TTN – Tibial Muscular Dystrophy

Titin (TTN) is a giant sarcomeric protein critical for muscle elasticity and structural integrity, encoded by 363 exons on chromosome 2q31. Tibial muscular dystrophy (TMD; Udd myopathy) manifests as late adult-onset weakness of anterior lower leg muscles, often with calf hypertrophy, foot drop, gait disturbance and selective fatty degeneration on MRI. The disorder follows autosomal dominant inheritance with high but variable penetrance, typically presenting after the fifth decade and progressing slowly. Phenotypes may include facial diplegia or scapular winging in some cohorts. Although first described in Finnish patients, TMD has been documented worldwide, confirming TTN as the causative gene. Recognizing TMD facilitates targeted genetic testing of TTN C-terminal variants for diagnosis and familial counselling.

The most frequent pathogenic allele in TMD is the Finnish founder FINmaj, an 11-bp insertion/deletion in the M-line region of TTN (c.107780_107790delinsTGAAAGAAAAA p.Glu35927_Trp35930delinsValLysGluLys). In a genotyping study of 386 individuals, 207 heterozygous carriers were identified, of whom 189 (91%) exhibited classic tibial myopathy (PMID:15728284). Heterozygotes develop TMD, whereas homozygotes or compound heterozygotes with additional truncating variants present with early-onset LGMD2J, illustrating a dose-dependent titinopathy spectrum (PMID:15728284). Segregation across multiple families confirms robust autosomal dominant transmission with consistent genotype–phenotype correlation.

Independent case reports extend the allelic and ethnic diversity of TMD. An Italian family showed a heterozygous c.107837A>C (p.His35946Pro) TTN variant segregating with TMD in four affected relatives, absent in 100 controls (PMID:19911250). A Saudi patient with bilateral foot drop, facial diplegia, and scapular winging harbored c.85652C>G (p.Pro28551Arg), suggesting novel missense alleles outside Finland (PMID:31218166). An Estonian kindred without known Finnish ancestry carried heterozygous FINmaj in the father and compound heterozygous FINmaj plus a splice variant c.64672+2dup in two siblings, confirming trans-ethnic occurrence of the founder allele (PMID:39807212).

The variant spectrum in TMD is confined to the last two exons (Mex5 and Mex6) and adjacent M-line segments. Recurrent mutations include the FINmaj indel and missense alleles such as c.107837A>C (p.His35946Pro), with additional truncating variants in Mex5 correlating with earlier or more severe distal myopathy (PMID:18948003). Founder mutations display population-specific prevalence, whereas private missense changes arise in diverse cohorts. Absence of these variants in healthy controls supports pathogenicity across populations (PMID:19911250).

Functional studies demonstrate that C-terminal truncations disrupt titin–calpain 3 interactions, causing secondary calpain3 deficiency in patient muscle and in the mdm mouse model (PMID:11294923; PMID:11829483). Biophysical analyses of the M10 domain with missense mutations reveal misfolding, loss of obscurin binding and domain instability at physiological temperatures (PMID:25739468). This evidence supports a dominant-negative or haploinsufficiency mechanism whereby impaired C-terminal titin integrity leads to sarcomere disorganization and distal muscle vulnerability.

Collectively, heterozygous TTN mutations in the C-terminal region are definitively associated with autosomal dominant TMD, supported by extensive segregation, founder effects and concordant functional data. Genetic testing for TTN Mex5/Mex6 variants enables precise diagnosis, prognostic guidance and family counselling. Emerging therapeutic approaches, such as exon-skipping, may target specific truncating alleles. Key take-home: Autosomal dominant C-terminal TTN mutations cause tibial muscular dystrophy with high penetrance and a predictable phenotype spectrum.

References

• Neurology • 2005 • Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2J. PMID:15728284
• Journal of neurology • 2010 • The first Italian family with tibial muscular dystrophy caused by a novel titin mutation. PMID:19911250
• Intractable & rare diseases research • 2019 • A novel mutation in TTN gene in a Saudi patient with bilateral facial weakness and scapular winging. PMID:31218166
• Neurology. Genetics • 2024 • TTN-Related Muscular Dystrophies, LGMD, and TMD, in an Estonian Family Caused by the Finnish Founder Variant. PMID:39807212
• Neurology • 2001 • Secondary calpain3 deficiency in 2q-linked muscular dystrophy: titin is the candidate gene. PMID:11294923
• Genomics • 2002 • The muscular dystrophy with myositis (mdm) mouse mutation disrupts a skeletal muscle-specific domain of titin. PMID:11829483
• Protein science : a publication of the Protein Society • 2015 • Biophysical characterization of naturally occurring titin M10 mutations. PMID:25739468

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