Abstract
Mutations in the ALDOB gene impair the activity of the hepatic aldolase B enzyme, causing hereditary fructose intolerance (HFI), an inherited autosomic recessive disease of carbohydrate metabolism, that can result in hypoglycemia, liver and kidney failure, coma, and death. Noninvasive diagnosis is possible by identifying mutant ALDOB alleles in suspected patients. We report the genetic characterization of a cohort of 18 HFI Caucasian patients, based on PCR-sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA), with the identification of two novel genetic lesions: a small duplication c.940_941dupT (p.Trp314fsX22) and a large deletion encompassing the promoter region and exon 1. MLPA and long range-PCR (LR-PCR) also identified the recently reported g.7840_14288del6448 allele with a surprisingly high frequency (11%) within our patients’ cohort. The most common p.Ala150Pro (44%), p.Ala175Asp (19%), p.Asn335Lys (8%), and/or the known c.360-363del4 (5%), p.Tyr204X (2.8%), IVS6 −2A>G (2.8%) mutant alleles were identified in 14 patients at a homozygous or compound-heterozygous level. The integration of PCR-sequencing analysis with exon-dosage tools [MLPA and quantitative fluorescent multiplex-PCR (QFM-PCR)] led to the full genotyping of patients within our cohort and to the identification of the new deletion encompassing the promoter region and exon 1.
Keywords
- Large Deletion
- Human Gene Mutation Database
- Hereditary Fructose Intolerance
- Autosomic Recessive Disease
- Heterozygous Large Deletion
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Competing interests: None declared
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Alì M, Rosien U, Cox TM (1993) DNA diagnosis of fatal fructose intolerance from archival tissue. Q J Med 86(1):25–30
Alì M, Rellos P, Cox TM (1998) Hereditary fructose intolerance. J Med Genet 35(5):353–365
Caciotti A, Donati MA, Adami A, Guerrini R, Zammarchi E, Morrone A (2008) Different genotypes in a large Italian family with recurrent hereditary fructose intolerance. Eur J Gastroenterol Hepatol 20(2):118–121
Coffee EM, Tolan DR (2010) Mutations in the promoter region of the aldolase B gene that cause hereditary fructose intolerance. J Inherit Metab Dis 33(6):715–725
Cross NC, Tolan DR, Cox TM (1988) Catalytic deficiency of human aldolase B in hereditary fructose intolerance caused by a common missense mutation. Cell 53(6):881–885
Cross NC, de Franchis R, Sebastio G et al (1990a) Molecular analysis of aldolase B genes in hereditary fructose intolerance. Lancet 335:306–309
Cross NC, Stojanov LM, Cox TM (1990b) A new aldolase B variant, N334K, is a common cause of hereditary fructose intolerance in Yugoslavia. Nucleic Acids Res 18(7):1925
Davit-Spraul A, Costa C, Zater M et al (2008) Hereditary fructose intolerance: frequency and spectrum mutations of the aldolase B gene in a large patients cohort from France—identification of eight new mutations. Mol Genet Metab 94(4):443–447
Dazzo C, Tolan R (1990) Molecular evidence for compound heterozygosity in hereditary fructose intolerance. Am J Hum Genet 46:1194–1199
Dobrovolny R, Nazarenko I, Kim J, Doheny D, Desnick RJ (2011) Detection of large gene rearrangements in X-linked genes by dosage analysis: identification of novel α-galactosidase A (GLA) deletions causing Fabry disease. Hum Mutat 32(6):688–695
Esposito G, Santamaria R, Vitagliano L et al (2004) Six novel alleles identified in Italian hereditary fructose intolerance patients enlarge the mutation spectrum of the aldolase B gene. Hum Mutat 24(6):534
Esposito G, Imperato MR, Ieno L et al (2010) Hereditary fructose intolerance: functional study of two novel ALDOB natural variants and characterization of a partial gene deletion. Hum Mutat 31(12):1294–1303
Hogervorst FB, Nederlof PM, Gille JJ et al (2003) Large genomic deletions and duplications in the BRCA1 gene identified by a novel quantitative method. Cancer Res 63(7):1449–1453
James CL, Rellos P, Alì M, Heeley AF, Cox TM (1996) Neonatal screening for hereditary fructose intolerance: frequency of the most common mutant aldolase B allele (A149P) in the British population. J Med Genet 33:837–841
Santamaria R, Scarano MI, Esposito G, Chiandetti L, Izzo P, Salvatore F (1993) The molecular basis of hereditary fructose intolerance in Italian children. Eur J Clin Chem Clin Biochem 31(10):675–678
Santer R, Rischewski J, von Weihe M et al (2005) The spectrum of aldolase B (ALDOB) mutations and the prevalence of hereditary fructose intolerance in Central Europe. Hum Mutat 25:594
Sebastio G, de Franchis R, Strisciuglio P et al (1991) Aldolase B mutations in Italian families affected by hereditary fructose intolerance. J Med Genet 28(4):241–243
Steinman B, Gitzelmann R, van den Berghe G (2001) Disorders of fructose metabolism. In: Scriver CR, Beaudet AL, Valle D, Sly WS (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 1489–1520
Tolan DR (1995) Molecular basis of hereditary fructose intolerance: mutations and polymorphisms in the human aldolase B gene. Hum Mutat 6:210–218
Tolan DR, Penhoet EE (1986) Characterization of the human aldolase B gene. Mol Biol Med 3:245–264
Acknowledgments
This work was partially supported by grants from AMMEC (Associazione Malattie Metaboliche Congenite ereditarie).
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Communicated by: Matthias Baumgartner
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Synopsis
The here combined exon-dosage MLPA and QFM-PCR tools ensured that two new ALDOB mutations were detected and that a known deletion emerged with a surprisingly high frequency.
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Ferri, L. et al. (2012). Integration of PCR-Sequencing Analysis with Multiplex Ligation-Dependent Probe Amplification for Diagnosis of Hereditary Fructose Intolerance. In: JIMD Reports - Case and Research Reports, 2012/3. JIMD Reports, vol 6. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2012_125
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DOI: https://doi.org/10.1007/8904_2012_125
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