see Minor NI Minor Minor 1 table 4). Del exon 18 N represents wild type chromosomes; 525 represents chromosomes containing the 525delT Minor Major Major Minor 6 mutation; d18 represents chromosomes containing the del exon 18 mutation. NI Major Major Minor 2 No denotes the number of individual chromosomes counted. Minor NI ND Minor 1 Minor Major ND Minor 1 Table 3 Distribution of the core haplotypes constructed from exon 3, 8, and 11 SNPs Minor Major NI ND 1 Minor Major Minor Minor 2 Minor Major Major Major 1 Haplotype Wild type 525delT Del exon 18 Other mutations* NI: genotyping was not informative. Minor-minor-minor0000 ND: genotyping was not carried out. Minor-minor-major8002 No: number of chromosomes. Minor-major-minor 8 14 0 0 Minor-major-major 10 0 7 4 Major-minor-minor0000 other polymorphisms on wild type chromo- Major-minor-major0000 somes, we first evaluated these three polymor- Major-major-minor0000 phisms as a core haplotype on mutant chromo- Major-major-major8003 somes. When the patients’ chromosomes were *The chromosomes not bearing a 525delT or del exon 18 mutation. divided into three groups, the 525delT, del haplotype frequencies, only families for which exon 18, and other mutations, respectively, a single core haplotype was found on all 525delT DNA was available for genotyping from the -8 patient and from both parents were included. chromosomes (p<10 ), and a single diVerent core haplotype was found on all del exon 18 Genotypes for a given polymorphic marker in a ≈ given family were only included in the statisti- chromosomes (p 0.0003), but no obvious cal analysis if completely unambiguous results shared haplotypes on the remaining mutant had been obtained for that marker in all avail- chromosomes (table 3). These data are consist- able DNA samples in that family. As a result of ent with a common founder for each of the two this rigorous constraint, the total number of common mutations separately. scorable haplotypes was not identical for all marker combinations. The statistical signifi- Origin of 525delT and del exon 18 cance of allelic association between various chromosomes polymorphisms on wild type chromosomes was Table 4 shows extended haplotypes of chromo- assessed using Fisher’s exact test. Haplotype somes bearing the 525delT and del exon 18 mutations, including the exon 17 SNP.This list frequencies were determined using the EM http://jmg.bmj.com/ algorithm, as implemented in the EH pro- also includes haplotypes from patients that gram.20 Table 2 summarises the frequencies of could be unequivocally reconstructed from the alleles observed for the SNPs in wild type incomplete families. Such haplotypes were not chromosomes (n=52) and the panel of included in the statistical analysis of core hap- 525delT (n=24) and del exon 18 (n=14) chro- lotypes because the inclusion of reconstructed mosomes. haplotypes introduces bias. Although wild type chromosomes did not show Wild type chromosomes linkage disequilibrium between the exon 11 on September 23, 2021 by guest. Protected copyright. The chromosomes that were not transmitted and exon 17 SNP, all of the 525delT chromo- by parents to their aVected children were con- somes shared the exon 3 (minor) - exon 8 sidered as wild type chromosomes. A pairwise (major) - exon 11 (minor) - exon 17 (minor) analysis of SNPs on non-transmitted (wild haplotype.
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