Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene

Tyfield, Linda; Reichardt, Juergen K.V.; Fridovich-Keil, Judy; Croke, David T.; Elsas, Louis J.; Strobl, Wolfgang; Kozák, Libor; Coşkun, Turgay; Novelli, Giuseppe; Okano, Yoshiyuki; Żekanowski, Cezary; Shin, Yoon S.; Boleda, Ma Dolores

doi:10.1002/(sici)1098-1004(1999)13:6<417::aid-humu1>3.0.co;2-0

Cited by 150 publications

(119 citation statements)

References 58 publications

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“…[18][19][20] Taken together, these data strongly indicate genetic diversity according to ethnicity. 1,10,21 In conclusion, we have shown here that the classical galactosemia caused by GALT deficiency is very rare in the Korean population and that a splicing mutation (c.252+1G4A) may be common in Korean patients with classical galactosemia. Identification and evaluation of a larger number of Korean patients with classical galactosemia are required to verify these genetic characteristics.…”

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confidence: 53%

Low prevalence of classical galactosemia in Korean population

et al. 2010

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This study described the clinical and molecular genetic features of classical galactosemia in Korean population to contribute to the insight in the spectrum of galactosemia in the world, as little is known about the spectrum and incidence of galactosemia in Asia. During the 11-year study period, only three Korean children were identified as having classical galactosemia on the basis of the enzymatic and molecular genetic analysis. Asians have been reported to have mutations distinct from those of Caucasians and African Americans, indicating that galactose-1-phosphate uridyltransferase mutations are ethnically diverse. Our three patients had a total of three mutations (c.252+1G4A, p.Q169H and p.E363K), two of which were novel (p.E363K and c.252+1G4A) mutations. Interestingly, c.252+1G4A, which leads to skipping of exon 2, was observed in all three patients (three of six alleles), indicating that this mutation may be common in Koreans with classical galactosemia. Screening for classical galactosemia in 158 126 Korean newborns identified no patient with classical galactosemia. In conclusion, our findings provide further evidence for the ethnic diversity of classical galactosemia, which may be as rare in Koreans as in other Asian populations.

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confidence: 53%

Low prevalence of classical galactosemia in Korean population

et al. 2010

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“…Among patients of European descent, c.563A > G (p.Q188R) is the most common variant and accounts for 64% of all pathogenic variants seen. 5 The c.404C > T (p.S135L) variant is associated with an attenuated phenotype, and is found almost exclusively in patients of African origin. 6 Other common pathogenic variants include: c.855G > T (p.K285N), c.626A > G (p. Y209C), c.413C > T (p.T138M), c.584T > C (p.L195P) and IVS2-2A > G. 5 A deletion of approximately 5.5 kb is common among Ashkenazi Jewish individuals.…”

Section: Introductionmentioning

confidence: 99%

“…5 The c.404C > T (p.S135L) variant is associated with an attenuated phenotype, and is found almost exclusively in patients of African origin. 6 Other common pathogenic variants include: c.855G > T (p.K285N), c.626A > G (p. Y209C), c.413C > T (p.T138M), c.584T > C (p.L195P) and IVS2-2A > G. 5 A deletion of approximately 5.5 kb is common among Ashkenazi Jewish individuals. 7,8 All of these variants are associated with near or complete loss of enzyme activity, although for p.S135L the deficiency may be confined to RBCs.…”

Section: Introductionmentioning

confidence: 99%

Laboratory diagnosis of galactosemia: a technical standard and guideline of the American College of Medical Genetics and Genomics (ACMG)

Pasquali

Coffee

2018

Genetics in Medicine

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“…[13][14][15][16][17] The disorder is caused by mutations in the GALT gene, which profoundly impair GALT enzymatic activity. 15,18,19 GALT is located in chromosome 9p13, arranged into 11 exons spanning about 4.0 kb of genomic sequence, and encodes a 379 amino-acid polypeptide, which is assembled as a B87 kDa homodimer. [19][20][21][22] As many other autosomal recessive metabolic disorders, classic galactosemia displays great allelic heterogeneity with 4260 variations described (http://arup.utah.edu/database/GALT/GALT_display.php; http://databases.lovd.nl/shared/genes/GALT).…”

