Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:5.4.2.8 (phosphomannomutase)
 238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Congenital disorders of glycosylation (CDGs) are a rapidly enlarging group of inherited diseases with abnormal N-glycosylation of glycoconjugates. Most patients have CDG-Ia, which is due to a phosphomannomutase (PMM) deficiency. In this article, we report that a significant portion (9 of 54) of patients with CDG-Ia had a rather high residual PMM activity in fibroblasts included in the normal range (means of the controls +/- 2 SD) and amounting to 35%-70% of the mean control value. The clinical diagnosis of CDG-Ia was made difficult by the fact that most (6 of 9) of these patients belong to a subgroup characterized by a phenotype that is milder than classical CDG-Ia. These patients lack some of the symptoms that are suggestive for the diagnosis, such as inverted nipples and abnormal fat deposition, and, as a mean, had higher residual PMM activities in fibroblasts (2.05+/-0.61 mU/mg protein, n=9; vs. controls 5.34+/-1.74 mU/mg protein, n=22), compared with patients with moderate (1.32+/-0.86 mU/mg protein, n=18) or severe (0.63+/-0.56 mU/mg protein, n=27, P<.001) cases. Yet they all showed mild mental retardation, hypotonia, cerebellar hypoplasia, and strabismus. All of them had an abnormal serum transferrin pattern and a significantly reduced PMM activity in leukocytes. Six of the nine patients with mild presentations were compound heterozygotes for the C241S mutation, which is known to reduce PMM activity by only approximately 2-fold. Our results indicate that intermediate PMM values in fibroblasts may mask the diagnosis of CDG-Ia, which is better accomplished by measurement of PMM activity in leukocytes and mutation search in the PMM2 gene. They also indicate that there is some degree of correlation between the residual activity in fibroblasts and the clinical phenotype.
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PMID:High residual activity of PMM2 in patients' fibroblasts: possible pitfall in the diagnosis of CDG-Ia (phosphomannomutase deficiency). 1115 36

The congenital disorders of glycosylation (CDG) constitute a new group of recessively inherited metabolic disorders that are characterized biochemically by defective glycosylation of proteins. Several types have been identified. CDG-Ia, the most frequent type, is a multisystemic disorder affecting the nervous system and numerous organs including liver, kidney, heart, adipose tissue, bone, and genitalia. A phosphomannomutase (PMM) deficiency has been identified in CDG-Ia patients and numerous mutations in the PMM2 gene have been identified in patients with a PMM deficiency. We report on a French family with 3 affected sibs, with an unusual presentation of CDG-Ia, remarkable for 1) the neurological presentation of the disease, and 2) the dissociation between intermediate PMM activity in fibroblasts and a decreased PMM activity in leukocytes. This report shows that the diagnosis of CDG-Ia must be considered in patients with non-regressive early-onset encephalopathy with cerebellar atrophy, and that intermediate values of PMM activity in fibroblasts do not exclude the diagnosis of CDG-Ia.
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PMID:Neurological presentation of a congenital disorder of glycosylation CDG-Ia: implications for diagnosis and genetic counseling. 1134 37

Congenital disorders of glycosylation (CDG) are caused by autosomal recessive mutations in genes affecting N-glycan biosynthesis. Mutations in the PMM2 gene, which encodes the enzyme phosphomannomutase (mannose 6-phosphate <--> mannose 1-phosphate), give rise to the most common form: CDG-Ia. These patients typically present with dysmorphic features and neurological abnormalities, cerebellar hypoplasia, ataxia, hypotonia, and coagulopathy, in addition to feeding problems. However, the clinical symptoms vary greatly. The great majority of known CDG-Ia patients are of European descent where the most common mutant alleles originated. This ethnic bias can also be explained by lack of global awareness of the disorder. Here we report an Asian patient with prominent systemic features that we diagnosed with CDG-Ia resulting from two new mutations in the PMM2 gene (310C --> G resulting in L104V and an intronic mutation IVS1-1G --> A). The latter mutation seems to result in lower mRNA levels, and the L104V has been functionally analyzed in a yeast expression system together with known mutations. The Filipino and Cambodian origins of the parents show that CDG-Ia mutations occur in these ethnic groups as well as in Caucasians.
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PMID:Functional analysis of novel mutations in a congenital disorder of glycosylation Ia patient with mixed Asian ancestry. 1135 Jan 85

