GMPPB – Limb-Girdle Muscular Dystrophy Type 2T

Autosomal recessive limb-girdle muscular dystrophy type 2T (LGMD2T) is caused by biallelic mutations in GDP-mannose pyrophosphorylase B (GMPPB). Affected individuals present with childhood-onset proximal weakness, elevated serum creatine kinase, myogenic changes on biopsy, and hypoglycosylation of α-dystroglycan ([HP:0003236]).

Genetic evidence for GMPPB-LGMD2T includes eight unrelated probands identified by exome sequencing (PMID:23768512), five compound heterozygous cases with C-terminal missense alleles (PMID:28433477), and a single adult patient with novel missense variants (PMID:31211170), totaling 14 affected individuals. All carry two rare missense or loss-of-function alleles segregating in trans under an autosomal recessive model. No extended multiplex segregation beyond proband series has been reported.

The variant spectrum is dominated by missense changes clustering in catalytic or C-terminal domains. A representative allele is c.803T>C (p.Ile268Thr), which disrupts enzyme folding and leads to cytoplasmic aggregation (PMID:31211170). Several splice and frameshift alleles have also been reported, supporting loss-of-function as a key mechanism.

Functional studies demonstrate that mutant GMPPB causes hypoglycosylation of α-dystroglycan in patient muscle and fibroblasts, which is partially rescued by wild-type GMPPB expression (PMID:23768512). Zebrafish knockdown of gmpb recapitulates muscle defects and reduced α-DG glycosylation, while heterozygous knockout mice show essential roles in muscle development and viability (PMID:38419795).

A pathogenic mechanism involving autophagy-lysosome degradation has been described: mutant GMPPB colocalizes with LC3-II positive autophagosomes and is degraded in a lysosome-dependent manner, providing a link between protein instability and LGMD2T pathology (PMID:31211170).

No credible conflicting evidence disputing the association has been reported. Overall, the genetic and experimental data meet ClinGen criteria for a Strong gene-disease validity classification, supporting molecular diagnosis and potential enzyme-replacement therapies.

Key Take-home: Biallelic GMPPB mutations cause autosomal recessive LGMD2T via loss of enzymatic activity, α-dystroglycan hypoglycosylation, and enhanced autophagic degradation, enabling targeted diagnostic and therapeutic strategies.

References

• American Journal of Human Genetics • 2013 • Mutations in GDP-mannose pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan PMID:23768512
• Neuromuscular Disorders • 2017 • Novel mutations in the C-terminal region of GMPPB causing limb-girdle muscular dystrophy overlapping with congenital myasthenic syndrome PMID:28433477
• Annals of Clinical and Translational Neurology • 2019 • Lysosomal degradation of GMPPB is associated with limb-girdle muscular dystrophy type 2T PMID:31211170
• Frontiers in Molecular Neuroscience • 2024 • Consequences of GMPPB deficiency for neuromuscular development and maintenance PMID:38419795

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