Mutations in PMM2 that cause congenital disorders of glycosylation, type Ia (CDG-Ia)

Matthijs, Gert; Schollen, E; Bjursell, Cecilia; Erlandson, Anna; Freeze, Hudson H.; Imtiaz, Faiqa; Kjærgaard, Susanne; Martinsson, Tommy; Schwartz, Marianne; Seta, Nathalie; Vuillaumier‐Barrot, Sandrine; Westphal,; Winchester, Bryan

doi:10.1002/1098-1004(200011)16:5<386::aid-humu2>3.0.co;2-y

Cited by 138 publications

(112 citation statements)

References 26 publications

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“…Mutations in nine genes that affect N-glycosylation have been shown to cause various types of CDG, 9,43 and essentially all reported CDG cases have two mutations in a single affected gene leading to the disorder. 5,15,44 Because most of the consequences of CDG are thought to result from hypoglycosylation of proteins, i.e., the same endpoint for each disease, the broad spectrum of clinical presentations is surprising. The one exception is that the most common PMM2 mutation (R141H) is apparently lethal when homozygous.…”

Section: Discussionmentioning

confidence: 99%

“…10 -13 The disease can have a lethal outcome in early childhood. 14,15 Over 50 different mutations have to date been identified in PMM patients, 15 and a recent study shows some correlation of the clinical severity of mildly affected CDG-Ia patients with the residual activity of PMM. 16 In this study, we analyze four untyped CDG patients (two of them siblings).…”

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confidence: 99%

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Functional significance of PMM2 mutations in mildly affected patients with congenital disorders of glycosylation Ia

Westphal

Peterson

Patterson

et al. 2001

Genetics in Medicine

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Purpose: Congenital disorders of glycosylation (CDG) result from mutations in N-glycan biosynthesis. Mutations in phosphomannomutase (PMM2) cause CDG-Ia. Here, we report four clinically mild patients and their mutations in PMM2. Methods: Analysis of the PMM2 cDNA and gene revealed the mutations affecting the glycosylation efficiency. Results: The patients have 30% to 50% normal PMM activity in fibroblasts due to different mutations in PMM2, and we studied the effect of each mutation on the PMM activity in a Saccharomyces cerevisiae expression system. Conclusions: Each patient carried a severe mutation that decreased the PMM activity to less than 10% as well as a relatively mild mutation. A new mutation, deletion of base 24, changed the reading frame. The C9Y, C241S, and L32R mutations showed 27% to 45% activity when expressed in the eukaryotic expression system, and the more severe D148N was shown to be thermolabile. Genet Med 2001:3(6):393-398.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Functional significance of PMM2 mutations in mildly affected patients with congenital disorders of glycosylation Ia

Westphal

Peterson

Patterson

et al. 2001

Genetics in Medicine

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“…The incidence of CDG-Ia is 1:20 000, and probably half of them are diagnosed. 11 So, when investigating a hydropic newborn, the differential diagnosis always should include congenital disorders of glycosylation, especially when additional dysmorphic features (inverted nipples) or other symptoms (thrombocytopenia, hypoglycemia) are seen. Although isoelectric focusing of transferrin is thought to be unreliable in the first days of life, the two patients from van de Kamp and co-workers showed an abnormal pattern on the second day of life, suggesting that the more severe presentations of CDG-Ia with fetal hydrops can be diagnosed in the first days of life.…”

Section: Commentmentioning

confidence: 99%

Congenital disorders of glycosylation type Ia as a cause of mirror syndrome

et al. 2007

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Mirror syndrome (that is fetal hydrops with subsequent edema in the pregnant woman) is a rare condition. Early diagnosis is warranted, as maternal and fetal morbidity and mortality is increased if not diagnosed and treated properly. In most cases, the underlying cause remains unclear. We report a woman who has had two pregnancies complicated by mirror syndrome. Congenital disorder of glycosylation type Ia (CDG-Ia) was identified as the underlying fetal disease in both cases.

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“…It seems that no hotspots exist be it that some mutations are more frequent, due to founder effects. 5,6 For PMM2, more than 50 different mutations have been described. 6 Only six of them have been found in more than 10 families.…”

Section: Introductionmentioning

confidence: 99%

“…5,6 For PMM2, more than 50 different mutations have been described. 6 Only six of them have been found in more than 10 families. In MPI and ALG6, 13 and 6 different mutations have been described in 10 and 9 patients respectively.…”

Section: Introductionmentioning

confidence: 99%

DHPLC analysis as a platform for molecular diagnosis of congenital disorders of glycosylation (CDG)

et al. 2002

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Since 1997, the molecular basis of six different types of Congenital Disorders of Glycosylation with a defect in the synthesis of N-glycans (CDG-I) has been identified. To assure an efficient molecular diagnosis of the six genes involved in these types, we established a denaturing high-pressure liquid chromatography (DHPLC) screening procedure. Primers were designed and conditions were optimised for the analysis of each exon of the PMM2, MPI, ALG6, ALG3, DPM1 and MPDU1 genes. Forty previously described PMM2 mutations were tested to evaluate the method. All of them could be detected. Hence, the sensitivity of the technique is virtually 100%. Screening of 17 novel cases with a tentative, clinical diagnosis of CDG-Ia identified mutations on both alleles in 14 of them, thereby confirming the diagnosis. Six of these mutations were not previously reported (G15E, G42R, Y64C, E93A, G214S and D223N). Sequencing of the complete coding sequence of PMM2 in the remaining three patients did not reveal mutations, corroborating the good performance of the DHPLC method. A similar DHPLC approach was also applied to CDG-Ib, CDG-Ic, CDG-Id, CDG-Ie and CDG-If samples. New mutations were identified in MPI (Y129C) and ALG6 (G227E). All results were confirmed by sequencing. We conclude that the DHPLC platform is a sensitive and efficient method for the rapid analysis of disease genes with a limited number of exons.

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Mutations in PMM2 that cause congenital disorders of glycosylation, type Ia (CDG-Ia)

Cited by 138 publications

References 26 publications

Functional significance of PMM2 mutations in mildly affected patients with congenital disorders of glycosylation Ia

Functional significance of PMM2 mutations in mildly affected patients with congenital disorders of glycosylation Ia

Congenital disorders of glycosylation type Ia as a cause of mirror syndrome

DHPLC analysis as a platform for molecular diagnosis of congenital disorders of glycosylation (CDG)

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