Novel Mutations in B3GALNT2 Gene Causing Alpha-Dystroglycanopathy in Chinese Patients

For parents, watching a child hit developmental milestones—first smile, first step, first word—is a joy. But for two Chinese families, those milestones came late, or not at all. Their daughters’ struggles—delayed walking, trouble speaking, small head size—traced back to rare mutations in the B3GALNT2 gene, a finding that’s expanding what we know about alpha-dystroglycanopathy (a-DGP), a rare inherited muscular dystrophy that affects muscles, brains, and sometimes eyes.

Reported in the Chinese Medical Journal by researchers from Peking University First Hospital and The University of Tokyo, the study highlights how B3GALNT2 mutations can lead to milder forms of a-DGP—challenging prior assumptions about this often-severe disorder.

What Is Alpha-Dystroglycanopathy?

Alpha-dystroglycanopathy is a subgroup of congenital muscular dystrophies (CMDs), disorders present from birth that weaken muscles over time. It’s inherited in an autosomal recessive pattern, meaning a child must inherit a faulty copy of a gene from both parents to develop the condition.

The root cause? A problem with O-glycosylation—a process where sugar molecules attach to the alpha-dystroglycan (a-DG) protein. Think of a-DG as a “glue” that holds muscle cells to their surroundings and helps brain cells develop properly. Without the right sugar “coating,” a-DG can’t do its job, leading to muscle weakness, brain malformations, and sometimes eye issues (like cataracts or glaucoma).

B3GALNT2 is one of the genes critical to this process. It makes an enzyme that builds a unique sugar structure—GalNAc-beta-1,3-GlcNAc—needed for a-DG to function. Mutations in B3GALNT2 often cause severe forms of a-DGP, like Walker-Warburg syndrome (fatal in infancy) or muscle-eye-brain disease (MEB, which affects muscles, eyes, and brain). But the two Chinese girls had milder MEB-like symptoms—no eye problems, less severe brain damage—showing B3GALNT2 mutations can lead to a wider range of outcomes than previously thought.

The Two Patients: Stories of Milder a-DGP

Both girls were born full-term with no complications, but their development stalled early:

Patient 1: A 2-Year-11-Month-Old Girl

The second child of healthy, non-related parents, she struggled to interact at 10 months and didn’t stand alone until age 2. Today, she can walk short distances but has a wide, unsteady gait. She can’t follow instructions or say complex words.

Tests revealed:

A small head (44.5 cm, below the 25th percentile, called microcephaly).
Weak arm/leg muscles and slow tendon reflexes.
A brain MRI at 11 months showing polymicrogyria (too many small folds in the brain), abnormal signals in brain white matter, tiny cerebellum cysts, and a misshapen cerebellum/brainstem.

Her muscle enzyme (creatine kinase, or CK) level, hearing, and eye exams were normal—unlike many severe a-DGP cases.

Patient 2: A 1-Year-9-Month-Old Girl

The first child of healthy parents, she said simple words at 8 months, stood with help at 1 year, and walked with support at 15 months—but hasn’t improved since.

Tests revealed:

A small head (45 cm, below the 25th percentile).
Weak muscles and normal knee reflexes.
An elevated CK level (565 U/L, vs. normal <170 U/L)—a sign of muscle damage.
A brain MRI at 7 months showing slightly abnormal white matter signals, a misshapen cerebellum, and mildly enlarged brain ventricles.

Unlike many B3GALNT2 patients, she has no eye or hearing problems.

Genetic Findings: Two Mutations, Two Stories

To find the cause, researchers used whole exome sequencing (reading all protein-coding genes) and confirmed results with Sanger sequencing (a gold-standard method for checking specific gene changes). Both girls had mutations in B3GALNT2, and their parents were carriers (each had one faulty copy, no symptoms).

Patient 1: Known Mutations, Milder Symptoms

She carried two previously reported B3GALNT2 mutations:

c.979G>A (p.D327N): A change in the enzyme’s catalytic domain (the part that builds sugar structures). Despite hitting the enzyme’s “active site,” this mutation only slightly harms function—five Iranian siblings with the same mutation had milder symptoms (developmental delay, mild brain changes, epilepsy) but no muscle weakness or severe brain damage.
c.1421_c.1423delCTC (p.P474del): A missing amino acid outside the catalytic domain—but a site conserved across species (meaning it’s critical for function). A prior study linked this mutation (with another) to severe MEB, so it’s likely the main driver of Patient 1’s symptoms.

Patient 2: Novel Mutations, More Severe Impact

She carried two never-before-seen B3GALNT2 mutations:

c.48dupG (p.L17fs): A frameshift mutation that truncates the B3GALNT2 protein, making it useless.
c.1183G>A (p.G395R): A missense mutation in the catalytic domain, predicted to destroy enzyme activity.

She also had a copy number variant (CNV)—an extra 550,000-base-pair stretch of chromosome 12. While this CNV isn’t common in healthy people, there’s no proof it’s harmful, so its role is unclear.

Why This Matters: Mutation Severity Over Location

The biggest takeaway? The severity of a-DGP symptoms depends on how much a mutation damages B3GALNT2 enzyme function—not just where the mutation is.

Patient 1’s p.D327N mutation (in the catalytic domain) is mild, while her p.P474del mutation (outside the domain) is severe.
Patient 2’s novel mutations are more destructive: The frameshift mutation makes a nonfunctional protein, and the missense mutation hits the enzyme’s active site. Together, these likely explain her higher CK level (muscle damage) and more severe developmental delay.

What’s Next for a-DGP Research?

These two cases are a critical addition to a-DGP science. They:

Show B3GALNT2 mutations can cause milder MEB-like phenotypes—not just severe forms.
Add two new mutations to the B3GALNT2 “mutation catalog,” helping doctors diagnose more patients.
Highlight the need for more research on how mutations affect enzyme activity—and why some cause eye problems while others don’t.

For families of kids with rare genetic disorders, this study is a small but important step forward. It proves even “mild” cases of a-DGP have a genetic cause—and that understanding those genes can lead to better care, support, and someday, treatments.

Chen XY, Song DY, Fan YB, Tan DD, Chang XZ, Xiao JX, Toda T, Xiong H. Novel mutations in B3GALNT2 gene causing alpha-dystroglycanopathy in Chinese patients. Chinese Medical Journal. 2021;134(12):1483-1485. doi:10.1097/CM9.0000000000001283

Was this helpful?

0 / 0