Identification of a novel mutation (867delA) in the glucose-6-phosphatase gene in two siblings with glycogen storage disease type Ia with different phenotypes Communicated by: Mark H. Paalman Online Citation: Human Mutation, Mutation in Brief #3

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We identified a novel mutation (867delA) in the glucose-6-phosphatase gene of two siblings with glycogen storage disease type Ia. Although both siblings share the same mutations, their phenotype regarding adult height and hepatomegaly differs. In
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   MUTATION IN BRIEF HUMAN MUTATION Mutation in Brief #304 (2000) Online © 2000   WILEY-LISS, INC. Received 30 September 1999; Revised manuscript accepted 27 December 1999. Identification of a Novel Mutation (867delA) in theGlucose-6-phosphatase Gene in Two Siblings withGlycogen Storage Disease Type Ia with DifferentPhenotypes Jan Peter Rake 1 , Annelies M. ten Berge  2 , Gepke Visser 1 , Edwin Verlind 2 , Klary E. Niezen-Koning 1 , Charles H.C.M. Buys 2 , G. Peter A. Smit 1  and Hans Scheffer 2 1  Department of Metabolic Diseases, Beatrix Children’s Hospital; 2  Department of Medical Genetics, University of Groningen, The Netherlands *Correspondence to Jan Peter Rake, Department of Metabolic Diseases, Beatrix Children’s Hospital, UniversityHospital Groningen, P.O.Box 30.001, 9700 RB Groningen, The Netherlands; Phone: +31 50 361 2478; Fax: +3150 361 4235; E-mail: Communicated by Mark H. Paalman We identified a novel mutation (867delA) in the glucose-6-phosphatase gene of two siblingswith glycogen storage disease type Ia. Although both siblings share the same mutations, theirphenotype regarding adult height and hepatomegaly differs. In glycogen storage diseasetype Ia, substantial heterogeneity in phenotype is observed. Till so far, no evidence for aclear genotype-phenotype correlation has been found.  © 2000 Wiley-Liss, Inc. KEY WORDS: glycogen storage disease type Ia, GSD Ia, glucose-6-phosphatase, G6Pase, genotype-phenotype correlation INTRODUCTION Glycogen storage disease type Ia (GSD Ia, MIM# 232200) is a severe autosomal recessive inborn error of metabolism caused by microsomal glucose-6-phosphatase (G6Pase, E.C. deficiency. The diseasephenotype is characterized by marked hepatomegaly, short stature, severe fasting hypoglycemia,hyperlactacidemia, hyperuricemia and hyperlipidemia. Life expectancy in GSD I has improved considerably,thanks to intensive dietary therapies as frequent meals, slowly released carbohydrates and continuous nocturnalgastric drip feeding. However, with ageing, numerous complications, such as liver adenomas, progressive renaldisease and osteopenia may develop (Fernandes and Chen 1995).After identification of the gene encoding the G6Pase catalytic unit (G6PC; GDB 231927; Lei et al. 1993), asteadily growing list of mutations has been reported (Rake et al. 2000). Here, we report a novel mutation in theG6Pase gene, identified in two siblings with different phenotypes.  2Rake et al.PATIENTS AND METHODS The affected index cases are a 24-year-old brother (Sibling 1) and a 20-year-old sister (Sibling 2), progeny of unrelated healthy Dutch Caucasian parents. In Sibling 1 the diagnosis GSD Ia was suspected at the age of sixmonths, in Sibling 2 shortly after birth. Enzyme assays in liver tissue obtained by biopsy revealed 10% residualG6Pase activity in Sibling 1 and no residual G6Pase activity in Sibling 2. From early infancy both patients hadbeen treated with frequent lactose-restricted feedings during day and night. At four years of age and one year of age respectively, continuous nocturnal gastric drip feeding was introduced. At twelve years of age and eight yearsof age respectively, uncooked cornstarch during the day was introduced. The patients are raised in a family inwhich dietary therapy was maintained stringently for both.At this time, both patients are in good clinical condition. They share some of the disease phenotypecharacteristics: mild hypercholesterolemia, hypertriglyceridemia and hyperuricemia requiring a xanthine-oxidaseinhibitor. Furthermore, both patients have microalbuminuria and