2011
DOI: 10.1007/s10545-011-9328-2
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Expression analysis revealing destabilizing mutations in phosphomannomutase 2 deficiency (PMM2‐CDG)

Abstract: Deficiency of phosphomannomutase (PMM2, MIM#601785) is the most common congenital disorder of glycosylation. Herein we report the genetic analysis of 22 Spanish PMM2 deficient patients and the functional analysis of 14 nucleotide changes in a prokaryotic expression system in order to elucidate their molecular pathogenesis. PMM2 activity assay revealed the presence of six protein changes with no enzymatic activities (p.R123Q, p.R141H, p.F157S, p.P184T, p.F207S and p.D209G) and seven mild protein changes with re… Show more

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Cited by 48 publications
(56 citation statements)
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References 25 publications
(56 reference statements)
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“…1A). Similar correlations between mutants that misfold in vivo and also show problems in recombinant expression have been observed in many other inherited metabolic diseases, including deficiencies in cystathione ␤-synthase (23), medium-chain acyl-CoA dehydrogenase (24,25), phosphomannomutase 2 (26), and phenylalanine hydroxylase (27)(28)(29).…”
Section: Discussionmentioning
confidence: 57%
“…1A). Similar correlations between mutants that misfold in vivo and also show problems in recombinant expression have been observed in many other inherited metabolic diseases, including deficiencies in cystathione ␤-synthase (23), medium-chain acyl-CoA dehydrogenase (24,25), phosphomannomutase 2 (26), and phenylalanine hydroxylase (27)(28)(29).…”
Section: Discussionmentioning
confidence: 57%
“…The latter has previously been described as a polymorphism (22). Four different nsSNPs were predicted by Polyphen to be probably damaging: NPHS1 H1174Y (heterozygote in patient 21), MYO1E I531M (heterozygote in patient 34), MYH9 K910G (homozygous in patient 23; previously described in a patient with Fechtner syndrome but also in control) (23), and SMARCAL1 E377Q (heterozygous in patient 12; previously described; probable polymorphism) (24).…”
Section: Sequencing Resultsmentioning
confidence: 98%
“…Structural studies show that the R141H mutant is impaired in substrate binding and has essentially no activity (25). If R141H allele is in combination with another allele that produces an unstable protein (V231M) or protein impaired in dimer interface interaction (F119L, P113L) (25,26), then no improvement is observed with MPI inhibitor. Even if Man-6-P pools were mobilized toward mutant PMM2, they could not be utilized for glycosylation.…”
Section: Discussionmentioning
confidence: 99%