MYOT – Myofibrillar Myopathy 3

Myotilin, encoded by MYOT, is a Z-disc protein critical for myofibrillar integrity. Heterozygous MYOT mutations cause autosomal dominant myofibrillar myopathy type 3 (Myofibrillar Myopathy 3), characterized by progressive muscle weakness and protein aggregation in muscle fibers. Onset is typically in adulthood with distal or proximal limb involvement and variable rates of progression.

Genetic evidence includes six unrelated probands (2 families with p.Ser55Phe; 2 siblings homozygous for p.Ser60Phe; 1 with Tyr4_His9del; 1 with p.Phe460Ser) (PMID:19027924, PMID:27854214, PMID:37553249, PMID:19458539, PMID:39973468). Segregation in Family 1 supports autosomal dominant inheritance with three additional affected relatives (PMID:19027924).

The variant spectrum is dominated by missense changes (e.g., c.179C>T (p.Ser60Phe), c.165C>T (p.Ser55Phe), c.1379T>C (p.Phe460Ser)) and small in-frame deletions (c.11_28del (p.Tyr4_His9del)). No recurrent founder alleles have been reported; population screening shows MYOT variants in ~2.6% of Chinese MFM patients (PMID:39973468).

Functional studies demonstrate a dominant-negative mechanism: the exon 9 p.Phe460Ser variant impairs myotilin homodimerization and α-actinin binding in yeast two-hybrid and immunoprecipitation assays (PMID:19458539), while zebrafish expressing Tyr4_His9del MYOT RNA exhibit sarcomeric disorganization and motor deficits (PMID:37553249).

Taken together, MYOT variants show concordant genetic and experimental evidence supporting pathogenicity via disrupted sarcomeric assembly. No conflicting reports have refuted this association. Additional large-scale cohorts and natural history studies would strengthen genotype–phenotype correlations.

Key Take-home: MYOT testing should be included in gene panels for adult-onset myofibrillar myopathies to guide diagnosis and genetic counseling.

References

• Journal of the neurological sciences • 2009 • Generalized muscle pseudo-hypertrophy and stiffness associated with the myotilin Ser55Phe mutation: a novel myotilinopathy phenotype? PMID:19027924
• Journal of neuromuscular diseases • 2016 • Homozygosity of the Dominant Myotilin c.179C>T (p.Ser60Phe) Mutation Causes a More Severe and Proximal Muscular Dystrophy. PMID:27854214
• Clinical genetics • 2023 • A novel in-frame deletion in MYOT causes an early adult onset distal myopathy. PMID:37553249
• Journal of neuropathology and experimental neurology • 2009 • Defective myotilin homodimerization caused by a novel mutation in MYOT exon 9 in the first Japanese limb girdle muscular dystrophy 1A patient. PMID:19458539
• Journal of neuromuscular diseases • 2024 • Mutational and clinical spectrum of myofibrillar myopathy in one center from China. PMID:39973468

Evidence Based Scoring (AI generated)