Mutation spectrum in the French cohort of galactosemic patients and structural simulation of 27 novel missense variations

Boutron, Audrey; Marabotti, Anna; Facchiano, Angelo; Cheillan, David; Zater, Mokhtar; Oliveira, Christophe; Costa, Cathérine; Labrune, Philippe; Brivet, M.

doi:10.1016/j.ymgme.2012.07.025

Cited by 27 publications

(32 citation statements)

References 48 publications

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“…The underlying mechanism of these long-term pathologies is not fully known, and the role of accumulated galactose-1-phosphate in the process remains controversial [8]. In addition, understanding phenotype-genotype correlations is difficult as compound heterozygosity plays a role in disease [9]. This is because the hGALT protein functions as a dimer (Figure 1) [10-12].…”

Section: Introductionmentioning

confidence: 99%

Misfolding of galactose 1-phosphate uridylyltransferase can result in type I galactosemia

McCorvie

Gleason

Fridovich‐Keil

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Type I galactosemia is a genetic disorder that is caused by the impairment of galactose-1-phosphate uridylyltransferase (GALT; EC 2.7.7.12). Although a large number of mutations have been detected through genetic screening of the human GALT (hGALT) locus, for many it is not known how they cause their effects. The majority of these mutations are missense, with predicted substitutions scattered throughout the enzyme structure and thus causing impairment by other means rather than direct alterations to the active site. To clarify the fundamental, molecular basis of hGALT impairment we studied five disease-associated variants p.D28Y, p.L74P, p.F171S, p.F194L and p.R333G using both a yeast model and purified, recombinant proteins. In a yeast expression system there was a correlation between lysate activity and the ability to rescue growth in the presence of galactose, except for p.R333G. Kinetic analysis of the purified proteins quantified each variant’s level of enzymatic impairment and demonstrated that this was largely due to altered substrate binding. Increased surface hydrophobicity, altered thermal stability and changes in proteolytic sensitivity were also detected. Our results demonstrate that hGALT requires a level of flexibility to function optimally and that altered folding is the underlying reason of impairment in all the variants tested here. This indicates that misfolding is a common, molecular basis of hGALT deficiency and suggests the potential of pharmacological chaperones and proteostasis regulators as novel therapeutic approaches for type I galactosemia.

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Section: Introductionmentioning

confidence: 99%

Misfolding of galactose 1-phosphate uridylyltransferase can result in type I galactosemia

McCorvie

Gleason

Fridovich‐Keil

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…All known patients, except one, are included in the survey. The birth incidence of GALT deficiency in Sweden is approximately 1/100 000, which is the same as in France and Italy, but lower than the reported incidence of 1/30 000‐40 000 for most other European countries …”

Section: Discussionmentioning

confidence: 61%

“…Included in the six synonymous variants, predicted to affect splicing, are the three variants proven to be pathogenic: p.(Pro36=), p.(Pro109=) and the earlier presumably benign synonymous variant, p.(Gly338=) (c.1014C>G). The latter has been shown to be disease‐causing by activating an alternative splice donor site, resulting in the exclusion of 46 nucleotides at the end of exon 10 . The two synonymous variants described in this article both result in reduced GALT activity.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity of disease‐causing variants in the Swedish galactosemia population: Identification of 16 novel GALT variants

Ohlsson

Hunt²,

Wedell

et al. 2019

J of Inher Metab Disea

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The aim was to determine disease‐causing variants in the GALT gene which codes for the enzyme galactose‐1‐phosphate uridylyltransferase. Loss of activity of this enzyme causes classical galactosemia—a life threatening, treatable disorder, included in the Swedish newborn screening program since 1967. A total of 66 patients with the disease are known in Sweden and 56 index patients were investigated. An additional two patients with Duarte galactosemia were included. The disease‐causing variants were identified in all patients. As reported from other countries only a few variants frequently recur in severe disease. The two variants p.(Gln188Arg) (c.563A>G) and p.(Met142Lys) (c.425T>A) are present in several index patients whereas the remaining are found in one to three patients each. The most common variant, p.(Gln188Arg), has an allele frequency of 51% in the cohort. A total of 16 novel variants were found among the 33 different variants in the cohort. Two of these are synonymous variants affecting splicing, demonstrating the importance of the evaluation of synonymous variants at the cDNA level. Concise sentence: Galactosemia is a rare disease in Sweden and the disease‐causing variants are heterogenous including two synonymous variants.

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“…In the research laboratory the GALT gene was PCR amplified as a single~6 kb amplicon using the primers 5 0 -AGTACCAGGGGAG-GA AT TAAT TTG AAT TTT-3 0 and 5 0 -ATTCAGT-CACTGTCCAGCCTTAGTGTGATTT-3 0 as described previously (Boutron et al 2012), and the relevant region was sequenced using the following custom primers: hGALT-F4(2): 5 0 -AAGCTTTGGTTCTGGGGAGT-3 0 (3 0 end anneals to position 1324), hGALT-F03(1): 5 0 -CCCTGGTCGG ATGTAACG-3 0 (3 0 end anneals to position 1164), and hGALT-R3: 5 0 -GTGTCTGGTAGGGC-CATGTT-3 0 (3 0 end anneals to position 2111). Both the clinical and research labs identified the same two mutations: the common c.563A>G (p.Q188R) missense mutation and also a novel c.563A>C (p.Q188P) missense mutation, each found in the patient in the compound heterozygous state.…”

Section: Study Volunteersmentioning

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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Mutation spectrum in the French cohort of galactosemic patients and structural simulation of 27 novel missense variations

Cited by 27 publications

References 48 publications

Misfolding of galactose 1-phosphate uridylyltransferase can result in type I galactosemia

Misfolding of galactose 1-phosphate uridylyltransferase can result in type I galactosemia

Heterogeneity of disease‐causing variants in the Swedish galactosemia population: Identification of 16 novel GALT variants

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

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