TTN and Autosomal Recessive Limb-Girdle Muscular Dystrophy Type 2J

Titin, encoded by TTN, is a giant sarcomeric protein essential for myofibril elasticity and stability. Biallelic truncating mutations in the extreme C-terminus of titin cause autosomal recessive limb-girdle muscular dystrophy type 2J (LGMD2J) (Limb-Girdle Muscular Dystrophy Type 2J). Patients present with progressive proximal limb‐girdle weakness, dystrophic muscle histology with rimmed vacuoles, and secondary calpain 3 deficiency.

Compound heterozygous LoF mutations were first reported in a Han Chinese family, where two siblings with early adult‐onset proximal lower‐limb weakness harbored novel elongation and truncation variants, c.107962_107963del (p.Ile35988SerfsTer26) and c.99125_99128dup (p.Ser33043ArgfsTer9), respectively (PMID:35239051). Both variants occurred in the last exon, predicted to escape nonsense‐mediated decay and disrupt the M-band region.

An independent multi-family study reanalyzed eight patients from seven European pedigrees, identifying three individuals with an LGMD2J phenotype who carried novel frameshift mutations in the C-terminus of titin. Unequal mRNA expression suggested severe reduction of mutant alleles via NMD, correlating with more pronounced C-terminal titin loss on Western blot (PMID:24395473).

Inheritance is autosomal recessive, with segregation of compound heterozygous truncating alleles in affected sibs and absence in parents. Affected relatives: 1 additional sibling segregating both variants. The variant spectrum in LGMD2J is dominated by frameshift and nonsense mutations clustered in the M-band exon cluster.

Mechanistically, C-terminal truncations disrupt titin’s interaction with calpain 3, leading to secondary CAPN3 deficiency and myofibril instability. Mouse mdm mutants recapitulate calpain 3 loss and apoptotic myonuclei (PMID:11294923), while yeast two-hybrid and co-immunoprecipitation confirm titin–CAPN3 and titin–myospryn binding defects (PMID:20634290). In vitro analyses of C-terminal processing revealed altered CAPN3 cleavage and M-band integrity in TMD/LGMD2J mutants (PMID:25877298).

Integration of genetic and functional data supports a Strong gene‐disease association: multiple unrelated probands, confirmed segregation, and concordant mechanistic studies. Diagnostic sequencing of TTN’s C-terminus is essential for LGMD2J diagnosis, and emerging exon‐skipping strategies targeting mutant exons may offer therapeutic avenues.

Key Take-home: Biallelic C-terminal truncating TTN variants cause LGMD2J via haploinsufficiency and CAPN3 deficiency; targeted genetic testing informs diagnosis and future RNA-based therapies.

References

• Neurological sciences • 2022 • Novel compound heterozygous mutations in the TTN gene: elongation and truncation variants causing limb-girdle muscular dystrophy type 2J in a Han Chinese family PMID:35239051
• Annals of neurology • 2014 • Atypical phenotypes in titinopathies explained by second titin mutations PMID:24395473
• Neurology • 2001 • Secondary calpain3 deficiency in 2q-linked muscular dystrophy: titin is the candidate gene PMID:11294923
• The Journal of biological chemistry • 2010 • Interactions with M-band titin and calpain 3 link myospryn (CMYA5) to tibial and limb-girdle muscular dystrophies PMID:20634290
• Human molecular genetics • 2015 • CAPN3-mediated processing of C-terminal titin replaced by pathological cleavage in titinopathy PMID:25877298

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