renal hyperfiltration, requiring an angiotensinconverting enzyme inhibitor. Liver adenomas could not be detected in either sibling. In both patients’ bone mineraldensity is reduced. The clinical phenotype regarding adult height and hepatomegaly however differs Sibling 1 hasreached an adult height of 195.4 cm (+ 2.0 SDS), Sibling 2 of 166.0 cm (- 0.4 SDS). In Sibling 1 hepatomegaly(liver 2 cm below costal margin in medioclavicular line) is less pronounced than in Sibling 2 (liver 9 cm).Genomic DNA preparations, PCR amplification, single-stranded conformation polymorphism (SSCP) andsequence analysis were performed as described in Rake et al. (1999). RESULTS AND DISCUSSION In both siblings, SSCP analyses of exon 1 and exon 5-5' revealed aberrant migration patterns. Subsequentsequencing of the PCR-amplified exon 1 fragment revealed a known frameshift mutation (175delGG, Rake et al.(1999). Sequencing of the PCR-amplified exon 5-5' fragment revealed a deletion of an adenine at nucleotide 867(867delA) resulting in a stopcodon at position 300. This frame shift mutation has not been described before.Although no transient expression analyses have been performed, most likely both mutations lead to proteinproducts with completely abolished G6Pase activity. Lei et al (1995) presented data demonstrating that the 8carboxyl-terminal amino acids (350-357) in human G6Pase are not essential for G6Pase activity or membraneretention. A stop codon preceding these 8 residues, however, causes loss of catalytic activity of G6Pase.Both siblings share the same mutations in the G6Pase gene However, their phenotype regarding residualactivity of G6Pase in liver tissue, adult height, and hepatomegaly differs. The difference in residual enzymeactivity could reflect differences in quality of liver tissue (fat and glycogen storage displace normal liver tissue),differences in biopsy localization (hepatic zonation of G6Pase activity) or analytical considerations (enzymeassays were performed in different laboratories). However, the in vitro observed variability could also reflect realdifference in residual enzyme activity. The difference in phenotype regarding adult height and hepatomegaly couldreflect this difference in residual enzyme activity, but also hepatic glycogen breakdown or glucose production byalternative pathways may play a role. Furthermore, it is possible, that other modifying genes may be involved.Since substantial heterogeneity in phenotype in GSD Ia is observed, a genotype-phenotype correlation may bevery helpful to adjust dietary and pharmacological strategies. However, no evidence for a clear genotype-phenotype correlation in GSD Ia has been found so far. Even in the presented siblings who share the samemutations in the G6Pase gene, their phenotypes differ.In summary: for glycogen storage disease type Ia, heterogeneity in genotype and phenotype is observed. Todate, no evidence for a clear genotype-phenotype correlation has been found.  REFERENCES Fernandes J, Chen YT (1995) Glycogen storage diseases. In: Fernandes J, Saudubray JM, van den Berghe G (eds). Inbornmetabolic diseases. 2nd edn. Springer Verlag, Berlin Heidelberg New York: 71-85Lei KJ, Shelly LL, Pan CJ, Sidbury JB, Chou JY (1993) Mutations in the glucose-6-phosphatase gene that cause glycogenstorage disease type 1a. Science 262:580-583  Mutation Analysis in GSD Ia 3 Lei KJ, Pan CJ, Liu JL, Shelly LL, Chou JY (1995) Structure-function analysis of human glucose-6-phosphatase, the enzymedeficient in glycogen storage disease type 1a. J Biol Chem 270:11882-11886Rake JP, ten Berge AM, Verlind E, Visser G, Niezen-Koning KE, Buys CHCM, Smit GPA, Scheffer H (1999) Glycogenstorage disease type Ia: Four novel mutations (175delGG, R170X, G266V and V338F) identified. Human Mut 13:173(online citation: mutation in brief (1998) #220) Rake JP, ten Berge AM, Visser G, Verlind E, Niezen-Koning KE, Buys CHCM, Smit GPA, Scheffer H (2000) Glycogenstorage disease type Ia: recent experience with mutation analysis, a summary of mutations reported in the literature, and anewly developed diagnostic flowchart. Eur J Pediatr (in press)
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