rs28937900 — FKRP L276I

FKRP L276I — The Most Common European Muscular Dystrophy Mutation

The FKRP gene encodes fukutin-related protein¹¹ fukutin-related protein
A Golgi-resident enzyme that adds sugar molecules to alpha-dystroglycan, a key protein linking muscle fibers to the surrounding extracellular matrix, a glycosyltransferase enzyme that modifies the surface of muscle fiber membranes. The c.826C>A mutation (L276I) substitutes leucine with isoleucine at amino acid position 276, partially disrupting this enzyme's function. In the autosomal recessive inheritance pattern, two copies of the risk allele are needed to cause disease — but single-copy carriers are clinically important for reproductive counseling.

This variant is a European founder mutation: the same ancestral chromosomal haplotype has been identified in patients of European descent across the UK, Germany, Scandinavia, North America, and Brazil, suggesting a single common ancestor. It is essentially absent from East Asian and South Asian populations. In Northern European cohorts such as Norway, the population prevalence of LGMD R9²² population prevalence of LGMD R9
Limb-girdle muscular dystrophy R9, previously called LGMD2I — R9 refers to the FKRP gene in the revised 2017 nomenclature reaches 2.84 per 100,000, the highest reported worldwide.

The Mechanism

FKRP normally catalyses the transfer of ribitol-5-phosphate onto the O-mannosyl glycan chain³³ O-mannosyl glycan chain
A chain of sugar molecules attached to serine or threonine residues on alpha-dystroglycan via oxygen linkage of alpha-dystroglycan (α-DG). This glycan chain is the molecular "glue" that lets muscle fibers attach to laminin and other proteins in the extracellular matrix. Without proper glycosylation, the muscle membrane is structurally fragile and tears during repeated contraction cycles, triggering progressive degeneration and fibrosis.

The L276I mutation reduces but does not abolish FKRP enzyme activity. This partial loss explains why homozygous carriers typically develop a milder, later-onset muscular dystrophy compared to patients with FKRP null alleles (frameshift or nonsense mutations), who can present with severe Walker-Warburg syndrome in infancy. In the mouse model⁴⁴ mouse model
Krag TO & Vissing J. A New Mouse Model of Limb-Girdle Muscular Dystrophy Type 2I Homozygous for the Common L276I Mutation. J Neuropathol Exp Neurol, 2015, homozygous L276I mice show a 78% reduction in α-DG glycosylation by 20 months, accompanied by progressive fibrosis and myopathy — faithfully mirroring the human disease.

The Evidence

The Global FKRP Registry⁵⁵ Global FKRP Registry
Murphy LB et al. Global FKRP Registry: Observations in More Than 300 Patients with Limb Girdle Muscular Dystrophy R9. Ann Clin Transl Neurol, 2020 analysed 305 genetically confirmed LGMD R9 patients: 67.9% were homozygous for c.826C>A, 28.5% compound heterozygous. Among the cohort, 75.1% remained ambulant at time of enrollment, and 23.2% had documented cardiac impairment.

A Norwegian national cohort study⁶⁶ Norwegian national cohort study
Jensen SM et al. Epidemiology and Natural History in 101 Subjects with FKRP-Related Limb-Girdle Muscular Dystrophy R9. Neuromuscular Disorders, 2023 of 101 patients found that 88% were homozygous for c.826C>A. Disease showed a bimodal age-of-onset distribution, and one-third of patients developed respiratory insufficiency before losing ambulation. Cardiomyopathy correlated with male sex but not with age or functional stage.

A dedicated cardiomyopathy study⁷⁷ cardiomyopathy study
Libell EM et al. Cardiomyopathy in Limb Girdle Muscular Dystrophy R9, FKRP Related. Muscle Nerve, 2020 of 56 LGMD R9 patients found cardiomyopathy in 45% overall. Among those homozygous for c.826C>A, the median age at cardiomyopathy onset was 54.2 years — substantially later than patients carrying other, more severe FKRP mutations (median 18.1 years). This genotype-specific timeline is clinically meaningful for structuring cardiac surveillance programs.

Practical Actions

Homozygous AA carriers require regular cardiac screening (echocardiogram and ECG at diagnosis, then every 2–3 years), pulmonary function monitoring, and referral to a neuromuscular specialist for management of progressive proximal muscle weakness. Physical therapy focused on maintaining ambulation and respiratory muscle strength should begin proactively. Gene therapy trials are actively ongoing — enrolling in a clinical trial registry⁸⁸ clinical trial registry
ClinicalTrials.gov FKRP gene therapy trials is appropriate.

Heterozygous CA carriers do not develop disease themselves but carry a 50% per-pregnancy chance of passing the risk allele. When both reproductive partners are carriers, each pregnancy has a 25% chance of producing an affected (AA) child. Preconception genetic counseling and, if desired, preimplantation genetic testing (PGT-M) are clinically appropriate options.

Interactions

No compound heterozygosity interactions are captured here for L276I specifically, since the disease mechanism requires homozygosity or trans-compound heterozygosity with a second FKRP pathogenic allele. Other FKRP variants that can compound with L276I in trans to cause LGMD R9 include deletion/frameshift mutations in FKRP that individually cause more severe phenotypes (Walker-Warburg syndrome). Compound heterozygotes with one c.826C>A allele and one severe allele typically present with an intermediate phenotype, more severe than homozygous L276I but milder than homozygous null alleles.