Complete loss of N-glycosylation is lethal in both yeast and mammals. Substantial deficiencies in some rate-limiting biosynthetic steps cause human congenital disorders of glycosylation (CDG). Patients have a range of clinical problems including variable degrees of mental retardation, liver dysfunction, and intestinal disorders. Over 60 mutations in phosphomannomutase (encoded by PMM2) diminish activity and cause CDG-Ia. The severe mutation R141H in PMM2 is lethal when homozygous, but heterozygous in about 1/70 Northern Europeans. Another disorder, CDG-Ic, is caused by mutations in ALG6, an alpha 1,3glucosyl transferase used for lipid-linked precursor synthesis, yet some function-compromising mutations occur at a high frequency in this gene also. Maintenance of seemingly deleterious mutations implies a selective advantage or positive heterosis. One possible explanation for this is that production of infective viruses such as hepatitis virus B and C, or others that rely heavily on host N-glycosylation, is substantially inhibited when only a tiny fraction of their coat proteins is misglycosylated. In contrast, this reduced glycosylation does not affect the host. Prevalent functional mutations in rate-limiting glycosylation steps could provide some resistance to viral infections, but the cost of this insurance is CDG. A balanced glycosylation level attempts to accommodate these competing agendas. By assessing the occurrence of a series of N-glycosylation-compromising alleles in multi-genic diseases, it may be possible to determine whether impaired glycosylation is a risk factor or a major determinant underlying their pathology.
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PMID:Balancing N-linked glycosylation to avoid disease. 1153 Feb 12

Congenital disorders of glycosylation (CDG) are a group of metabolic disorders with multisystemic involvement characterized by abnormalities in the synthesis of N-linked oligosaccharides. The most common form, CDG-Ia, resulting from mutations in the gene encoding the enzyme phosphomannomutase (PMM2), manifests with severe abnormalities in psychomotor development, dysmorphic features and visceral involvement. While this disorder is panethnic, we present the first cases of CDG-Ia identified in an African American family with two affected sisters. The proband had failure to thrive in infancy, hypotonia, ataxia, cerebellar hypoplasia and developmental delay. On examination, she also exhibited strabismus, inverted nipples and an atypical perineal fat distribution, all features characteristic of CDG-Ia. Direct sequencing demonstrated that the patient had a unique genotype, T237M/c.565-571 delAGAGAT insGTGGATTTCC. The novel deletion-insertion mutation, which was confirmed by subcloning and sequencing of each allele, introduces a stop codon 11 amino acids downstream from the site of the deletion. The presence of this deletion-insertion mutation at cDNA position 565 suggests that this site in the PMM2 gene may be a hotspot for chromosomal breakage.
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PMID:A deletion-insertion mutation in the phosphomannomutase 2 gene in an African American patient with congenital disorders of glycosylation-Ia. 1189 94

Serum- and glucocorticoid-regulated kinase (Sgk1) is considered to be an essential convergence point for peptide and steroid regulation of ENaC-mediated sodium transport. We tried to identify molecular partners of Sgk1 by yeast two-hybrid screening. Yeast two-hybrid screening showed a specific interaction between Sgk1 and phosphomannomutase (PMM)2, the latter of which is an enzyme involved in the regulation of glycoprotein biosynthesis. The interaction was confirmed in intact cells by coimmunoprecipitation and colocalization detected using confocal microscopy. We were then able to demonstrate that Sgk1 phosphorylated PMM2 in an in vitro assay. In addition, we found that the enzymatic activity of PMM2 is upregulated by insulin treatment and that Sgk1 completely inhibits PMM2 activity both in the absence and in the presence of insulin stimulation. These data provide evidence suggesting that Sgk1 may modulate insulin action on the cotranslational glycosylation of glycoproteins.
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PMID:Serum and glucocorticoid-regulated kinase Sgk1 inhibits insulin-dependent activation of phosphomannomutase 2 in transfected COS-7 cells. 1534 40

Congenital disorders of glycosylation (CDG) represent a newly delineated group of inherited multisystem disorders characterized by defective glycoprotein biosynthesis. In the present study we report and discuss the clinical and neuropathological findings in a newborn with CDG type Ia (CDG-Ia). The patient presented mild dysmorphic facial features, inverted nipples, progressive generalized edema, hypertrophic cardiomyopathy, hepatosplenomegaly, muscular hypotonia and had severe hypoalbuminemia. Deficiency of phosphomannomutase (PMM)-2 activity was detected. Molecular analysis showed V231M/T237R mutations of the PMM2 gene. Muscular biopsy, disclosed myopathic alterations with myofibrillar disarray by electron microscopy. The patient died at 1 month of age of circulatory and respiratory failure. Autopsy showed liver fibrosis and renal abnormalities. Neuropathological abnormalities were mainly confined to the cerebellum. Histological and immunocytochemical examination of cerebellar tissue showed partial atrophy of cerebellar folia with severe loss of Purkinje cells, granular cell depletion and various morphological changes in the remaining Purkinje cells and their dendritic arborization. Autopsy findings confirm the complexity of the CDG-Ia syndrome, and indicate that CDG-Ia is a distinct disease entity, which can be differentiated from other neurological disorders and other types of CDG, not only clinically, but also based on unique pathological findings. The data proved useful in determining the underlying disease process associated with a defective N-glycosylation pathway.
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PMID:Congenital disorder of glycosylation type Ia: a clinicopathological report of a newborn infant with cerebellar pathology. 1571 16