Section: Introductionmentioning

confidence: 99%

“…23 Although most are missense mutations, other variations have been reported, namely silent, nonsense and noncoding changes. 18,24,25 Moreover, several intronic variations have been identified in the GALT gene, approximately half of which are known to affect splicing. 23 Mutational analysis of 42 Portuguese patients confirmed c.563A4G (p.Q188R) as the prevalent molecular defect (67.1%), and surprisingly revealed an intronic variation, c.820 þ 13A4G (IVS8þ 13A4G), as the second most frequent mutation, accounting for 8.0% of the mutant alleles.…”

Section: Introductionmentioning

confidence: 99%

Functional correction by antisense therapy of a splicing mutation in the GALT gene

et al. 2014

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In recent years, antisense therapy has emerged as an increasingly important therapeutic approach to tackle several genetic disorders, including inborn errors of metabolism. Intronic mutations activating cryptic splice sites are particularly amenable to antisense therapy, as the canonical splice sites remain intact, thus retaining the potential for restoring constitutive splicing. Mutational analysis of Portuguese galactosemic patients revealed the intronic variation c.820 þ 13A4G as the second most prevalent mutation, strongly suggesting its pathogenicity. The aim of this study was to functionally characterize this intronic variation, to elucidate its pathogenic molecular mechanism(s) and, ultimately, to correct it by antisense therapy. Minigene splicing assays in two distinct cell lines and patients' transcript analyses showed that the mutation activates a cryptic donor splice site, inducing an aberrant splicing of the GALT pre-mRNA, which in turn leads to a frameshift with inclusion of a premature stop codon (p.D274Gfs*17). Functional-structural studies of the recombinant wild-type and truncated GALT showed that the latter is devoid of enzymatic activity and prone to aggregation. Finally, two locked nucleic acid oligonucleotides, designed to specifically recognize the mutation, successfully restored the constitutive splicing, thus establishing a proof of concept for the application of antisense therapy as an alternative strategy for the clearly insufficient dietary treatment in classic galactosemia. European Journal of Human Genetics (2015) 23, 500-506; doi:10.1038/ejhg.2014.149; published online 23 July 2014 INTRODUCTIONOver the last years, splicing mutations emerged as an important pathogenic mechanism, underlying 10-30% of genetic diseases (HGMD Professional 2013.1). 1 Splicing accuracy depends not only on the recognition of exon-intron junctions, defined by intronic ciselements: 5 0 splice site, 3 0 splice site, branch site and poly-pyrimidine tract, 2-4 but also on more discrete elements, entitled splicing regulatory elements, which direct the splicing machinery to use the correct splice sites. Exonic and intronic splicing enhancers stimulate splicing and serve as binding sites mainly for serine/arginine-rich proteins. Exonic and intronic splicing silencers repress splicing, and often function by binding proteins from the heterogenous nuclear ribonucleoprotein family. 2,4-6 Although most reported splicing mutations directly abolish an authentic splice site or create a novel one, an increasing number of disease-associated variations that alter splicing enhancers or silencers have been reported. 2,7-9 Each nucleotide modification should be considered a potential candidate for splicing alterations, as not only intronic but also nonsense, missense and silent modifications may impact splicing. 7 Accordingly, constitutive and regulated splicing reactions are considered potential therapeutic targets and novel strategies for their correction are evolving. Among these, antisense oligonucleotides display an exquisi...

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Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene

Cited by 150 publications

References 58 publications

Low prevalence of classical galactosemia in Korean population

Low prevalence of classical galactosemia in Korean population

Laboratory diagnosis of galactosemia: a technical standard and guideline of the American College of Medical Genetics and Genomics (ACMG)

Functional correction by antisense therapy of a splicing mutation in the GALT gene

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