The Analysis of Variants in the General Population Reveals That PMM2 Is Extremely Tolerant to Missense Mutations and That Diagnosis of PMM2-CDG Can Benefit from the Identification of Modifiers

Abstract

Type I disorders of glycosylation (CDG), the most frequent of which is phosphomannomutase 2 (PMM2-CDG), are a group of diseases causing the incomplete N-glycosylation of proteins. PMM2-CDG is an autosomal recessive disease with a large phenotypic spectrum, and is associated with mutations in the PMM2 gene. The biochemical analysis of mutants does not allow a precise genotype⁻phenotype correlation for PMM2-CDG. PMM2 is very tolerant to missense and loss of function mutations, suggesting that a partial deficiency of activity might be beneficial under certain circumstances. The patient phenotype might be influenced by variants in other genes associated with the type I disorders of glycosylation in the general population.

Keywords: clinical informatics; disorder of glycosylation; modifier genes; variant analysis.

Figure 1

Val129 and Val231 in the structure of phosphomannomutase2. Phosphomannomutase 2 (PMM2) (single chain) is represented as cartoons. Asp12, Val129, and Val231 are shown as sticks in magenta, blue, or red, respectively. Glucose-1,6-bisphosphate (G16) is represented by sticks and is colored by atom types. Mg²⁺ is represented by a green sphere. Different orientations of the same molecule are shown.

Figure 2

Observed versus expected variants for disease genes. Box-plots are drawn for the ratios between the number of observed and predicted variants in the general population for disease genes. Each dot represents a gene, the red dot is PMM2, yellow dots are the other genes associated with glycosylation (CDG)-I, and the blue dots are the genes associated with CDG-II. The medians are indicated by thick black lines; the lower and upper quartiles, representing observations outside the 25–75 percentile ranges, are indicated by dashed black lines; and the relative minimum and relative maximum values are indicated by dashed red lines.

Figure 3

Distribution of CADD scaled scores and PolyPhen2 deleteriousness predictions for PMM2 frequent variants. The medians are indicated by thick black lines; the lower and upper quartiles, representing observations outside the 25–75 percentile ranges, are indicated by dashed black lines; and the relative minimum and relative maximum values are indicated by dashed red lines.