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Identification of Four Novel PMM2 Mutations in Congenital Disorders of Glycosylation (CDG) Ia French Patients

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Identification of Four Novel PMM2 Mutations in Congenital Disorders of Glycosylation (CDG) Ia French Patients J Med Genet 2000;37:579–580 579 Identification of four novel PMM2 mutations in J Med Genet: first published as 10.1136/jmg.37.8.579 on 1 August 2000. Downloaded from congenital disorders of glycosylation (CDG) Ia French patients Sandrine Vuillaumier-Barrot, Gilles Hetet, Anne Barnier, Thierry Dupré, Maryvonne Cuer, Pascale de Lonlay, Valérie Cormier-Daire, Geneviève Durand, Bernard Grandchamp, Nathalie Seta Abstract missense mutations and a single base pair dele- We screened 11 unrelated French patients tion have been reported. Most of the mutations with congenital disorders of glycosylation are located in exons 5 and 8, and most of the (CDG) Ia for PMM2 mutations. Twenty patients are compound heterozygotes. We one missense mutations on the 22 chro- screened 11 previously unreported unrelated mosomes (95%) including four novel mu- French patients with CDG Ia for mutations tations were identified: C9Y (G26A) in and studied the PMM activity of the new exon 1, L32R (TA95GC) in exon 2, and mutant proteins in an E coli expression system. T226S (C677G) and C241S (G722C) in exon 8. We studied the PMM activity of these four novel mutant proteins and of Methods the R141H mutant protein in an E coli PATIENTS expression system. The T226S, C9Y, L32R, Eleven unreported CDG Ia French patients Biochimie A, Hôpital and C241S mutant proteins have de- were included in the study. Blood, cultured Bichat-Claude creased specific activity (23 to 41% of nor- fibroblasts from forearm biopsy and/or lym- Bernard, 46 rue Henri phoblasts were referred to our laboratory for Huchard, 75877 Paris mal), are all more or less thermolabile, Cedex 18, France and R141H has no detectable activity. Our enzyme assay and molecular diagnosis. S Vuillaumier- Barrot results indicate that the new mutations A Barnier identified here are less severe than the SEQUENCING AND RESTRICTION ANALYSIS T Dupré inactive R141H mutant protein, confer- RNA and DNA were isolated from fresh blood M Cuer ring residual PMM activity compatible G Durand or cultured fibroblasts of CDG Ia patients. Two N Seta with life. overlapping fragments were obtained from (J Med Genet 2000;37:579–580) mRNA using RT-PCR and were sequenced on INSERM U409, Faculté both strands. The intron-exon junctions were http://jmg.bmj.com/ de Médecine X Bichat, Keywords: CDG; phosphomannomutase; PMM2 muta- tions also sequenced in some patients after PCR 75870 Paris Cedex 18, from genomic DNA using available intronic France 2 G Hetet primers. Mutations were confirmed by restric- B Grandchamp Congenital disorder of glycosylation, previ- tion analysis of genomic DNA (excepted for ously called carbohydrate deficient glycopro- C9Y, confirmed on cDNA) with mutagenic Pediatrics, Hôpital tein syndrome (CDG) Ia (OMIM 212065), is primers introducing diagnostic restriction Necker, 75743 Paris an autosomal recessive disorder characterised sites, if necessary, and intronic primers. Cedex 15, France P de Lonlay by central nervous system dysfunction and on September 24, 2021 by guest. Protected copyright. multiorgan failure owing to defective serum CONSTRUCTS FOR EXPRESSION IN E COLI Genetics, Hôpital glycoprotein N-glycosylation, phosphomanno- Mutated cDNA was cloned into the expression Necker, 75743 Paris mutase (PMM) deficiency, and mutations in plasmid pGEX-KG, thereby encoding a Cedex 15, France the PMM2 gene.1 PMM2 gene mutations have PMM-glutathione S-transferase (GST) fusion V Cormier-Daire been described in white CDG Ia patients2–4 and recombinant protein. The mutant and normal 5 Biochimie Hormonale in two Japanese families. A total of 27 diVerent cDNAs were obtained by PCR from the cDNA et Génétique, Hôpital Bichat-Claude Table 1 PMM activities and PMM2 mutations in 11 unrelated French CDG Ia patients. Enzymatic activity is expressed Bernard, 75877 Paris in U/g protein. 1 U enzyme is the activity corresponding to the formation of 1 µmol NADPH/min under the assay Cedex 18, France conditions. Control activities were means (SD): leucocytes (le) 4.8 (1.5) U/g (n= 93), fibroblasts (f) 4.54 (0.94) U/g B Grandchamp (n=14), and lymphoblasts (ly) 11 (3.9) U/g (n=4) Laboratoire de Santé Mutation 1 Mutation 2 Identification PMM activity Mutation 1 nucleotide amino acid Mutation 2 nucleotide amino acid Publique, Faculté de Pharmacie, Paris V, PL 0.9 (le), 2.3 (ly) G26A (exon 1) C9Y G425A (exon 5) R141H 75270 Paris Cedex, Co A 0.1 (f) TA95GC (exon 2) L32R ? ? France MT <0.1 (f) G385A (exon 5) V129M G425A (exon 5) R141H N Seta HA <0.1 (f) T395C (exon 5) I132T G368A (exon 5) R123Q DL <0.1 (f), <0.1 (le) T395C (exon 5) I132T G425A (exon 5) R141H PA ND T395C (exon 5) I132T G425A (exon 5) R141H Correspondence to: SD 0.5 (f), <0.1 (le) C677G (exon 8) T226S G425A (exon 5) R141H Dr Seta, nathalie.seta@ GL <0.1 (f) G691A (exon 8) V231M G425A (exon 5) R141H bch.ap-hop-paris.fr PJ <0.1 (f) G691A (exon 8) V231M G425A (exon 5) R141H Ch A 0.5 (f) G691A (exon 8) V231M G425A (exon 5) R141H Revised version received RN <0.1 (le) G722C (exon 8) C241S G425A (exon 5) R141H 14 February 2000 Accepted for publication ND = not determined. 