Congenital disorder of Glycosylation type Ia is an autosomal recessive disorder, characterized by a central nervous system dysfunction and multiorgan failure associated with defective N-glycosylation and phosphomannomutase (PMM) deficiency related to mutations in the PMM2 gene (mRNA U85773.1, gene ID 5373). More than 75 different mutations have been previously described. In our study, 38 different mutations were found in 52 French families with CDG-Ia. Eleven mutations had not been previously published in CDG-Ia patients: eight missense and three splice mutations. We studied the PMM activity of eight novel recombinant mutant proteins in an E. coli expression system, comparing them with the wild type protein, c.422 G>A (R141H), and c.415 G>A (E139K) mutant proteins. We also studied the previously described c.590 C>A (E197A) found on the same allele as c.394 A>T (I132F). All mutant proteins studied except E197A had decreased activity and/or were thermolabile, and were pathogenic mutations. Haplotype studies revealed a founder effect for E139K mutation, only described in France and found in seven CDG-Ia families (7.6%). In contrast, at least two different haplotypes were observed for the R141H mutation in France, studied in 23 families. The R141H seems to be a combination of the "old" R141H mutation found all over Europe and a second "French" R141H, and could be substantially older than E139K.
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PMID:A new insight into PMM2 mutations in the French population. 1584 18

Patients with Type I congenital disorders of glycosylation (CDG-I) make incomplete lipid-linked oligosaccharides (LLO). These glycans are poorly transferred to proteins resulting in unoccupied glycosylation sequons. Mutations in phosphomannomutase (PMM2) cause CDG-Ia by reducing the activity of PMM, which converts mannose (Man)-6-P to Man-1-P before formation of GDP-Man. These patients have reduced Man-1-P and GDP-Man. To replenish intracellular Man-1-P pools in CDG-Ia cells, we synthesized two hydrophobic, membrane permeable acylated versions of Man-1-P and determined their ability to normalize LLO size and N-glycosylation in CDG-Ia fibroblasts. Both compounds, compound I (diacetoxymethyl 2,3,4,6-tetra-O-acetyl-alpha-D-mannopyranosyl phosphate) (C-I) and compound II (diacetoxymethyl 2,3,4,6-tetra-O-ethyloxycarbonyl-alpha-D-mannopyranosyl phosphate) (C-II), contain two acetoxymethyl (CH2OAc) groups O-linked to phosphorous. C-I contains acetyl esters and C-II contains ethylcarbonate (CO2Et) esters on the Man residue. Both C-I and C-II normalized truncated LLO, but C-II was about 2-fold more efficient than C-I. C-II replenished the GDP-Man pool in CDG-Ia cells and was more efficiently incorporated into glycoproteins than exogenous Man at low concentrations (25-75 mM). In a glycosylation assay of DNaseI in CDG-Ia cells, C-II restored glycosylation to control cell levels. C-II also corrected impaired LLO biosynthesis in cells from a Dolichol (Dol)-P-Man deficient patient (CDG-Ie) and partially corrected LLO in cells from an ALG12 mannosyltransferase-deficient patient (CDG-Ig), whereas cells from an ALG3-deficient patient (CDG-Id) and from an MPDU1-deficient patient (CDG-If) were not corrected. These results validate the general concept of using pro-Man-1-P substrates as potential therapeutics for CDG-I patients.
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PMID:Hydrophobic Man-1-P derivatives correct abnormal glycosylation in Type I congenital disorder of glycosylation fibroblasts. 1607 17

Congenital disorder of glycosylation Ia (CDGIa) is an autosomal recessive disease that is caused by mutations in the gene PMM2 encoding phosphomannomutase, an enzyme that synthesizes mannose-1-phosphate, an important intermediate for the N-glycan biosynthesis. Here, we investigated the susceptibility of CDGIa fibroblasts to cell death induction. CDGIa fibroblasts were more sensitive than control fibroblasts to staurosporine-induced apoptosis. Supplementation with mannose, which corrects N-glycosylation in CDGIa fibroblasts, did not abrogate their higher sensitivity to staurosporine. These results show that the sensitivity of CDGIa fibroblasts to apoptosis is not directly related to their defective N-glycosylation.
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PMID:Defect of N-glycosylation is not directly related to congenital disorder of glycosylation Ia fibroblast sensitivity to staurosporine-induced cell death. 1608 95


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