Disease relevance of PMM2

• Carbohydrate-deficient glycoprotein syndrome type 1 (CDG1 or Jaeken syndrome) is the prototype of a class of genetic multisystem disorders characterized by defective glycosylation of glycoconjugates [1].
• Seven mutant forms of human phosphomannomutase 2 were produced in Escherichia coli and purified [2].
• The clinical picture presents with several features similar to CDG-Ia (phosphomannomutase 2 deficiency) such as hypotonia and atactic-dystonic movements [3].
• IG and CDG1 subjects reported that tooth loss and denture wearing problems had a much greater impact on their quality of life than subjects seeking conventional dentures [4].
• The CDGS III glycoprotein abnormality most probably represents a distinct disorder of glycoprotein metabolism, and needs to be considered in unclear hypsarrhythmia with developmental delay [5].

Psychiatry related information on PMM2

• Therefore, young patients with spinal deformities in combination with mental retardation, failure to thrive, abnormal fat distribution, and other symptoms of CDGS Type 1a should be assessed for this disorder, and patients with CDGS Type 1a should be screened also for spinal deformities [6].

High impact information on PMM2

• Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome) [1].
• 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 [7].
• Deficiency of dolichyl-P-Glc:Man9GlcNAc2-PP-dolichyl glucosyltransferase is the cause of an additional type of carbohydrate-deficient glycoprotein syndrome (CDGS type V) [8].
• We therefore compared the frequency of this variant in 301 controls and in 101 CDG patients who carry known mutations in other genes involved in CDG, i.e. PMM2 (CDG-Ia; 91 patients) and MPI (CDG-Ib; 10 patients) [9].
• Clinical severity of mildly affected sibs with the same PMM2 mutations did not correlate with F304S genotype [9].

Biological context of PMM2

• We found eleven different missense mutations in PMM2 in 16 CDG1 patients from different geographical origins and with a documented phosphomannomutase deficiency [1].
• The processed pseudogene is more closely related to PMM2 . Remarkably, several base substitutions in PMM2 that are associated with disease are also present at the corresponding positions in the pseudogene [10].
• All these patients were compound heterozygotes for mutations in the phosphomannomutase (PMM2) gene, with 7 out of the 10 families having the common R141H mutation [11].
• We investigated the DNA sequence of PMM2 in two unrelated Japanese families with CDG1 [12].
• Our findings confirm that mutations in the PMM2 gene account for at least some Japanese patients with CDG1 similar to that seen in Caucasians and that exons 5 and 8 are hot spots of mutations of CDG1 caused by the PMM2 gene [12].

Anatomical context of PMM2

• High residual activity of PMM2 in patients' fibroblasts: possible pitfall in the diagnosis of CDG-Ia (phosphomannomutase deficiency) [7].
• Carbohydrate-deficient glycoprotein syndrome type Ia (CDGS) 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 [13].
• Serum and glucocorticoid-regulated kinase Sgk1 inhibits insulin-dependent activation of phosphomannomutase 2 in transfected COS-7 cells [14].

Associations of PMM2 with chemical compounds

• The Ka values for both mannose 1,6-bisphosphate and glucose 1,6-bisphosphate are significantly lower in the case of PMM2 than in the case of PMM1 [15].
• Fructose 1,6-bisphosphate does not activate PMM2 but causes a time-dependent stimulation of PMM1 due to the progressive formation of mannose 1,6-bisphosphate from fructose 1,6-bisphosphate and mannose 1-phosphate [15].
• 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 [16].
• This paper reviews the structure of the glycan chains of proteins and structural alterations in CDGS [17].
• Mutations in the cytosolic enzyme phosphomannomutase 2 (PMM2), which catalyzes the conversion of mannose-6-phosphate to mannose-1-phosphate, cause the most common form of congenital disorders of glycosylation, termed CDG-Ia [18].

Enzymatic interactions of PMM2

• We were then able to demonstrate that Sgk1 phosphorylated PMM2 in an in vitro assay [14].

Analytical, diagnostic and therapeutic context of PMM2

• Experiments with specific antibodies, kinetic studies and Northern blots indicated that PMM2 is the only detectable isozyme in most rat tissues except brain and lung, where PMM1 accounts for about 66 and 13% of the total activities, respectively [15].
• In this study, 61 CDG type IA patients (122 chromosomes) were screened for mutations in the PMM2 gene using a combination of SSCP and sequence analysis [19].
• Using data from radiation hybrid panel we have refined the position of the PMM2 gene to very close to marker D16S3020 in the interval between D16S406 and AFM282ze1 on the distal side and D16S3087 on the proximal side [20].
• DHPLC was set up for PMM2 by optimizing eight different PCR fragments, one for each exon [21].
• Thus, we wanted to investigate if denaturing high-performance liquid chromatography (DHPLC) was a more suitable mutation screening method for PMM2 [21].

References