17 April 2000 ? = no mutations found in cDNA and intron-exon junctions. www.jmedgenet.com 580 Vuillaumier-Barrot, Hetet, Barnier, et al 120 was found in exon 1, in which no mutations have previously been described, in two adult J Med Genet: first published as 10.1136/jmg.37.8.579 on 1 August 2000. Downloaded from sibs. 100 We studied the PMM activity of the four novel mutant proteins and of the R141H 80 mutant protein in an E coli expression system. All the clones expressed the recombinant 60 PMM-GST protein to the same degree and with no change in the apparent molecular weight on western blotting (data not shown). 40 The activity of the R141H mutant protein was undetectable, with values no diVerent from the 20 control clone without PMM2 cDNA (fig 1). This result confirms the absence of residual 0 PMM activity for the most frequent mutant C241S T226S C9Y L32R R141H Normal No PMM protein, R141H, which would explain the lack Figure 1 PMM activity of recombinant PMM2 proteins. The white bars are the mean of homozygotes for this mutation, as it is prob- (SD) (n>3) of the PMM2 protein activity expressed as a percentage of the normal 7 enzyme. The grey bars show the residual PMM2 protein activities after heating at 46°Cfor ably lethal. five minutes. The C241S, C9Y, L32R, and T226S mutant proteins exhibited 23 to 41% of the normal of heterozygous patients, using the Boerhinger protein activity (fig 1). They were all more Expand High Fidelity PCR. thermolabile than the control as they lost from 26 to 56% activity after heating at 46°C for five PHOSPHOMANNOMUTASE ASSAY minutes, compared to 7% for the normal pro- Clones were grown at 37°C overnight and bac- tein (fig 1). terial cells were lysed by osmotic and mechani- Expression studies indicate that all the new cal shock. Expression of PMM2 protein in the mutations that we described in this paper aVect cell lysate was checked by western blot analysis. PMM2 activity but are less severe than R141H. The PMM activity of the recombinant proteins These results may be related to the corre- was assayed in the cell lysate, as described sponding mutation localisation on the gene, 6 elsewhere. Thermolability was assessed by distant from exon 5. Studies of the functional treating the lysates at 46°C for five minutes domain of phosphomannomutase are required before determining activity. All assays were to understand exactly how these mutations done at least in triplicate. aVect PMM2 protein function. Results and discussion We are grateful to the patients and their families. This work was Twenty one missense mutations were identified supported by a grant from Delegation à la Recherche Clinique, on the 22 chromosomes (95%) (table 1). The Assistance Publique-Hôpitaux de Paris (CRC 97139). most frequent mutation, R141H in exon 5, was http://jmg.bmj.com/ found in nine (41%) of the 22 chromosomes in 1 Matthijs G, Schollen E, Pardon E, Veiga-Da-Cunha M, keeping with previous data.23 Jaeken J, Cassiman JJ, Van Schaftingen E. Mutations in PMM2, a phosphomannomutase gene on chromosome Mutations I132T in exon 5 and V231M in 16p13, in carbohydrate-deficient glycoprotein type I exon 8 were each found three times (14%). We syndrome. Nat Genet 1997;16:88-92. (Published erratum appears in Nat Genet 1997;16:316.) did not find the F119L mutation, which was 2 Matthijs G, Schollen E, Van Schaftingen E, Cassiman JJ, present in 16% of CDG Ia alleles from the 56 Jaeken J. Lack of homozygotes for the most frequent patients of diVerent geographical origins2 and disease allele in carbohydrate-deficient glycoprotein syn- drome type Ia. Am J Hum Genet 1998;62:542-50. on September 24, 2021 by guest. Protected copyright. in 44% of CDG Ia alleles from the 18 Danish 3 Kjaergaard S, Skovby F, Schwartz M. Absence of homozy- 3 gosity for predominant mutations in PMM2 in Danish patients. This mutation thus seems to be more patients with carbohydrate-deficient glycoprotein syn- prevalent in northern Europe than in France. drome type 1. Eur J Hum Genet 1998;6:331-6. 4 Vuillaumier-Barrot S, Barnier A, Cuer M, Durand G, Furthermore, we observed a variety of muta- Grandchamp B, Seta N. Characterization of the 415G>A tions in this French population in contrast to (E139K) PMM2 mutation in carbohydrate-deficient glyco- protein syndrome type Ia disrupting a splicing enhancer the Scandinavian countries, where two muta- resulting in exon 5 skipping.
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