rs28936415 — PMM2 R141H

PMM2 R141H — The Most Common CDG Mutation and Its Implications for Carriers

Every protein destined for export, membrane display, or passage through the secretory pathway must be decorated with sugar chains — a process called N-linked glycosylation¹¹ N-linked glycosylation
The attachment of oligosaccharide chains to the nitrogen of asparagine residues in proteins destined for the endoplasmic reticulum. "N-linked" refers to the nitrogen atom of asparagine that anchors the glycan.. This process depends on a supply of activated sugar building blocks, and the enzyme phosphomannomutase 2 (PMM2) is the gatekeeper for one of them: it converts mannose-6-phosphate to mannose-1-phosphate, the precursor of GDP-mannose, which is incorporated into the oligosaccharide core. When PMM2 fails, cells cannot build complete N-glycan chains, and hundreds of glycoproteins are produced in aberrant forms — affecting brain development, liver function, blood coagulation, hormones, and more.

The c.422G>A variant (rs28936415) changes arginine to histidine at position 141 of the PMM2 protein (p.Arg141His, commonly written R141H). It is the most frequent pathogenic PMM2 allele worldwide, particularly in European populations²² particularly in European populations
European carrier frequency approximately 1/79 in the Netherlands and 1/60 in Denmark per Schollen et al. 2000, and accounts for roughly half of all disease-causing PMM2 alleles identified in CDG patients.

The Mechanism

PMM2 functions as a homodimer — two identical PMM2 subunits join to form the active enzyme. The Arg141 residue sits in a conserved region critical for protein folding and stability. The R141H substitution introduces a smaller, less basic histidine in place of the bulky positively charged arginine, destabilizing the protein structure.

Protein folding studies³³ Protein folding studies
Yuste-Checa P et al. The Effects of PMM2-CDG-Causing Mutations on the Folding, Activity, and Stability of the PMM2 Protein. Hum Mutat, 2015 confirmed that R141H is a destabilizing variant that substantially reduces enzyme activity, and that the protein may be partially rescuable with pharmacological chaperones — a finding relevant to emerging treatment strategies.

A critical fact distinguishes R141H from other PMM2 variants: homozygous R141H (two copies of this exact mutation) has never been observed in any living person. Population genetics analysis⁴⁴ Population genetics analysis
Schollen E et al. Lack of Hardy-Weinberg equilibrium for the most prevalent PMM2 mutation in CDG-Ia. Eur J Hum Genet, 2000 confirmed that given the observed carrier frequency (1/79 in Dutch neonates), homozygous infants should appear in the population if they survived — but they don't. R141H homozygosity leaves too little PMM2 activity for embryogenesis to complete. All living PMM2-CDG patients who carry R141H are compound heterozygotes⁵⁵ compound heterozygotes
Carry two different pathogenic PMM2 alleles — R141H on one chromosome and a different mutation (e.g. F119L, V44A, I132T) on the other. Neither allele alone causes disease; both are needed.: they carry R141H on one chromosome and a different, less severe PMM2 mutation on the other that preserves just enough residual enzyme activity to allow survival.

The Evidence

PMM2-CDG (formerly CDG type Ia, or Jaeken syndrome) was the first CDG identified and remains by far the most common, with over 1,000 cases worldwide. The PMM2 gene was discovered in 1997⁶⁶ 1997
Matthijs G et al. Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome. Nat Genet, 1997, with R141H among the original mutations identified.

A landmark French cohort study Schiff et al. 2017⁷⁷ Schiff et al. 2017
Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG. J Med Genet, 2017 of 96 PMM2-CDG patients documented the full clinical spectrum: cerebellar ataxia in virtually all patients, intellectual disability, neonatal hypotonia, liver involvement, cardiac abnormalities in 20%, and a mortality rate of ~12.5% (12 deaths at mean age 3.8 years, primarily from cardiac complications). R141H was present in approximately 50% of all disease-causing alleles in this cohort. Biochemical markers consistently show elevated liver enzymes, abnormal coagulation parameters (low protein C, antithrombin), elevated TSH, and hypocholesterolemia.

ClinVar (VCV000007706) lists R141H as Pathogenic with criteria provided by over 50 independent submitters including Mayo Clinic Laboratories, ARUP, GeneDx, and Invitae — one of the most extensively classified pathogenic variants in the CDG field.

Practical Actions

For heterozygous carriers: A single R141H allele does not cause PMM2-CDG. Carriers have one fully functional PMM2 gene and maintain normal glycosylation. The primary significance is reproductive: if both partners carry a pathogenic PMM2 allele (any combination), each pregnancy has a 25% chance of inheriting compound heterozygous PMM2 variants and developing CDG.

For compound heterozygous individuals (disease): PMM2-CDG requires multidisciplinary management by metabolic physicians, neurologists, cardiologists, and hepatologists. Biochemical monitoring of transferrin glycoform analysis, liver enzymes, coagulation factors, and thyroid function is essential. While no curative therapy exists, emerging approaches include dietary mannose supplementation and repurposed drugs. Epalrestat, an aldose reductase inhibitor approved for diabetic neuropathy in Japan, showed 30–400% increases in PMM2 enzyme activity⁸⁸ showed 30–400% increases in PMM2 enzyme activity
Iyer S et al. Repurposing the aldose reductase inhibitor and diabetic neuropathy drug epalrestat for PMM2-CDG. Dis Model Mech, 2019 in patient fibroblasts across multiple PMM2 genotypes, and is the only small-molecule activator of PMM2 identified to date.

Interactions

PMM2-CDG is defined by compound heterozygosity: one R141H allele paired with a second, distinct PMM2 pathogenic variant on the other chromosome. The most common compound heterozygous combinations include R141H + F119L and R141H + V44A, with phenotypic severity correlating broadly with residual enzyme activity — milder second alleles yield milder disease. Any individual carrying R141H who is diagnosed with PMM2-CDG should have full sequencing of both PMM2 alleles to characterize the specific compound genotype, as this informs prognosis and eligibility for emerging genotype-specific treatments.