Mutation database for the galactose-1-phosphate uridyltransferase (GALT) gene

Calderon, Fernanda R.O.; Phansalkar, Amit; Crockett, David K.; Miller, Martin L.; Mao, Rong

doi:10.1002/humu.20544

Cited by 115 publications

(88 citation statements)

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“…26 Although this transition is currently classified as benign, complete sequence of a galactosemic patient homozygous for c.820 þ 13A4G revealed no other alteration in his genomic DNA. 23,26 Furthermore, this variation has never been identified in controls and was found in Portuguese patients either in homozygous or compound heterozygous state. 26 The aim of this study is to confirm that the c.820 þ 13A4G transition is indeed a disease-causing mutation, to elucidate its pathogenic mechanism, by in vivo, ex vivo and in vitro approaches, to functionally characterize the resulting protein and, finally, to use antisense oligonucleotides to modulate the deleterious effect of the mutation.…”

Section: Introductionmentioning

confidence: 94%

“…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. 26 Although this transition is currently classified as benign, complete sequence of a galactosemic patient homozygous for c.820 þ 13A4G revealed no other alteration in his genomic DNA.…”

Section: Introductionmentioning

confidence: 97%

“…[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). 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.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…Sequencing the GALT alleles in patients with classic galactosemia reveals striking allelic heterogeneity with >250 distinct causal or ostensibly causal variants and a small number of ostensibly neutral polymorphisms reported as of January 2013 ( (Calderon et al 2007), http://arup.utah. edu/database/GALT/GALT_welcome.php).…”

Section: Introductionmentioning

confidence: 99%

“…Most variants are coding missense substitutions, but some are small insertions, deletions, or indels. Finally, some variants impact only noncoding sequence, and two are large deletions that remove most or all of the GALT gene (e.g., (Calderon et al 2007;Coffee et al 2006;Gort et al 2006;Papachristoforou et al 2014;Tyfield et al 1999), http://arup. utah.edu/database/GALT/GALT_welcome.php).…”

Section: Introductionmentioning

confidence: 99%

A De Novo Variant in Galactose-1-P Uridylyltransferase (GALT) Leading to Classic Galactosemia

et al. 2014

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Classic galactosemia (CG) is a potentially lethal genetic disease that results from profound impairment of galactose-1-P uridylyltransferase (GALT), the middle enzyme in the Leloir pathway of galactose metabolism. Patients with CG carry pathogenic loss-offunction mutations in both of their GALT alleles; the parents of patients are considered obligate carriers. We report here a first exception to that rule -a de novo GALT variant in a patient with classic galactosemia. The new variant, c.563A>C (p.Q188P), which introduces a missense substitution near the active site of the GALT enzyme, was found in the compound heterozygous state in a child with classic galactosemia, but not in either of her parents. Extensive genomic studies of DNA from the child and both parents confirmed the expected degrees of relationship in the trio as well as inheritance of a common c.563A>G (p.Q188R) GALT mutation from the mother. This result demonstrates that not all pathogenic GALT mutations are inherited and raises concern that GALT may have a higher new mutation rate than previously believed.

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Histidine Triad ( HIT ) Superfamily

Brenner

2007

Encyclopedia of Life Sciences

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Histidine triad (HIT) enzymes are an ancient superfamily of nucleotide hydrolases and transferases that catalyse mechanistically similar but biologically distinct reactions on nucleotide‐containing substrates in pathways important for cellular growth, apoptosis and deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and carbohydrate metabolism. Four branches of HIT enzymes function as nucleotide hydrolases. These enzymes include homologues and paralogues of histidine triad nucleotide‐binding (Hint) protein, fragile histidine triad (Fhit) protein, Aprataxin and scavenger decapping protein (Dcps). One diverse branch of the HIT superfamily contains nucleotide transferases and phosphorylases related to galactose‐1‐phosphate uridylyltransferase (GalT), AppppA phosphorylase, adenylylsulfate:phosphate adenylyltransferase (APAT), adenosine diphosphate (ADP)‐glucose phosphorylase, and Vtc2, the guanosine diphosphate (GDP)‐ l ‐galactose phosphorylase. This review provides tools to discern the identities and the probable functions of new HIT enzymes from their sequences.

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Mutation database for the galactose-1-phosphate uridyltransferase (GALT) gene

Abstract: Communicated by Alastair BrownClassical galactosemia is an autosomal recessive disorder caused by mutations in the galactose-1-phosphate uridyltransferase (GALT) gene. Our group developed a disease-specific database containing all of the reported sequence variants in GALT (

Cited by 115 publications

References 24 publications

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

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

A De Novo Variant in Galactose-1-P Uridylyltransferase (GALT) Leading to Classic Galactosemia

Histidine Triad ( HIT ) Superfamily

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