TRAPPC11 – Limb-Girdle Muscular Dystrophy Type R18

TRAPPC11 encodes a subunit of the multisubunit transport protein particle (TRAPP) complex involved in ER-to-Golgi and Golgi-to-plasma membrane trafficking. Pathogenic biallelic variants in TRAPPC11 underlie autosomal recessive limb-girdle muscular dystrophy type R18 (MONDO:0014144). Affected individuals frequently present with early-onset muscle weakness, elevated serum creatine kinase, and dystrophic changes on muscle biopsy. Extramuscular features include microcephaly, global developmental delay, seizures, cataracts, liver disease and movement disorders.

In an initial report, two siblings with uncharacterized limb-girdle muscular dystrophy were found by whole-exome sequencing to carry compound heterozygous TRAPPC11 variants including c.2330A>C (p.Gln777Pro). Their phenotype of muscle weakness, microcephaly, global developmental delay, seizures and cataracts confirmed the emerging LGMD2S spectrum (2 probands total) ([PMID:28827486]).

A consanguineous Syrian family (n = 3) and a Hutterite kindred (n = 5) were subsequently shown to harbor homozygous missense TRAPPC11 variants c.2938G>A (p.Gly980Arg) and splice-site c.1287+5G>A (p.Ala372_Ser429del), respectively. Both groups exhibited limb-girdle muscular dystrophy, movement disorders and intellectual disability, with segregation consistent with autosomal recessive inheritance ([PMID:23830518]).

A founder effect was demonstrated in 25 Roma individuals with homozygous c.1287+5G>A (p.Ala372_Ser429del), who showed early-onset muscle weakness, microcephaly, intellectual disability and infection-triggered pseudometabolic crises with seizures (25 probands) ([PMID:37197784]).

A recent review of 54 TRAPPC11-opathy cases expanded the phenotype to include congenital muscular dystrophy with systemic involvement in 42 individuals and pure LGMD in 12. Common features across these 54 unrelated patients included global developmental delay, microcephaly, seizures, cerebellar abnormalities, scoliosis, liver disease, and cataracts ([PMID:38564972]).

Cellular studies demonstrate that TRAPPC11 loss-of-function impairs TRAPP complex assembly, disrupts Golgi architecture, delays ER-to-Golgi and Golgi-to-plasma membrane trafficking, and leads to hypoglycosylation of LAMP1/LAMP2 glycoproteins in patient fibroblasts. These assays recapitulate key neuromuscular and glycosylation defects seen in humans ([PMID:23830518]).

In zebrafish trappc11 knockdown, FGF8 suppression triggers Notch-mediated epithelial–mesenchymal transition and myofibrosis, while exogenous FGF8 restores motor function, highlighting potential therapeutic avenues ([PMID:36827861]). Together, genetic, cellular, and animal data support a loss-of-function mechanism for TRAPPC11 in LGMD R18. Key take-home: TRAPPC11 variant screening enables molecular diagnosis, informs prognosis, and suggests pathways for targeted therapy.

References

• Journal of clinical neuromuscular disease • 2017 • Siblings With Mutations in TRAPPC11 Presenting With Limb-Girdle Muscular Dystrophy 2S. PMID:28827486
• American journal of human genetics • 2013 • Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability. PMID:23830518
• Journal of medical genetics • 2023 • Expanding the phenotypic spectrum of TRAPPC11-related muscular dystrophy: 25 Roma individuals carrying a founder variant. PMID:37197784
• Molecular genetics and metabolism • 2024 • TRAPPC11-CDG muscular dystrophy: Review of 54 cases including a novel patient. PMID:38564972
• Biochemical and biophysical research communications • 2023 • FGF8 rescues motor deficits in zebrafish model of limb-girdle muscular dystrophy R18. PMID:36827861

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