POGLUT1 – Autosomal Recessive Limb-Girdle Muscular Dystrophy Type 2R1

POGLUT1 encodes protein O-glucosyltransferase 1, a key enzyme for O-glucosylation of Notch receptors. Biallelic POGLUT1 variants have been linked to autosomal recessive limb-girdle muscular dystrophy type 2R1 (LGMD R21), characterized by progressive proximal muscle weakness and a distinctive imaging pattern. The clinical phenotype includes muscle weakness with an “inside-to-outside” pattern of fatty degeneration, reduced satellite cell pools, and α-dystroglycan hypoglycosylation, consistent across ethnically diverse families (POGLUT1, autosomal recessive limb-girdle muscular dystrophy type 2R1).

Genetic evidence for this association derives from 15 affected individuals from nine unrelated families with onset spanning congenital to adult ages (15 probands; nine families) (PMID:31897643). All cases harbor biallelic POGLUT1 variants consistent with autosomal recessive inheritance. Parental segregation in multiple families confirms trans configuration of pathogenic alleles.

The variant spectrum includes predominantly missense substitutions affecting conserved residues in the catalytic domain and rare protein-truncating alleles. A representative variant is c.293G>A (p.Arg98Gln) (PMID:31897643), which abrogates enzymatic activity in vitro. Other reported changes include p.Tyr156Asn, p.Ile129Thr, p.Arg183Trp, and premature termination alleles.

Muscle biopsies from patients show markedly reduced levels of the NOTCH1 intracellular domain, a decreased satellite cell pool, and hypoglycosylation of α-dystroglycan in immunohistochemistry and Western blot assays. These findings link POGLUT1 loss to impaired Notch signaling and extracellular matrix defects in human muscle (PMID:31897643).

In vivo functional validation using transgenic Drosophila expressing human POGLUT1 variants demonstrated reduced myogenic activity in indirect flight muscle development, recapitulating muscle degeneration seen in patients (PMID:31897643).

Patient‐derived satellite cells exhibit decreased proliferation, accelerated differentiation, and impaired regenerative capacity in cell‐based assays, underscoring a mechanism of stem cell depletion in LGMD R21 (PMID:31897643).

Taken together, genetic and experimental data meet ClinGen criteria for a strong gene–disease relationship, with robust case‐level and functional evidence. POGLUT1 variant analysis enables molecular diagnosis and carrier screening for LGMD 2R1. Patient‐derived iPSC and muscle imaging biomarkers support both clinical management and future therapeutic development.

References

• Acta neuropathologica • 2020 • POGLUT1 biallelic mutations cause myopathy with reduced satellite cells, α-dystroglycan hypoglycosylation and a distinctive radiological pattern PMID:31897643

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