Phosphoglucomutase Genetic Polymorphism and Body Mass

doi:10.1097/MAJ.0b013e3180a5e934

The American Journal of the Medical Sciences

Volume 334, Issue 6, December 2007, Pages 421-425

https://doi.org/10.1097/MAJ.0b013e3180a5e934 Get rights and content

ABSTRACT

Background

We have searched for a possible association of the genetic polymorphism of Phosphoglucomutase locus 1 (PGM₁), a key enzyme in carbohydrate metabolism, with body mass.

Methods

Adults (n = 257) with type 2 diabetes, 74 children referred for “obesity,” and 740 consecutive healthy newborn infants were studied. Body mass index, body weight, birth weight, and PGM₁ phenotype were determined. Sexes were analyzed separately.

Results

In type 2 diabetes, females carrying the PGM₁*2 allele are less represented among subjects with extreme body mass index deviation as compared with other classes of subjects. Among children referred for “obesity,” females carrying the PGM₁*2 allele are less represented among children with extreme body weight deviation. Among consecutive infants, in both sexes the proportion of those showing a birth weight higher than the 3rd quartile is lower in homozygous PGM₁2/2 subjects than in other PGM₁ phenotypes.

Conclusions

The data suggest that during extrauterine life, females carrying the PGM₁*2 allele are relatively protected from extreme body mass increase. During intrauterine life, PGM₁2/2 homozygotes show a tendency to low body mass increase. Because PGM₁ enzymatic activity depends on its phosphorylation status by the kinase Pak1, both structural differences of the PGM₁ allelic product and different rates of activation by Pak between sexes might be responsible for the pattern observed. At present, the effect of other genes near PGM₁ and in linkage disequilibrium with it cannot be ruled out.

Section snippets

Phosphoglucomutase Polymorphism

Phosphoglucomutase is an enzyme widely distributed in nature that catalyzes the reversible reaction: glucose-1-phosphate <—> glucose-6-phosphate, an essential step in carbohydrate metabolism. Four separate loci determine distinct sets of PGM isozymes: PGM₁, PGM₂, PGM₃, and PGM_4.11., 12., 13., 14. About 85% to 95% of total PGM activity is determined by the PGM₁ locus, that shows an electrophoretic polymorphism determined by the occurrence of 2 codominant alleles: PGM_1*1 and PGM₁*2 at a locus on

Adults With Type 2 Diabetes

Adults (n = 257) with type 2 diabetes from the Caucasian population of Penne, a small rural town in southeastern Italy, were studied. The sample was chosen randomly from a population of about 2000 subjects under care at the Center of Diabetology of the local hospital. Samples were collected over a period of about 18 months from patients scheduled for metabolic control on a previously fixed day of the week. The sample includes male and female patients (mean age, 66.3 years; SD, 9.8).

Children Referred for ‘Obesity’

Caucasian

Results

Table 1 shows the proportion of subjects with extreme body mass distribution (body mass index [BMI] >35) in subjects with type 2 diabetes and in children referred for “obesity” (weight >4 SD) in relation to PGM₁ phenotype and gender. In subjects with type 2 diabetes, there is a significant interaction between PGM₁ phenotype, BMI, and gender. In carriers of the PGM₁*2 allele (PGM₁2/1 and 2/2), severe obesity (BMI>35) is less frequent in females than in males. In children referred for “obesity”

Discussion

The data suggest that during extrauterine life, females carrying the PGM₁*2 allele are relatively protected from extreme body mass increase. During intrauterine life PGM₁2/2 subjects of either sex show a tendency to reduced body mass increase. The association between PGM₁ and body mass is similar in 3 independent conditions arguing against the possibility of sampling chance artifact.

Considering the key role of PGM₁ in glycide metabolism, we are disposed to consider a causal mechanism for the

Acknowledgments

We thank Prof. James MacMurray for helpful advice.

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We also show here for the first time using purified proteins that three common polymorphisms of PGM1 (K68M, R221C, and Y419H) have enzymatic activity essentially equivalent to that of WT PGM1, the most common allele in the human population (15, 16). Although some studies have suggested that certain alleles of PGM1 may be associated with differences in body mass (30, 31), these polymorphisms have no known association with disease. This is consistent with their high enzymatic activity in vitro (Table 2).
Recent studies have identified phosphoglucomutase 1 (PGM1) deficiency as an inherited metabolic disorder in humans. Affected patients show multiple disease phenotypes, including dilated cardiomyopathy, exercise intolerance, and hepatopathy, reflecting the central role of the enzyme in glucose metabolism. We present here the first in vitro biochemical characterization of 13 missense mutations involved in PGM1 deficiency. The biochemical phenotypes of the PGM1 mutants cluster into two groups: those with compromised catalysis and those with possible folding defects. Relative to the recombinant wild-type enzyme, certain missense mutants show greatly decreased expression of soluble protein and/or increased aggregation. In contrast, other missense variants are well behaved in solution, but show dramatic reductions in enzyme activity, with k_cat/K_m often <1.5% of wild-type. Modest changes in protein conformation and flexibility are also apparent in some of the catalytically impaired variants. In the case of the G291R mutant, severely compromised activity is linked to the inability of a key active site serine to be phosphorylated, a prerequisite for catalysis. Our results complement previous in vivo studies, which suggest that both protein misfolding and catalytic impairment may play a role in PGM1 deficiency.
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ArticlesPhosphoglucomutase Genetic Polymorphism and Body Mass

ABSTRACT

Background

Methods

Results

Conclusions

Section snippets

Phosphoglucomutase Polymorphism

Adults With Type 2 Diabetes

Children Referred for ‘Obesity’

Results

Discussion

Acknowledgments

J Nutr Biochem

J Nutr

Diabetes Metab

J Forensic Sci Soc

Energy balance in obesity

Proc Nutr Soc

Obesity: a disease or a biological adaptation?

Obes Rev

Obesity studies in candidate genes

Med Clin

The human obesity gene map: the 2003 update

Obes Res

Diabetic pregnancy: fetal development and maternal phosphoglucomutase phenotype

Dis Markers

Genetic polymorphism and intrauterine development: the role of maternal PGM1 and MNSs genotypes

Am J Dis Child

Birth weight and parental PGM1 alleles

Am J Hum Biol

Phosphoglucomutase polymorphism in man

Nature

A third phosphoglucomutase locus in man

Ann Hum Genet

The relative activities attributable in three phosphoglucomutase loci (PGM1, PGM2, PGM3) in human tissues

Ann Hum Genet

Phosphoglucomutase evidence for a new locus expressed in human milk

Science

Human phosphoglucomutase locus 1: red cell enzymatic activities associated with common isoelectric focusing phenotypes

Hum Hered

Articles
Phosphoglucomutase Genetic Polymorphism and Body Mass

Genetic polymorphism and intrauterine development: the role of maternal PGM₁ and MNSs genotypes

Birth weight and parental PGM₁ alleles